University of Groningen

Brain-selective nutrients in pregnancy and lactation

Stoutjesdijk, Eline

DOI:
10.33612/diss.146373942

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Stoutjesdijk, E. (2020). Brain-selective nutrients in pregnancy and lactation. University of Groningen.
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 1
Introduction:
Brain-selective nutrients
Chapter 1
Abbreviations
1,25(OH)2D, 1,25-dihydroxyvitamin D;
25(OH)D, 25-hydroxyvitamin D;
1C, one carbon;
AA, arachidonic acid;
AI, adequate intake;
ALA, acid alpha-linolenic acid;
ARA, antirachitic activity;
As, arsenic;
AT, adipose tissue;
Br, bromide;
Ca, calcium;
CAD, coronary heart disease;
Cd, cadmium;
Cu, copper;
CYP27B1, 25(OH)D-1-α-hydroxylase;
DBP, vitamin D binding protein;
DHA, docosahexaenoic acid;
DMEQ-TAD, 4-[2-(6,7-dimethoxy-4-
methyl-3-oxo-3,4-dihydroquinoxalyl)
ethyl]-1,2-4-triazoline-3,5-dione; DRIs,
Dietary Reference Intakes;
DWGV, drinking water guideline values;
EAR, estimated average requirement;
EFA, essential fatty acids; EFAD,
essential fatty acid deficiency;
EPA, eicosapentaenoic acid;
EQ, encephalization quotient;
FAC, functional adequate
concentration;
Fe, iron;
GEE, generalized estimation equation;
GOED, Global Organization for EPA and
DHA Omega3s;
GW, gestational weeks;
Hb haemoglobin;
K, potassium;
I, iodine;
ICP-MS, inductively coupled plasma
mass spectrometry;
IF, intrinsic factor;
10
IO-, hypoiodite;
IOM, Institute of Medicine;
LA, linoleic acid;
LCP, long chain polyunsaturated fatty
acids;
LC-MS/MS, liquid chromatography-
tandem mass spectrometry;
LOQ, limit of quantification;
Ma, manganese;
Mg, magnesium;
MMA, methylmalonic acid;
Mo, molybdenum;
Na, sodium;
nd, not detectable;
NIS, sodium/iodine symporter;
NTD, neural tube defects;
P, phosphorus;
PP, postpartum;
PPARs, peroxisome proliferator-
activated receptors;
PTAD, 4-phenyl-1,2,4-triazoline-3,5-
dione;
PTH, parathyroid hormone;
PTHrP, parathyroid-hormone related
peptide;
RAE, retinol activity equivalents;
RBC, erythrocyte;
RCTs, randomized controlled trials;
RDA, recommended dietary allowance;
RE, retinol equivalents;
Se, selenium;
SOD, superoxide dismutase;
TC-II, transcobalamin II;
TSH, thyroid-stimulating hormone;
UL, tolerable upper intake level;
US-EPA, United States Environmental
Protection Agency;
WHO, World Health Organization;
ya, years ago;
Zn, zinc
General introduction: Brain-selective nutrients
Brain-selective nutrients
One of the most remarkable features that distinguish us from other animals is the large
size of our brain compared to total body size, also named the encephalization quotient 1
(EQ). Compared with the cat (EQ=1.0)1, our brain/body ratio is about 7.6 times higher
(EQ=7.4-7.8), followed by the dolphin (EQ=5.3) and monkeys and apes, notably our closest
extant relative, the chimpanzee (EQ=2.5), with whom we share a common ancestor some
6 million years ago (ya). Our brain growth started about 2.5 million ya at the time of Homo
habilis and Homo erectus (Figure 1). A major question is ‘what made our brain grow’ from
the about 400 mL then to the current 1,300-1,500 mL now, and why didn’t it occur as
well in our closest extant relative, the chimpanzee, with a current adult brain volume of
about 400 mL? Such knowledge is important, since it might provide us with information
on what particular foods, nutrients, and especially nutrient-combinations, are needed for
optimal brain functioning, assuming that brain growth and functioning coevolved. Energy
sources and essential nutrients are, of course, important for the functioning of each organ,
but it has become clear that certain nutrients are particularly important for the proper
functioning of our brain. This has led to the concept of ‘brain-selective nutrients’, first
coined by Professors Stephen Cunnane, Michael Crawford and Leigh Broadhurst2-7. These
nutrients comprise at least: iodine, selenium, iron, zinc, copper, vitamins A and D, vitamin B12
and the fish oil fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)4.
According to Cunnane: ‘Brain selective nutrients are a collective term encompassing those
nutrients needed especially for normal human brain development, and although they are
important for brain, these nutrients aren’t specific to the brain; they are used elsewhere
in the body as well. If the requirement for any one of the brain selective nutrients is not
met at the correct stage of development, permanent retardation results’7. Each of these
brain-selective nutrients is abundantly present in the so called ‘land-water ecosystem’,
(see below) where our Palaeolithic ancestors are likely to have hunted and gathered
from 2.5 million to 10,000 ya; the so called Palaeolithic Era. It is in this era that our genes
adapted to the environment to ultimately provide us with a large brain according to the
principles of Darwin’s ‘adaptation to the conditions of existence’, implying that knowledge
on the ecosystem to which they were exposed in that era is key to the understanding of
who we are and what our relatively large brain needs. The underlying mutations are of
course important, but without the necessary nutrients, such mutations would eventually
disappear by natural selection. Interestingly, a similar brain growth occurred in the above
mentioned dolphin8, with whom we share a common ancestor some 95 million ya and
who, after inhabiting the land, returned to the sea about 50 million ya. All of this occurred
long before the brains of the ancestral dolphin and humans started to grow, the dolphin
prior to the human lineage, suggesting that close contact with (sea) water is needed for
such an event to occur8,9.
11
Chapter 1
Figure 1. Human brain growth during evolution.
Obtaining a clear picture of our subsistence diet over the past 2.5 million years is of
course an illusion, but one may try to reconstruct by combining information from many
disciplines, including the Paleo-environment, comparative anatomy, biogeochemistry,
archaeology, anthropology, (patho)physiology and epidemiology. It is commonly accepted
that most of our evolution occurred in Africa10, notably in the East African Rift Valley. This
Valley is a geographical trench, where two tectonical plates drift apart, stretching from
Tanzania into Ethiopia and exhibiting a fair amount of volcanic activity that adds new
minerals, such as iodine, to the local environment11,12. The East Rift is some 22-25 million
years old and constituted an important habitat for Homo and its ancestral Ardipithecines
and Austalophecines. South-Africa is, however, also a major archaeological excavation site13,
but as a matter of fact our ancestors’ remains have been found all over Africa, such as those
of the 316,000 years old anatomically-less-modern Homo sapiens found in a cave at Jebel
Irhoud-Morocco14-16. As Hublin of the Max Planck Institute for Evolutionary Anthropology
explained: ‘There is no Garden of Eden in Africa, or if there is, it is of the size of Africa’16.
The currently oldest anatomically modern Homo sapiens, i.e. Homo sapiens idaltu, is about
160,000 years old and was found in Herto-Ethiopia near the middle part of the Awash river17.
This Middle Awash has produced some 300 excavation localities and is the only place in the
12
General introduction: Brain-selective nutrients
world where fossils have been discovered spanning the entire hominin1 evolution. One of
them, the 3.2 million years old ‘Lucy’, an Australopithecus from Haddar-Ethiopia, is among
the widely known. Importantly, all of the remains in the Rift Valley were found in the vicinity 1
of water18,19, whether fresh or salt (lake) water, in contrast to the savanna20. Remains of
shallow-water animals, notably catfish and cichlids, turtles, frogs and crocodiles were found
in the vicinity of the 5.8 million years old Ardipithecus Ramidus from the Middle Awash21,
who is considered to have been an omnivore. Another important Rift-Valley excavation
site at Lake Turkana-Kenya produced fossils of various mammals and bovidae, but also of
bony fish, catfish, crocodile and turtle of which various carried cut-marks, attributed to
the activity of hominins predating Homo erectus and taking place some 1.95 million ya22.
Hunting and gathering activities by hominins on the savannah, a widespread hypothesis
referring to the foraging activities of our ancestors, is rather unlikely. It is difficult to hunt
animals in the wild savannah, even with modern weapons. An upright position while
hunting in a flat open plain is not the favoured posture for success, and the daily need of
at least 2 litres of fresh water, as required in the hot African savannah, would have been
difficult to fulfil. The current view, based on genetics, is that Homo sapiens may derive
from South Africa23, where excavations in e.g. the coastal caves at Pinnacle Point are still
on going. These caves show e.g. evidence of shellfish consumption about 164,000 ya24.
Shellfish (like oysters, Table 1) are rich sources of brain-selective nutrients, notably iodine,
selenium, iron, zinc, copper, vitamin B12 and the fish oil fatty acids EPA and DHA. Easily
harvested seaweed at low tide is a rich source of iodine and selenium (Table 1), while fish
livers (Table 1) contain high amounts of vitamin A, vitamin D, and the other brain-selective
nutrients. It has been estimated that eating 680, 800, 900, 500 and 300 g of shellfish,
respectively, is needed to meet the daily requirements for iodine, iron, copper, zinc and
selenium7. It is, however, unlikely that shellfish provided the only source of energy, e.g.
because of its high protein content and the associated danger of protein poisoning29.
Seaweed might have been a source of folate (Table 1), but is unlikely to have been the
only dietary source. A diet from the land-water ecosystem might have lowered the
requirements of both folate and choline, because of the local abundance of betaine,
which is the oxidized (carboxylic) form of choline (an alcohol). Folate, choline and
betaine find a common function in 1C metabolism in which a methyl group from
5-methyltetrahydrofolate (via vitamin B12-dependent methionine synthase and vitamin B2-
dependent methionine synthase reductase) or from betaine (via zinc-dependent betaine
1 Hominin – the group consisting of modern humans, extinct human species and all our immediate ancestors (including
members of the genera Homo, Australopithecus, Paranthropus and Ardipithecus); Hominid – the group consisting of all
modern and extinct Great Apes (that is: modern humans, chimpanzees, gorillas and orang-utans plus all their immediate
ancestors
13
Chapter 1 General introduction: Brain-selective nutrients

homocysteine methyltransferase) is transferred to homocysteine for the regeneration of

Fish oil, cod RDA, AI (IOM; M,

methionine25. Methionine regeneration from homocysteine with betaine is confined to the

31-50 y)46-50
kidneys and the liver, and spares the catabolic use of choline as a precursor of betaine26,27. 1
Choline is uniquely needed for the synthesis of acetylcholine (a neurotransmitter) and

5501
400
900
150

2.4
0.9
55

15
11
8
phosphatidylcholine (an abundant membrane phospholipid). In a similar manner the use of

(per 100 g)45

betaine as methyl donor also spares the expenditure of 5-methyltetrahydrofolate and the

Content
cofactors vitamins B2 and B12 that are needed in this reaction, and thereby saves the use of

30,000

23,039
liver

250
folate for its unique functioning (folate cycle) in the synthesis of purines and pyrimidines,

0
0
0
both being building blocks for nucleic acid synthesis. Betaine is an osmolyte28, which is an

Haddock, liver

(per 100 g)44

intracellular compound that maintains osmotic pressure, notably upon abiotic (salt) stress.

Content
Not surprisingly, betaine is abundant in the land-water ecosystem, with high amounts

60,000
0.005

0.007
0.074

0.06
occurring in e.g. shrimp (218-219 mg betaine/100 g;29,30, some seaweeds31 and plants

400

500
oil

0
growing close to the seashore to maintain osmotic balance, such as known of spinach

(per 100 g)43

Cod, liver,
(600-645 mg betaine/100 g;29,30). Mollusks and crustaceans living in shallow depths use

Content
canned
betaine as one of the most abundant osmolytes and plants, such as the afore mentioned

0.007

5,100

9,411
0.06
63.5

10.6
500

100
2.1
spinach32 and sugar beets, notably the wild ancestor of all beet crops33, accumulate organic

0
osmolytes, such as betaine, when subjected to abiotic (salt) stress34,35. We hypothesize

(per 100 g dry

that betaine is, or has been, abundant at the South African coast and also in the vicinity

P. haitanensis
Red algae
of the salt lakes located in the Rift Valley, both considered to be the cradles of the current

Seaweed:

weigh)42
Content

240,700

± 0.237
12,600
homo sapiens.

± 365

70.05
± 98

*Pehrsson et al. Am J Clin Nutr 201651; Food Standard Australia, New Zealand52,1; AI
It has been suggested that the exploitation of the local resources from the sea not only

Seaweed: nori,

(per 100 g dry

drastically changed social and technological behaviour to a society structure with e.g. small

red algae

weight)42
P. tenera
Content
scale food production, that is unusual for hunter-gatherers36, but also saved Homo sapiens

310,800

± 0.203
20,400
± 103
± 424
from extinction due to the harsh climatic conditions following its emergence in Africa37.

18
This would imply a genuine ‘bottleneck’ in Homo’s recent evolution, suggesting that all

(per 100 g)41

Seaweed,
laver, raw
current Homo sapiens are descendants from a population that lived at the South African

Content
Coast and survived the catastrophe of a long glacial stage known as Marine Isotope Stage

0.264
1.05

10.4

260
146
0.7

1.8

80
6 (MIS6) lasting from 195,000 to 123,000 ya37. It is also possible that human populations

0
0
Table 1. Brain selective nutrients in seafood.

Dimension Mollusks, oyster,

easter, wild, raw
living at the South African coastal region were the only survivors of a decade or more

(per 100 g)40

of volcanic winter that followed the eruption of the Toba volcano in Sumatra-Indonesia

109 - 160
about 74,000 ya38. Consumption of shellfish from sea or fresh water was not a trait unique

Content

2.858
for that period, but also occurred much earlier by Homo erectus, about 430,000-540,000

8.75
39.3
4.61
19.7

313
65

13
7

1
ya in Trinil Mid-Java, Indonesia39.

mg

mg

mg
mg
mg
μg

μg

μg

Vitamin B12 μg
μg

μg
Vitamin D

EPA+DHA
Vitamin A
Selenium
Nutrient

Choline
Copper
Iodine

Folate

(RAE)
Zinc
Iron
14 15
Chapter 1
Homo sapiens left Africa some 70,000-100,000 ya to become the only current Homo
species in the world. The local ‘conditions of existence’ caused humans to evolve into
the present five races53, as adaptations to e.g. ultraviolet radiation54, but also many other
environmental conditions, such as climate, altitude and notably infectious agents55,56.
What factors exerted selection pressure57,58 is difficult to disentangle, since climate
changes with latitude, but so does biodiversity, including pathogen diversity59. Infection
by microorganisms is likely to have exerted very strong selection pressure, and still does,
such as e.g., witnesses by the many mutations conferring some protection from malaria
parasites60,61. Lactose persistence62, intuitively considered an advantage because it enables
the intake of macro- and micronutrient rich milk, and amylase copy number variation63
for enhanced starch digestion starting high in the gastrointestinal tract64, might as well
be adaptations to promote (rapid) simultaneous uptake of glucose, sodium and water
to prevent life-threatening dehydration following vomiting and diarrhoea caused by
exposure to mycotoxins on grains (introduced by the agricultural revolution), and exposure
to zoonoses (that came along with animal domestication)65.
Whatever the genuine environmental factors, recent selection since the agricultural
revolution introduced little genetic variation when compared to the already existing
variation in the first Homo sapiens as a group66. For instance: genetically, two members of
the same race are likely to differ more strongly from each other than the average member
of their race differs from the average member of another race. In other words: genetically
we are remarkably similar, which does not trivialise important genetic differences (such
as polymorphisms, copy number variation) aiming at ‘adaptations to local environmental
conditions’. The high incidence of skin cancer in white people who migrated to Australia
is just one of the many examples reminding us that changes in environmental conditions
to which humans became adapted may coincide with various health issues of the current
time. The underlying ‘dysfunctional’ genes that received the blame are often referred to
as ‘disease susceptibility’ genes67, which is a bizarre notion in the light of the evolutionary
theory. It masks the influence of our current lifestyle in which >70% of colon cancer and
stroke, >80% of coronary heart disease and >90% of type 2 diabetes mellitus can be
prevented if we have more attention for specific aspects of diet, overweight, physical
inactivity and smoking68. With a generation time of about 25 years, and only mild selection
pressure that predominantly affects health at post-reproductive age, post agricultural
revolution human populations are unlikely to have adapted their genes rapidly by natural
selection following a sudden dietary change that does not cause acute deficiency or
toxicity with severe short-term adverse reproductive consequences. The ensuing
‘mismatch’ between our Palaeolithic genes and this new, self-chosen, environment, and
lifestyle in general, constitutes the basis of the so called ‘mismatch hypothesis’ that is
fundamental to the discipline of ‘evolutionary medicine’69-75.
16
General introduction: Brain-selective nutrients
The Out-of-Africa diaspora is considered to have occurred via the coast76, with inland
movements in e.g. the Americas occurring from there, notably by following rivers77. This
suggests continuing availability of brain-selective nutrients from the land-water interface. 1
Some evidence for the exploitation of food from the land-water ecosystem following
‘Out-of-Africa’ comes from shellfish fossils attributed to the activity of Neanderthals
(who arrived earlier in Europe and are not in the Homo sapiens lineage) in the Bajondillo
Cave (Malaga, Spain) dated 191,000-130,000 ya78, and the consumption of molluscs, seal,
(scavenged) dolphin, and fish by Neanderthals about 42,000 ya in Gibraltar-caves. Many
of the recovered animal remains were found to carry cut-marks, such as discovered on a
bone fragment of a Mediterranean seal79. Stable isotope studies of bones recovered from
early modern humans in China, near Beijing, and dated 40,000 ya, revealed consumption
of dietary proteins that to a substantial portion derived from the freshwater ecosystem,
probably freshwater fish80. The oldest fish hooks, made from shells were found together
with remains of a variety of pelagic and other fish species, in Jerimalai Cave in East Timor
Indonesia, dated 42,000 ya81. There is a 1-meter long life-size sculpture of a male salmon in
the Abri du Poisson rock shelter (Franco-Cantabrian region), dated 23,000 ya, and located
in the valley of the Gorge d’Enfer (valley of the Vezere River), close to Les Eyzies-de-Tayac
in the Dordogne, France82. A painting of a giant black fish, thought to be a halibut, about
1.5 m in length, and dated about 18,000 BC, has been found in the ‘Fish Chamber’ of
the La Pileta Cave (Cueva de la Pileta, Province of Malaga, Andalucia, Southern Spain)83.
Chemical analysis of food residues (d13C values of 16:0 and 18:0 fatty acids in recovered
lipids) adhering to pottery from Torihama and Taisho (Japan), dated 15,000 to 11,800 years
BP (the incipient, so called, Jomon period), unequivocally revealed processing of freshwater
and marine organisms. Most of the 101 charred deposits that were analysed from locations
across the major islands of Japan were derived from aquatic food84.
With the event of the agricultural revolution and the concomitant domestication of
(land) animals, starting some 10,000 ya in Mesopotamia, our ancestors started to replace
their original hunter-gatherer diet for a mostly terrestrial diet composed of an eventually
limited number of cultivated crops, such as cereal grains85, and (products of) domesticated
ruminants like sheep, goats and cows86,87, and fowl like chickens, ducks and geese. The
transformation from hunter-gatherer to (cattle) farmer changed our diet in a drastic
manner, but as matter of fact our lifestyle in general. The fossil record indicates a sharp
change in the 13C content of collagen isolated from human bones in coastal Britain at the
onset of the Neolithic (4,000 ya), suggesting a rather sudden shift from a marine-based to
terrestrial-based diet, concomitant with the estimated arrival of the agricultural revolution
at those locations88,89. Using a combination of lipid biomarkers, stable carbon isotope
signatures of individual fatty acids preserved in cooking vessels from the coastal Eastern
North Atlantic (mainland Britain, Scottish isles and the isles of Man and Ireland), together
17
Chapter 1
with archaeozoological and human skeletal collagen bulk stable carbon isotope proxies,
it was shown that early farmers rejected marine resources coinciding with the adoption
of intensive dairy farming and the overwhelming use of dairy products. After an initial
sharp decline in the exploitation of marine resources from 4,600-4,300 BC (Late Mesolithic,
retrieval of shell middens, fishing gear) to 3,800-2,200 BC (Neolithic, introduction of pottery,
cattle, sheep) there was a subsequent gradual increase in the use of marine resources from
2,200-800 BC (Bronze age, intensified farming. limited fishing) to 800 BC-1,400 (Viking, deep
sea fishing, intensification of trade). This increase, however, did not restore the use of marine
resources to the level of the late Mesolithic90,91. In line with abandoning a diet from the
land-water ecosystem there was an increase of many diseases of civilization, attributed at
least in part to lower intakes of brain-selective nutrients3-5,8,18. It is not a coincidence that
three brain-selective nutrients, i.e. iron, vitamin A and iodine currently belong to the class
of micronutrients exhibiting the most widespread deficiencies in both developing and
developed countries92-94.
Contemporary genetic adaptations, notably those of very recent origin, derive from
relatively mild selection pressure. Unlike in the past, there have been no environmental
threats that drove humans to near extinction and consequently no ‘bottlenecks’. Such
adaptations will consequently meet difficulty to reach fixation in the context of an
exploding world population with an estimated number of only 5 million people 10,000
ya, that was followed by an apparently linear growth that genuinely took off from 254
million in 1,000 AD to 6 billion in 2,000, and the reach of an anticipated number of 9.4
billion in 205095. This population growth is attributable to less infectious disease (in
notably the GI- and respiratory- tracts) because of public health measures in e.g. hygiene
and immunization, less violence because of changing culture, less famine thanks to the
agricultural revolution, and also the institution of secondary prevention via health care96.
Positive selection may on the other hand have speeded up in the past 40,000 years,
because in a large population there are simply more new spontaneous mutations and
because large population numbers exhibit less genetic drift (in which a new mutation
might get lost by the higher chance that comes along with small numbers)97. Whatever our
genetic adaptive ability, it is unlikely that the majority of us have evolved mechanisms to
cope with the continuing and still rapidly changing, self-chosen, environment and modern
lifestyle, rendering it at the same time conceivable that our current lifestyle reduces our
number of years without chronic disease98,99, also referred to as our chance of ‘healthy
aging’. This ongoing tragedy, with consequences for individuals and the costs of health
care, happens in the context of the recent increase in life expectancy, and may together
be viewed upon as a ‘double burden of disease’ distinct from its original definition by the
WHO as the ‘coexistence of undernutrition along with overweight/obesity or diet-related
non-communicable diseases’.
18
General introduction: Brain-selective nutrients
The loss of brain volume (175 mL for women and 158 mL for men; i.e. the size of about
one tennis ball) during the Holocene (11,700-present)100 may relate to the reduced intake
of brain-selective nutrients, and so may the seemingly rapid increase in psychiatric 1
diseases, e.g. depression, notably in younger cohorts101 and young adolescents, although
this epidemic is often attributed to the social media and insufficient sleep102. Also the
apparent loss of 14 IQ points since the Victorian Era103 may be a consequence. Although
not conclusive in this sense, it has been shown that ‘a poor diet’ is associated with a
comparatively more rapid decline of brain (hippocampal) volume in 60-64 years old
subjects104, while overweight and obesity are associated with more rapid loss of brain
white-matter volume at later age105. One of the links between poor diet and a lifestyle
with less brain-selective nutrients might derive from low long chain polyunsaturated fatty
acid (LCP) intake, notably the fish oil fatty acids EPA and DHA. It is e.g. known that in adults
the erythrocyte (RBC) omega-3 index (i.e. EPA+DHA) relates to total brain volume and
hippocampal brain volume106, and that male babies born to mothers receiving a 600 mg
DHA daily supplement from 23 gestational weeks (GW) until pregnancy end have larger
head circumference, total brain, cortex, corpus callosum and whole grey matter107.
It is clear that Homo sapiens is highly attracted to water, such as e.g. described by Elaine
Morgan in her book ‘The Aquatic Ape Hypothesis: The Most Credible Theory of Human
Evolution’ (1997)108. ‘The theory postulates that humans evolved through an aquatic stage,
prior to Homo habilis and Homo erectus, during which time our ancestors lived largely in
water’. The theory has both strengths and weaknesses109. Even today, over 50% of the
world’s population lives closer than 3 km to a surface freshwater body, over 70% lives closer
than 5 km to water and only 10% lives further than 10 km away110. Populations in Australia,
Asia, and Europe live closest to water, 40% of Americans live close to the seashore111 while
this latter applies to an even higher percentage of Australians112.
In the next paragraphs we will discuss the importance of some brain-selective nutrients
to health and especially the development of a healthy brain.
The importance of nutrition prior to conception and during pregnancy and
lactation.
The first 1,000 days, from conception to 2 years of age, are considered to constitute a
critical window of growth and development. Maternal nutrition prior to conception and
during pregnancy and lactation provides the embryo, fetus and breastfed infant with
the essential nutrients for brain development, healthy growth and an optimal immune
system113. Excessive or insufficient nutrient status in the period of conception, pregnancy
and lactation may cause irreversible disturbances in the offspring’s brain development,
or offspring physical growth, which leads to suboptimal cognitive performance in school,
19
Chapter 1
but can also render them more susceptible to infection and disease. Figure 2 depicts the
human development during the first 40 weeks of life and the important nutrients during
the various stages.
Figure 2. The function and timing of micronutrients that affect outcome in offspring. Reprinted with
permission of Springer Nature: Nature Reviews Endocrinology, Micronutrients deficiencies in pregnancy
worldwide: health effects and preventation. Gernand A.D., Schulze K.J., Stewart C.P., West K.P., Christian
P. 2016114.
It has been shown that the affected offspring also has an increased risk of later conditions
and diseases like obesity, type 2 diabetes, hypertension, coronary heart disease, chronic
lung and kidney disease, musculoskeletal disorders, some cancers and mental illness115-117.
As adverse exposures during early development shape the body´s responses to later
20
General introduction: Brain-selective nutrients
challenges, it is important to promote a healthy parental lifestyle, preferable during the
entire life, but certainly starting before conception.
1
Folate deficiency is probably the best-known example to illustrate the potentially
ill consequences of nutrient deficiencies on brain development. Folate is required for
nucleotide and DNA synthesis to support cell division. It is also involved in 1C metabolism
(see above). Intrauterine folate insufficiency strongly increases the risk of neural tube
defects (NTDs)118,119. These are congenital malformations resulting from improper closure
of the embryonic neural tube. The two most common NTDs are anencephaly and spina
bifida. The central nervous system is formed early in embryonic life and folds itself to
become a tube. Closure of the tube occurs in the fourth week of post-conception119.
Therefore, an adequate maternal folate status in the first weeks of pregnancy is necessary
to provide adequate infant levels and thereby prevent NTDs119,120. Food fortification with
folic acid (the synthetic form), is estimated to prevent approximately 1,300 NTD-affected
births annually in the United States121. Pre-conceptional supplementation with folic acid,
alone, or as a part of a multi-vitamin, has been shown to reduce the risk of NTDs by
35-75%119,122. Other examples of lifestyle-interventions supporting healthy pregnancies
are weight loss in obese women123, leading to increased natural conception rates124,125,
and healthy eating habits, physical activity and self-monitoring of blood sugar levels by
pregnant women with gestational diabetes to improve their own health and that of their
babies, at least in part by the reduction of macrosomia126.
The placenta plays a key role in normal fetal growth and development. It provides the
fetus with oxygen, nutrients and removes carbon dioxide and other waste products. The
placenta also metabolizes certain nutrients in maternal or fetal blood and has an important
function in fetal protection from injury, xenobiotics, infections and maternal diseases127,128.
Micronutrient deficiencies may induce a pro-inflammatory state, and influence placental
development and function, leading to impaired fetal growth129. Multi-nutrient supplements
have been shown to reduce the incidence of low birth weight and small-for-gestational-
age infants when supplied to women at high risk of deficiencies. In the first trimester of
pregnancy the basic organ structures of the infant are established during embryogenesis,
(2-8 GW). Important micronutrients for organogenesis are vitamins A and E, magnesium,
iron, zinc and copper. The central nervous system and fetal brain are developed in the first
post-conceptional weeks for which iron, zinc, copper, iodine, folic acid, choline, vitamin
B12, vitamin A, vitamin D and DHA+EPA are important. Later in gestation, micronutrients
are needed for organ size and function. In the second and third trimester the fetus grows
and accumulates nutrient stores114.
21
Chapter 1
Neonatal stores reflect both duration of gestation and maternal micronutrient status. The
neonatal stores are crucial for ensuring optimal supply of micronutrients when breast
milk, as a primary source of infant nutrition, does not contain adequate amounts of
micronutrients. Low milk nutrient contents may occur in spite of an adequate maternal
status. Building adequate infant stores seems especially important to prevent the use of
certain nutrients by unfavourable bacteria in the gastrointestinal tract. Iron, for which
mother-to-child transport seems safer during pregnancy than lactation, is a well-known
example. Vitamin B12 might be another130,131. It is estimated that during pregnancy, 7 mg
iron/day is transferred to the fetus132 to secure fetal iron stores, while breast milk only
provides about 0.27 mg/day49, of which only 50% is bioavailable. Milk iron is tightly bound
to milk proteins, notably lactoferrin, which contributes to the antimicrobial activity of
human milk. The iron-binding proteins transferrin and lactoferrin restrict the amount of
available ionic iron in body fluids to 10 -18 M. For the binding of vitamin B12 to intrinsic factor
that is 10 -15-10 -9 M133. These concentrations are insufficient to support bacterial growth134.
During the first 4 to 6 months after birth, iron becomes mobilised from the stores built
during fetal life. Consequently the requirement of exogenous iron is virtually zero. After 6
months, the stores have been utilized and exogenous iron is needed to meet the infant
requirement. In 7-12 months old infants, the daily iron need is estimated at 0.7 mg/day, of
which 0.2 mg/day is required to replace losses. Low maternal status is likely to preclude the
building of sufficient infant stores in utero114 and also preterm babies might have low stores.
The World Health Organization (WHO) advices mothers to exclusively breastfeed their
infants during the first six months of life135. Breast milk has advantages over formula milk.
Not only does breastfeeding increase the bond between mothers and their infants, it also
improves the infant’s immune system135. The composition of breast milk changes during
the lactation period, to meet the infant’s changing needs. The physiological background
encouraged the notion that breast milk is the “perfect food for infants”136, as popularized
to “breast is best”. However, when comparing breast milk from all over the world, some
similarities, but also many differences in composition are noted. Nutrients in breast milk
derive from maternal stores, or may be synthesized by the lactocytes in the breast. Smaller
amounts derive directly from the maternal diet137. Since nutrients in breast milk may derive
from different sources, they can be classified into two groups.
Group I milk nutrients become rapidly and/or substantially reduced by maternal depletion.
Maternal supplementation increases their breast milk concentrations and thereby improves
infant status. Examples are: thiamin (vitamin B1), riboflavin (vitamin B2), vitamin B6, vitamin
B12, choline, retinol, vitamin D, selenium, iodine and EPA and DHA. An adequate maternal
diet during lactation is important to allow sufficient intakes of these nutrients by the
infant137-139. Group II milk nutrients derive from their synthesis in the breast or from maternal
22
General introduction: Brain-selective nutrients
stores. In contrast to group I nutrients, those in group II, are considered relatively unaffected
by short-term maternal intake or status. When maternal intake is below the amount
secreted into milk, the mother becomes gradually depleted, and the infant turns into a 1
parasite. Examples are folate, calcium, iron, copper and zinc140.
This classification of nutrients into groups I and group II may need reconsideration, as it
could very well be possible that the breastfed infant depends on its own tissue stores (e.g.
of vitamin D, iron and vitamin B12) to maintain adequate status. It might be hypothesized
that the group I milk nutrients have been abundantly available during hominin evolution,
precluding the need to tightly regulate their milk outputs. For instance by evolving
transport systems with high concentrating ability as seen for e.g. iodine. In addition,
abundances may have caused the possibility to create adequate stores during fetal life
for e.g. vitamin B12. The close relation between maternal and infant nutritional status
implies that the requirement (RDA. AI; see below) for infants could be best derived from
(breast milk and blood) samples collected from life-long adequately fed mothers. However,
since lifestyle has drastically changed during the past 200 years, it is nowadays difficult
to define these requirements by studying ‘apparently healthy and well-fed’ mothers who
are randomly selected from a population75.
To provide nutritional guidelines and to serve as a scientific basis for the development of
food guidelines, the Institute of Medicine (IOM) developed Dietary Reference Intakes (DRIs).
These DRIs are specified on the basis of age, gender and lifestyle and cover a wide range
of nutrients141,142. The values and definitions that comprise the DRIs are:
• Estimated Average Requirement (EAR): “Reflects the estimated median requirement and
is particularly appropriate for applications related to planning and assessing intakes for
groups of person”.
• Recommended Dietary Allowance (RDA): “Derives from the EAR and is intended to cover
the requirement for 97-98 per cent of the population”.
• Tolerable Upper Intake Level (UL): “Highest average intake that is likely to pose no risk”.
• Adequate Intake (AI): “Used when an EAR/RDA cannot be developed. The AI is an average
intake level based on observed or experimental intakes”.
From the definition of the DRIs, it may be derived that EARs and RDAs are merely applicable
to populations, and not individuals. Furthermore, these DRIs have been established for
well-fed humans. Dietary needs of malnourished subjects or subjects with pre-existing
micronutrient deficiencies are expected to be higher. During pregnancy, DRIs are
determined by assessing the physiological requirements to support a healthy pregnancy.
DRIs in pregnancy are, however, difficult to establish due to plasma volume expansion and
23
24
Chapter 1

and some essential and toxic elements during pregnancy, lactation and early infant life.
using average intakes of full-term infants who are exclusively breastfed and are born to

results in the establishment of the actual requirements of nutrients in populations. In Table

other pregnancy adaptations. Therefore, the recommendations are usually extrapolations

apparently healthy, well nourished mothers. It is unknown to what extent this approach

vitamin B12, vitamin D, some essential fatty acids & long chain polyunsaturated fatty acids
describe the methods that have been used to establish these for 0-6-month-old infants,
for the average amounts secreted into breast milk142 For infants, the IOM established AI by
maternal demand to support tissue accretion and metabolism114. For lactating women,

and pregnant and lactating women. It is clear that for most nutrients, the DRIs are higher
in pregnancy and lactation than for non-pregnant or lactating women of childbearing-age.
the DRIs are extrapolated from estimates from non-pregnant counterparts and adjusted

In the next paragraphs we discuss the function, changes during pregnancy and intakes of
from estimates from DRIs for adults, as adjusted for fetal nutrient accumulation and

2 we summarize the EARs, RDAs and AIs for micronutrients at different life stages and

Table 2. Dietary Reference Intakes of the Institute of Medicine for micronutrients meant for women and their 0-6-month-old infants, together with their
derivation46-48,50,141,143-147

Life stage Criteria for setting:

Micronutrient Dimension Infants: 0-6- Females: Pregnant women: Lactating women: Females 19-50 years: Pregnancy
month old 19-50 years 19-50 years 19-50 years
EAR RDA EAR RDA EAR RDA
Vitamin A1 μg/day 400*, a 500 700 550 770 900 1,300c Computational analyse to assure Assure adequate fetal vitamin A stores
adequate body stores of vitamin A
Vitamin B12 μg/day 0.4*, a 2.0 2.4 2.2 2.6 2.4 2.8 c Maintain haematological and serum Absorption and utilization of vitamin B12, assure
vitamin B12 status in individuals with adequate fetal vitamin B12 stores,
pernicious anaemia in remission;
endogenous B12 lost in bile correcting for
bioavailability
Vitamin D μg/day 10b 10 15 10 15 10 15d Bone maintenance No evidence an increased intake is necessary,
based on observational studies which showed
no effect on maternal 25(OH)D levels on fetal
calcium homeostasis or skeleton outcome
Omega-3-fatty Not established; GOED advices 700 mg EPA+DHA during pregnancy and lactation
acids: EPA+DHA
Potassium mg/day 400*, a 2,600* 2,900* 2,800*, e Balance studies Median potassium intakes
Calcium mg/day 200*, a 800 1,000 800 1,000 800 1,000 d Balance studies No evidence an increased intake is necessary
Sodium mg/day 110*, a 1,500* 1,500* 1,500* Lowest sodium intakes from sodium trials; No evidence an increased intake is necessary
balance studies
Phosphorus mg/day 100*, a 580 700 580 700 580 700 d Relationship between serum Pi and No evidence an increased intake is necessary
absorbed intake
Magnesium mg/day 30*, a 265 320 290- 350-360 255- 310-320 d Balance studies Extrapolation of adults
300 265 (Serum Mg / Intracellular Mg / Balance studies
/ magnesium tolerance test / Pregnancy
outcome)
25
General introduction: Brain-selective nutrients

1
Chapter 1 General introduction: Brain-selective nutrients

Vitamin B12

for preformed vitamin A is the same as RE. a means AI established by average breast milk concentrations; b means AI is established on supplementation needed to maintain infant 25(OH)D levels ≥
accumulation by maternal and embryonic/fetal

Changes in a combination of biochemical Estimation of amounts of copper that must be

Additional fetal requirements: to saturate fetal

related tissue and iron utilized in expansion of

RAE = 1 μg retinol, 12 μg β-carotene, 24 μg α-carotene or 24 μg β-cryptoxanthin. The RAE for dietary provitamin A carotenoids is two-fold greater than retinol equivalents (RE), whereas the RAE
Additional fetal requirement + extrapolation
Additional iron deposited in the fetus and

This table presents Recommended Dietary Allowances (RDAs) in ordinary type and Adequate Intakes (AI) in ordinary type followed by an asterisk (*). 1 As retinol activity equivalents (RAEs): 1
Iodine balance, fetal thyroid requirement,
supplementation versus maternal status
tissues in the 4th quarter of pregnancy
Vitamin B12 sources, metabolism, and function 1
Additional average daily rates of zinc

Vitamin B12 is synthesized by certain bacteria and archaea, but not by plants and animals.

accumulated during pregnancy

From these micro-organisms vitamin B12 accumulates in animal tissues via the food chain.

Extrapolation from adults

absorption of dietary iron, estimated to be haemoglobin mass Good sources of vitamin B12 are meat, dairy and (shell) fish. In ruminants, vitamin B12 is
synthesized in the stomach by vitamin B12-synthesizing bacteria. Vitamin B12 is absorbed

selenoproteins
in the intestine and stored in the liver, muscle or excreted into the milk. Pigs and chickens

from adults
are omnivores, obtaining vitamin B12 from their diet. The vitamin B12 contents in products
from ruminant animals are higher than those in products of omnivorous animals. In aquatic
18 per cent for adults for the typical North

environments, bacteria live in symbiosis with phytoplankton, which become food for

EAR; AI was set based on median intakes

indicators resulting from varied levels of

Intake needed to maximize the activity

reported from the U.S. Food and Drug

of plasma selenoprotein glutathione
larval fish and bivalves. The bigger predatory fishes in the ocean food chain contain higher

Insufficient amount of data to set an

requirements for growth, as well as
Factorial analysis of zinc losses and

Iodine accumulation and turnover

30-50 nmol/L; c means additional infant requirement; d means no evidence was found that increased intake as necessary; e median intake.
Dividing the required amount of

vitamin B12 levels. Most plants do not produce or require vitamin B12, although low levels
absorbed iron by the fractional

of vitamin B12 have been found in some mushrooms and algae148.

Administration Total Diet

fractional absorption
Criteria for setting:

Vitamin B12 is released from protein when entering the acid environment of the stomach

Balance studies
American diet

copper intake

and is subsequently bound by intrinsic factor (IF). The IF-vitamin B12 complex is absorbed
peroxidase

in the small intestine by IF-receptor-(cubulin)-mediated endocytosis. Vitamin B12 is released

from IF and is bound to transcobalamin II (TC-II). The transcobalamin II-vitamin B12 complex
is transported in plasma and taken up in tissues by receptor-mediated endocytosis149.
1,000 1,300 c

In the cells, vitamin B12 is an important co-factor in two enzymatic reactions: the one-
2.6*, e
290 c

50 c
70 c
10.9 12 c

9c

carbon (1C) metabolic pathway and methylmalonic pathway, respectively (Figure 3). The
209
6.5

36
59

1C metabolic pathway is a series of biochemical reactions that are involved in amino acid
and nucleotide metabolism. It is named 1C metabolism, because the reactions involve
1,000

the addition, transfer, or removal of one-carbon groups. The 1C metabolism centres on

2.0*
220

60

50
27
11

the (re)methylation of homocysteine to methionine by methionine synthase, in which

800

160
9.5

40

5-methyltetrahydrofolate is converted to tetrahydrofolate, which is important for RNA- and

22

49

DNA synthesis. The other enzymatic reaction takes place in the mitochondrion, where
1.8*
900

150

vitamin B12 is involved in the conversion of methylmalonyl-CoA to succinyl-CoA, by the

45
55
18
8

enzyme methylmalonyl-CoA-mutase, which is important for fatty acid, cholesterol and lipid
700
6.8

8.1

34
95

45

metabolism, energy metabolism and the synthesis of haemoglobin150. In brain, vitamin B12
Life stage

is important for myelin formation151.

0.003*, a
0.27*, a

200*, a

110*, a

15*, a
2*, a

2*, a
mg/day

mg/day

mg/day
Table 2. (Continued)

μg/day

μg/day

μg/day

μg/day
Molybdenum
Manganese
Selenium
Copper

Iodine
Zinc

Iron

26 27
Chapter 1
Figure 3: One carbon metabolic pathways, vegetarian diets and effects of B12 insufficiency. X block; ll
‘secondarily’ inhibited; à stimulated; -| inhibited by metabolite. BHMT, Betaine-homocysteine S-meth-
yltransferase; CPT1, Carnitine palmitoyltransferase; CBS, Cystathionine-β-synthase; DNMT, DNA methyl-
transferase; GNMT, Glycine N-methyltransferase; MCM, methylmalonyl-CoA mutase; MMA-CoA, Methyl-
malonyl-CoA; MTR, Methionine synthase; MTHFR, methylentetrahydrofolate reductase; MS, Methionine
Syntase; R Methyl acceptors, including adenosine and cytosine; R-CH3 Methylated acceptor; SAH, S-ad-
enosyl homocysteine; SAM, S-adenosyl methionine; THF, Tetrahydrofolate. Reprinted with permission
from Springer Nature: European Journal of Clinical Nutrition, Vitamin B12: one carbon metabolism, fetal
growth and programming for chronic disease. Rush E.C., Katre, P. Yajnik, C.S., 2014150.
Vitamin B12 during pregnancy and lactation
Maternal cobalamin deficiency is related to an increased risk of early and recurrent
miscarriage, preterm birth, and low birth weight and may contribute to anaemia152. As
vitamin B12 is important for the rapidly developing fetal nervous system, low maternal
vitamin B12 status is, like folate, associated with NTD risk.
The course of vitamin B12 status during pregnancy is somewhat difficult to interpret. Widely
employed parameters of vitamin B12 status are plasma/serum vitamin B12 concentrations,
vitamin-B12 dependent concentrations of methylmalonic acid (MMA) and homocysteine
and holotranscobalamin. In a controlled feeding study, assessing the effect of reproductive
state on biomarkers of vitamin B12, it was found that serum vitamin B12 declines during
pregnancy, reaching about 21% lower values in the 3rd trimester of pregnancy as compared
to the non-pregnant state153. During pregnancy it has been found that holotranscobalamin
concentrations fall between preconception and the first trimester and then remain
relatively stable152, or remain similar to non-pregnant controls153, while MMA increases
and homocysteine decreases153. These changes in vitamin B12 biomarkers seem to be
based on physiological changes rather than vitamin B12 deficiency. A combination of
28
General introduction: Brain-selective nutrients
hemodilution, hormonal changes and vitamin B12 transfer from mother to infant may
decrease plasma vitamin B12 concentrations. Vitamin B12 recovers to normal values within
8 weeks postpartum154. 1
The infant’s postnatal vitamin B12 sources are its own liver stores and breast milk or
formula. Infants born to vitamin B12 adequate mothers have liver vitamin B12 stores of
~25-30 μg versus 2-5 μg in mothers with inadequate vitamin B12 status155. Infant vitamin B12
deficiency is a worldwide problem156. It may cause megaloblastic anaemia, microcephaly
and neurological symptoms such as irritability, failure to thrive, apathy, anorexia, hypotonia
and developmental delay157-159.
Occurrence of (sub)clinical vitamin B12 deficiency in pregnant women and
infants
Maternal vitamin B12 insufficiency may be widespread since 7% of women of reproductive
age exhibit low plasma vitamin B12, while 5% may be vitamin B12 deficient in early pregnancy
and 10% thereafter160. At delivery, low vitamin B12 status has been noted in 40% of UK
Caucasian mothers and 29% of their offspring161, while 13% of Belgian mothers and 0%
of their infants162 exhibited low vitamin B12, respectively. Vitamin B12 deficiency is more
prevalent in breastfed infants as compared to formula fed infants163,164.
RDA/AI of pregnant and lactating women and infants
Pregnant and lactating women have higher vitamin B12 needs than non-pregnant
counterparts due to fetal and infant requirements. The IOM has set the RDAs at 2.6, 2.8 and
2.4 μg/day, respectively48. The DRIs for women of childbearing age are based on normal
serum vitamin B12 (defined as ≥150 pmol/L), the estimated extra loss of 0.4 nmol/L vitamin
B12 in subjects with pernicious anaemia in remission and an average fractional absorption
of vitamin B12 of about 50%48. For pregnant- and lactating DRIs, the additional requirements
for the fetus and infant are added. However, these DRIs might not be sufficient to maintain
adequate vitamin B12 status153. Based on vitamin B12-related biomarker studies, the nutrition
societies of Germany, Austria and Switzerland recently raised their reference values for
vitamin B12 intakes to 4.0, 4.5 and 5.5 μg/day for non-pregnant, pregnant and lactating
women, respectively165.
For 0-6-month-old infants the IOM-AI is 0.4 μg/day. This AI is based on 9 milk samples of
healthy 2 months postpartum lactating women in Brazil166 with a mean milk vitamin B12
concentration of 310 pmol/L. Using an average intake of 780 mL/day167, this translates to
the consumption of 0.33 μg/day, which was rounded to 0.4 μg/day by the IOM. The 0.4 μg/
day corresponds with a milk vitamin B12 concentration of about 378 pmol/L. The inverse
relationship between urinary MMA and milk vitamin B12 at milk vitamin B12 concentrations
29
Chapter 1 General introduction: Brain-selective nutrients

less than 362 pmol/L confirmed the adequacy of this recommendation164. However, the
above-mentioned studies are based on small numbers of observations and the milk
vitamin B12 concentrations have been measured with methods that may have incorrectly
co-measured vitamin B12 analogues168,169. As a consequence, there is no well-established AI.
Aim of the vitamin B12 studies in this thesis
Currently there is a need for a well-established vitamin B12 AI, as derived from exclusively
breastfed infants. In Chapter 2 we describe the outcomes of vitamin B12 measurements in
mature milk of mothers living in various countries. The results were evaluated for ‘adequacy’
with the use of the 378 pmol/L vitamin B12/L estimate of the IOM, and also by employing a
Functional Adequate Concentration (FAC), calculated as the geometrical mean of milk of
mothers with ‘functional vitamin B12 adequacy’. The latter was derived from Vietnamese
mothers exhibiting a plasma vitamin B12 >221 pmol/L and a plasma MMA <210 nmol/L,
which, in combination, are considered to reflect an adequate vitamin B12 status170-172.
transported from the gastrointestinal tract to the liver by chylomicrons and subsequently
by other lipoproteins174,178.
1
In the liver, vitamin D is converted to 25(OH)D by 25-hydroxylase (CYP2R1), although other
organs can also perform this reaction. Compared with 25(OH)D, vitamin D is easily taken
up by various organs and excreted into e.g. breast milk, due its lower affinity to DBP.
25(OH)D has a higher binding affinity for DBP, which may explain its longer half-life of 3
weeks, compared with the 24 hours of the parent vitamin D. Uptake of the DBP-25(OH)D
complex is facilitated by megalin-cubulin-mediated endocytosis178. In the kidneys, but also
in other organs like the placenta and the brain, 25(OH)D may become converted to active
hormone 1,25-dihydroxyvitamin D [1,25(OH)2D] by 25(OH)D-1-α-hydroxylase (CYP27B1), as
shown in Figure 4.

Vitamin D

Vitamin D sources, metabolism and function

Cutaneous synthesis of parent vitamin D3 by exposure to UVB is widely regarded as
our principal source of vitamin D3. Vitamin D3 can also be obtained from animal foods,
especially fish, whereas vitamin D2 can be found in fungi and plants, but may also be
present in fish. However, the often-reported relatively low intake of vitamin D from fish
is somewhat artificial, because Western cultures do not exhibit the habit to consume
the vitamin D-rich fish liver (see Table 1). For instance, tuna liver may contain 32,500 µg
vitamin D/kg and the fatty meat 37 µg/kg, while mackerel liver may contain 2,400 µg/
kg and the fillet 155 µg/kg173. In view of these figures, it may be questioned whether
our (black) ancestors living in the land-water ecosystem found their principal vitamin D
source in cutaneous synthesis. This may be important since the pharmacokinetics, body
distribution, and therefore targets, of cutaneously-synthesized vitamin D are different from
dietary vitamin D174,175. In addition, no attention has until now been paid to the ingestion of
the 25-hydroxy metabolite of vitamin D [25(OH)D] from muscle meat, which functions as
a 25(OH)D store176,177. This pool may have been an important, and at least five times more Figure 4. the metabolic processes providing vitamin D and its metabolites to various tissues in the body.
Tissue distribution of vitamin D and 25(OH)D based on simple diffusion (red arrows) and endocytosis
efficient177, dietary vitamin D source of hunter-gatherers in the past.
(green arrows). Endocytosis requires the tissue-specific megalin-cubilin system, whereas simple diffu-
sion is primarly controlled by the dissociation constant of the vitamin D compound for the VDBP. Bolder
Following exposure of skin to UV-B from sunlight, pre-vitamin D3 is converted from red lines indicate greater diffusion rates due to higher dissociation constant, t½, half-life. Reprinted with
7-dehydrocholesterol to become thermally isomerized to vitamin D3. Once formed, vitamin permission from Springer Nature: Bone Research, New insights into the vitamin D requirements during
pregnancy. Hollis, B.W. Wagner, C.L. 2017179 This image is licensed under the Creative Commons Attribu-
D3 diffuses into the capillary beds to become transported by circulating vitamin D binding
tion 4.0, no changes were made. To view a copy of the Creative Commons license, please visit http://
protein (DBP) and to a lesser degree albumin. In contrast to cutaneously synthesized creativecommons.org/licenses/by/4.0/.
vitamin D3, dietary vitamin D3 and vitamin D2 [together referred to as ‘parent vitamin D’], are

30 31
Chapter 1
To preserve adequate vitamin D status after the migration from Africa to higher latitudes,
some adaptations took place. Skin depigmentation is likely an adaptation that enables
vitamin D synthesis at low UVB exposure180. In addition, mobilization of parent vitamin D
from adipose tissue181,182 and mobilization of 25(OH)D from muscle tissue176,183, might have
enabled populations at higher latitudes to preserve an adequate status during winters,
characterized by low UVB exposure and limited food sources.
The classical function of the vitamin D hormone lies in bone and calcium homeostasis,
that is: bone health and augmentation of calcium absorption. 1,25(OH)2D is, however,
also involved in the regulation of e.g. cell growth184,185. In addition, vitamin D is involved in
e.g. inflammation, mitochondrial protein expression186 and has an unproven anti-oxidant
effect187. It has been estimated that about 10% of the human genome is regulated directly
and/or indirectly by the vitamin D endocrine system188, involving more than 160 pathways
some of them linked to cancer, autoimmune disorders and cardiovascular disease189.
Developmental vitamin D deficiency has been shown to impact the expression of 36
proteins in the adult rat brain with functions in neurotransmission and synaptic plasticity
in neurons and astrocytes, and with oxidative phosphorylation, redox balance, calcium/ATP
homeostasis and organelle transport in mitochondria190. Vitamin D signalling may influence
brain development via its pro-differentiation and anti-apoptotic properties191 and may
also play a role in fetal programming192. Many areas of the brain, including the amygdala,
hippocampus, thalamus, cortex, and substantia nigra, express both vitamin D receptor
and 1α-hydroxylase. Neurons and microglia may use the synthesized active hormone to
regulate cell proliferation, differentiation, and survival193. Recently, developmental vitamin
D deficiency was shown to impact recognition memory in rats and that this effect is
independent of the applied time window of vitamin D deficiency194.
It was for long believed that 1,25(OH)2D was the only active metabolite, while parent
vitamin D and 25(OH)D were merely considered to be pro-hormones. Recently, Gibson et
al.195 showed that vitamin D and its metabolites are effective stabilizers of the endothelium
and can control ‘endothelial leak’. On an equal molar basis, parent vitamin D is more potent
than 25(OH)D and 1,25(OH)2D in this respect179,195.
Vitamin D in pregnancy and lactation
Low vitamin D status in pregnant women is associated with increased risk of uteroplacental
dysfunction196, bacterial vaginosis197, pre-eclampsia196, gestational diabetes197,198, intrauterine
growth restriction199, preterm delivery197,200, spontaneous pregnancy loss201 and higher
mother-to-child HIV transmission202. Vitamin D insufficiency during pregnancy is associated
with lower offspring birth weight and postnatal growth197,199, dental cavities203, lower
gross-motor development and fine-motor development at 30 months and lower social
32
General introduction: Brain-selective nutrients
development at 42 months, but not at older ages204, greater adiposity at 4 and 6 years205,
mildly- or moderately- severe language impairment at 5 and 10 years206, reduced lung
function and asthma at 6 years207, and lower peak bone mass at 20 years208. 1
Since the half-life of 25(OH)D is highest, plasma 25(OH)D is generally accepted as the best
vitamin D status parameter. Widely employed cut-off values are <25 nmol/L for vitamin
D deficiency, 25-50 nmol/L for vitamin D insufficiency and >50 nmol/L for vitamin D
sufficiency46. However, many vitamin D experts consider 25(OH)D levels between 50 and
75-80 nmol/L as hypovitaminosis D, and between 75-80 and 250 nmol/L as vitamin D
sufficiency209-211. During pregnancy, significant changes occur in vitamin D metabolism.
From 12 GW, maternal serum levels of 1,25(OH)2D are two- to threefold higher compared
to the non-pregnant state212. Also DBP increases during pregnancy as a response to the
increasing oestrogen concentrations213,214. In a cross-sectional study with unsupplemented
traditionally-living Tanzanian women with lifetime abundant sunlight exposure, we found
higher 25(OH)D in pregnancy, but similar concentrations at 3 days and 3 months PP, when
compared to non-pregnant counterparts215.
Postnatal vitamin D sources include stores, exposure to sunlight and breast milk or formula.
Breast milk contains both the parent vitamin D and 25(OH)D, which are usually summed
to the so-called antirachitic activity (ARA, in IU/L). Most breastfed infants in Western
societies receive supplemental vitamin D to reach an adequate vitamin D status. Infant
vitamin D deficiency is associated with low bone mass at 9 years216, autoimmune diseases
including diabetes mellitus type 1 and multiple sclerosis217, acute lower respiratory tract
infections218,219, autism and schizophrenia191 and asthma220,221.
Occurrence of (sub)clinical vitamin D deficiency in pregnancy and lactation, and
infants
Vitamin D deficiency and insufficiency are worldwide problems222. Among the vulnerable
groups are elderly people, persons with darker skin, subjects who cover their body and
often also avoid direct sunlight, pregnant and lactating women and their exclusively
breastfed infants222,223. Depending on definitions, it is estimated that the worldwide
prevalence of vitamin D deficiency and insufficiency during pregnancy ranges from 8
to 100%224. For instance, the Dutch ‘Generation R’ study reported vitamin D deficiency
(25(OH)D< 25 nmol/L) in 26%, and vitamin D insufficiency (25OHD ≥ 25 and <49.9 nmol/L)
in 27%, at 20 GW. Cord blood samples showed 46% deficiency and 34% insufficiency225.
Alarmingly, 50% of the non-European mothers in this study exhibited vitamin D deficiency
at midgestation, while 75% of their offspring was deficient at birth225.
33
Chapter 1
RDA/AI pregnant and lactating women and infants
The RDA for pregnant and lactating women is identical to that of non-pregnant adults up
to 70 years. They range from 10 μg/day (Health Council of the Netherlands226) to 15 μg/
day (IOM46). However, the median dietary vitamin D intake of 19-30 years Dutch women
is only 2.6 μg/day227. The Health Council of the Netherlands advices pregnant women
to take a 10 μg/day vitamin D supplement, starting preferably before conception30. The
current RDA of 10-15 μg/day might be insufficient to reach 50 nmol/L 25(OH)D in 97.5% of
the women at the pregnancy end. This can be concluded from two recent randomized
controlled trials (RCTs) conducted in pregnant women with median 25(OH)D levels of 55
nmol/L and 64-68 nmol/L at enrolment in the 2nd trimester in, respectively, New Zealand228
and Canada229. Still 7-12% of these women had 25(OH)D levels <50 nmol/L at 36 GW, after
supplementation with 25-50 μg vitamin D/day.
The IOM AI for vitamin D for 0-6-month-old infants amounts to 10 μg/day46. This AI is based
on some studies in Western countries showing that 10 μg/day maintains infant serum
25(OH)D at 40 to 50 nmol/L in the first postnatal year and thereby supports normal bone
accretion46. A 10 μg/day intake translates to a milk ARA of 513 IU/L at an average mature
milk consumption of 780 mL/day167. Breast milk ARA from Western mothers ranges from 8
to 331 IU/L230-232. It is unclear what vitamin D dose is needed to reach the IOM AI of 513 IU/L
in milk. The only successful study in reaching the IOM AI was published by Wagner et al.233.
They showed that supplementation of lactating women with 160 μg/day for 6 months
increased milk ARA to 873 IU/L at the study end. However, although perfectly safe, with
no adverse effects noted nor expected, a daily 160 μg/day vitamin D dose is well above
the current upper limit of 100 μg/day234. Finally, a strategy merely aimed at the postnatal
period provides no benefits for the mother and her developing child during pregnancy.
Aim of the vitamin D studies in this thesis
From an evolutionary point of view, it is puzzling why breast milk contains only low
amounts of vitamin D. We therefore investigated milk ARA from mothers with lifetime
abundant sunlight exposure. In Chapter 3.1 we investigated whether the milk ARA from
mothers with different cultural backgrounds, living at different latitudes, reaches the AI.
In Chapter 3.2 we investigated what dosages of vitamin D are needed to reach vitamin
D adequacy during pregnancy and lactation by supplementing pregnant Dutch women
with vitamin D (10, 35, 60 and 85 μg/day) from 20 GW up to 4 weeks postpartum (PP). We
furthermore investigated whether the corresponding milk ARA reaches the AI.
Since data on parent vitamin D during pregnancy and lactation are lacking, we developed
methods to measure parent vitamin D in plasma and adipose tissue, to gain a better
34
General introduction: Brain-selective nutrients
understanding of vitamin D metabolism during pregnancy and lactation. In Chapter 3.3
we describe the parent vitamin D concentrations in plasma and adipose tissue (AT) of
pregnant and non-pregnant women and infants in traditionally living people in Tanzania, 1
in relation to earlier published 25(OH)D data.
Essential fatty acids (EFA) and long chain polyunsaturated
fatty acids (LCP)
EFA sources, metabolism and functions
The omega-3 fatty acid alpha-linolenic acid (ALA) and omega-6 fatty acid linoleic acid (LA)
are essential fatty acids (EFA), meaning that they should derive from the diet. They cannot
be synthesized by the human body, and their deficiency causes disease. ALA and LA can be
converted to LCP with 20 and 22 carbon atoms, by alternating desaturating and elongating
enzymes that show preference in the order ω3FA> ω6FA> ω9FA235. The functionally of
the most important metabolites of these LCP derive from DHA (22:6ω3), EPA (20:5ω3) and
arachidonic acid (AA; 20:4ω6). Humans have limited capacity to synthesize EPA, DHA and
AA236, even during pregnancy and lactation. A strong argument is the, for long known,
postnatal decrease of infant LCP status, notably of DHA, following feeding with formula
that do not contain LCP. Thus, EPA, DHA and AA are considered ‘conditionally EFA’, but
some argue that these LCP should be regarded as the genuine EFA237. The exception is LA
that has a function of its own in the limitation of transepidermal water loss238.
Vegetable oils, nuts and seeds are rich sources of ALA and LA. Meat, eggs and poultry
are important sources of AA239, while fatty fish contain high levels of EPA and DHA. Lean
and tropical fishes are usually low in EPA240, but this often quoted misconception may, like
vitamin D, refer to the current habit to merely consume the muscle meat (see Table 1).
Fish muscle only contains high percentages EPA and DHA in ‘fatty fish’ that in contrast to
‘lean fish’ store triglycerides between cells, as opposed to the liver. The food chain of EPA
and DHA in fish starts with phytoplankton, where EPA can be found in the diatoms, and
DHA in the (dino)flagellates241.
Sixty percent of the brain is composed of fat, in which LCP, notably DHA and AA, are
abundant and play important roles in fetal and infant neurodevelopment242. In the
retina, 50% of the fatty acids in photoreceptor membranes consist of DHA, stressing
the importance of DHA for the human sight243. LCP are incorporated into membrane
phospholipids and are important for fluidity, flexibility, permeability and modulation of
membrane-bound proteins (lipid rafts)244,245. Furthermore DHA, EPA and AA, and their many
prostaglandin-like highly potent metabolites are involved in a variety of processes, via their
role in cell signalling and gene-expression by interaction with receptors in cell membranes
35
Chapter 1
and cell nuclei245. Active metabolites of DHA, EPA and AA are eicosanoids (consisting of
prostaglandins, thromboxane and leukotrienes), neuroprotectins, maresins and resolvins.
These lipid mediators have important functions in our inflammatory balance246,247, cell
growth, thermoregulation248, blood clotting and blood vessel diameter. LCP are among
others ligands for Peroxisome Proliferator-Activated Receptors (PPARs). PPARs have roles in
inflammatory reactions by decreasing cytokines, pro-inflammatory enzymes and oxidative
stress249 and, as integrators of inflammatory and metabolic signalling networks, they
modulate several biological processes that are disturbed in e.g. obesity250.
Essential fatty acid deficiency (EFAD) is a rare condition, occurring when the diet does not
provide sufficient quantities of ALA and LA. Isolated LA deficiency has not been noted in
humans. However due to a shift in dietary composition, poor ω3FA-status has become
widespread. The many Western countries the ω6FA/ω3FA ratio has changed from 1:1 to
10-20:1 and even higher in the past 200 years251. The ω3FA intake from Western diet is
generally low252-254, whereas the intake of LA has increased255,256, because of the notion
that polyunsaturated fatty acids are to replace saturated fatty acids to lower cardiovascular
disease risk. The current high LA status inhibits the conversion of ALA to EPA and DHA, due
to competition for the same desaturation and elongation enzymes257-260 and furthermore
interferes with the incorporation of EPA+DHA in membranes like those of red blood
cells261, and immune-competent cells262, altogether causing low EPA+DHA status. The
resulting high ω6FA/ω3FA ratio has been associated with among others higher incidence
of cardiovascular-, autoimmune and (neuro) psychiatric disease263-265. Decreasing the intake
of LA and increasing the intake of ALA is effective in improving ω3FA status266,267, but
supplementation of EPA+DHA remains most effective. A low fish oil fatty acid status is
associated with less optimal (brain) development, coronary heart disease (CAD), (neuro)
psychiatric diseases, pregnancy complications268, allergy269,270 and traumatic brain injury271.
However, RCTs with fish or fish oil in cardiovascular disease are inconclusive272-276. An RBC-
EPA+DHA content of 8 g% in adults confers the lowest CAD risk, lowest risks of sudden
cardiac death and non-fatal CAD events277, and the lowest risk of affective disorders265,
while it does not unfavourably affect the RBC-AA content278. An important target is the
whole blood AA/EPA ratio, showing lowest risk at 1.5-3.0. This target was unlikely to have
been reached in many, if not all, of the recent fish oil RCTs279,280, while also a fish is not some
elegant package for merely EPA and DHA, but also a rich source of other brain-selective
nutrients (see Table 1).
LCPω3 in pregnancy.
Low LCPω3-status during pregnancy is related to preterm delivery281, preeclampsia282,
gestational diabetes282 and the development of postpartum depression283,284. Hibbeln et
36
General introduction: Brain-selective nutrients
al. showed that a milk DHA reaching 1 g% is associated to the lowest risk of postpartum
depression285.
1
During pregnancy and lactation, DHA fulfils important roles in infant neurogenesis and
synaptogenesis286,287. The highest brain growth rate occurs from the 3rd trimester until the
age of 2 years, implying a high DHA requirement during lactation at least288. A daily intake
of 1 g DHA+EPA from seafood during pregnancy associates with the lowest risk of low
verbal IQ of the offspring at 8 years289. Maternal DHA-supplementation studies showed
improvements of sustained attention in their 4,6 and 9 months old infants290, improved
performance of problem-solving tasks in 9 months old infants291 and improvements of
hand- and eye- coordination in 2.5 years old children292. Meta-analyses of RCTs with fish
oil during pregnancy and lactation are, however, inconclusive293,294. Maternal fish intake
during pregnancy correlates negatively with allergic outcomes in infants/children295, but
RCTs with fish oil do not show clear benefits296.
Although endogenous LCP production does occur, the fetus and infant are dependent
on maternal supply. Maternal adipose tissue LCP stores are mobilized for placental transfer
or transferred to the breasts; DHA is preferentially transported compared to other fatty
acids, including AA and EPA235. The total lipid concentration in the maternal circulation
increases during pregnancy297. As circulating fetal fat concentrations are much lower,
placental transfer requires transport against a gradient. Although absolute concentrations
of DHA and AA are higher in circulating lipids of the mother, relative DHA and AA
contents are consistently higher in the fetus/infant298. Maternal-to-infant LCP-transport
during pregnancy and lactation is at the expense of maternal status, causing higher
percentages in the infant, named ‘biomagnification’299. However, at high maternal LCPw3
status (RBC DHA+EPA around 8 g%) we showed that this ‘biomagnification’ turns into
‘bioattenuation’’300.
Occurrence of low LCPw3 status in pregnancy, lactation and in infants
The global LCPω3 status of Western adults has been estimated to be ‘very-low’ (RBC-
DHA+EPA ≤ 4 g%) to ‘low’ (RBC-DHA+EPA 4-6 g%), with considerable variation301. The
global dietary intake of seafood-derived LCPω3, estimated at 163 mg/day, exhibits a large
variations at both national and regional scales, but shows that almost 80% of the global
population does not comply to the recommended seafood LCPω3 intake of 250 mg/
day302. Due to mobilization and loss of LCPω3 during pregnancy and lactation, LCPω3
status may expected to be even lower in pregnant and lactating women and seems to
decrease with increasing number of pregnancies. Intervention studies with LCPω3 found
baseline RBC-DHA between 4.3-4.6 g% in pregnant women from Western countries (van
Goor unpublished,303,304). Breast milk DHA contents vary worldwide from 0.13 to 0.37 g%
37
Chapter 1 General introduction: Brain-selective nutrients

in the Netherlands305 to 0.73 g% (Chole, Tanzania)306, 0.96 g% (Ukerewe, Tanzania)307, up to
1.4 g% (Inuit, Canada)308.
RDA/AI pregnant and lactating women and infants
The current Dutch advice for adults is to achieve a minimum average daily intake of 200
mg EPA+DHA, which translates to one portion of (oily) fish per week309. A recent study
showed that, in the preconception period, women with EPA+DHA intakes below this
recommendation had lower plasma phospholipid EPA+DHA contents than women
meeting the recommendations253. The Global Organization for EPA and DHA Omega
3s (GOED) recommends an intake of 700 mg DHA+EPA/day for pregnant and lactating
women147. From their dose-response study, Flock et al.310 concluded that adults with low
RBC DHA+EPA contents of about 4.3 g% need 1 g DHA+EPA/day for 5 months to reach
an RBC DHA+EPA of 8 g%.
Postnatal LCP sources include stores, endogenous synthesis and breast milk or formula,
of which breast milk is the main contributor to the infant-RBC DHA content311. The IOM
did not define an AI for EPA and DHA for 0-6-month-old infants47. The current view is that
during the first months of life, term infants should receive 100 mg DHA/day and 140 mg
AA/day312. Infant formulae should provide at least 0.3 g% DHA312, but there is currently no
consensus on the DHA and AA contents or DHA/AA ratios of infant formulae. As current
recommendations are based on human milk LCPω3 contents in Western countries with
low LCPω3 intakes, whereas we evolved on higher LCPω3 intakes from the land-water
ecosystem, it is plausible that these recommendations are inadequate.
RBC DHA+EPA of 8 % at 36 GW and a breast milk DHA+EPA content of 1 g% at 4 weeks
postpartum in pregnant Dutch women.
1
Elements
Elements can be divided into essential minerals, essential (trace) elements, and heavy
metals, the latter considered toxic. Calcium (Ca), chloride, phosphorus (P), potassium (K),
sodium (Na) and magnesium (Mg) are the essential minerals. The essential (trace) elements
are iron (Fe), copper (Cu), zinc (Zn), selenium (Se), iodine (I), cobalt and molybdenum (Mo).
Probably essential elements are: manganese (Ma), silicon, nickel, boron, vanadium and tin.
Chromium is the most controversial transition element; recent studies of 2017 found that
chromium is not essential313. Heavy metals like arsenic (As), cadmium (Cd), bromide (Br),
lead and mercury receive special attention in public health, since these may cause multi
organ damage, even at lower exposure levels314. When ingested at high levels and for a
long time, essential elements may also become toxic.
In Table 3 we present sources and function of the investigated elements. In the next
paragraphs we will focus on the minerals potassium, calcium, sodium, phosphorus, sulphur
(S) and magnesium; on the essential trace elements iron, copper, zinc, iodine, selenium,
manganese and molybdenum; and on the toxic elements bromine, cadmium and arsenic.

Previous cross-sectional studies in Africa by ourselves showed that pregnant women with
RBC-EPA+DHA contents of about 8 g% at delivery give birth to infants with RBC-EPA+DHA
contents of 7 g% at delivery. At lower maternal RBC-EPA+DHA contents, intrauterine
biomagnification occurs, which we interpreted as a sign of low, depleting, maternal status.
At higher status, bio-attenuation occurs, likely to prevent too much fetal DHA. Genuinely
intense DHA biomagnification occurs during lactation. At 3 days and 3 months postpartum
a maternal RBC-EPA+DHA of 8 g% corresponds with milk EPA+DHA of 1 g% and an infant
RBC-EPA+DHA of 8 g%300,307. Therefore, and aiming at lowest risk in adults of cardiovascular
disease277 and depression265, and optimal balance between DHA and AA status278, we
suggest a target of 8 g% maternal RBC EPA+DHA at the pregnancy end, which likely
corresponds with 1 g% EPA+DHA in mature breast milk.

Aim of the LCP studies in this thesis

In Chapter 4 we describe what supplemental dosages of DHA+EPA (225+90, 450+180,
675+270 and 900+360 mg) from 20 GW up to 4 weeks PP were needed to reach a maternal

38 39
 Chapter 1 General introduction: Brain-selective nutrients

Element sources and function

Electrolyte involved in maintenance of extracellular fluid volume, neural transmission, muscle contraction,
Electrolyte involved in maintenance of intracellular fluid volume; neural transmission; muscle contraction;

Cofactor for enzymatic reactions; homeostasis of K, Ca and Na; regulation of blood pressure; bone health

Brain development; thyroid hormone metabolism and many extra-thyroidal functions e.g. as antioxidant

Brain development; component of enzymes: glutathione peroxidase and thyroid hormone metabolism
Minerals: potassium, calcium, sodium, phosphorus, sulphur and magnesium 1
Important sources of potassium, calcium, phosphorus, sulphur and magnesium are

Brain development; catalytic, structural and regulatory functions; growth and development
Bone health; essential component of nucleic acids, phospholipids, high-energy phosphates
vegetables (potassium, calcium and magnesium), fruits (potassium), meat (potassium,
phosphorus, sulphur and magnesium), fish (potassium, phosphorus and sulphur), nuts
(potassium, calcium, sulphur and magnesium), dairy (potassium, calcium, phosphorus
and magnesium) and grain products (potassium, phosphorus and magnesium) (Table

Component of sulfite oxidase enzyme: degradation of sulphur amino acids

3)142,315-317. Potassium, magnesium and phosphate in living organisms are the predominantly
Bone health; muscle contraction; neural transmission; blood coagulation

Meat, shellfish, grain products, nuts, legumes, and Brain development; binding site for oxygen; structural and catalytic role
intracellular elements, while sodium, calcium and chloride are predominantly located in
the extracellular space. Evolution may have chosen for magnesium as counter ion for

Co-factor for enzymes in energy metabolism; bone metabolism

intracellular phosphate, and for calcium as universal intracellular signal transducer because
Brain development; cofactor for several metallo-enzymes of the 1,000 times faster binding reaction of calcium with phosphate, compared with
Molecular basis for amino acids, vitamins and enzymes

magnesium318. Because of the uneven distribution between the intra- and extracellular
compartments, natural whole foods of humans (fruits, vegetables, fish, meat, grains)
are rich in potassium and magnesium and do not contain high amounts of sodium (as
sodium chloride). Apart from a natural source (12%), our sodium intake comes mostly
from its addition by the food industry (77%), during cooking (5%) or as table salt (6%)142,315-
Principal function in the body

vascular tone; kidney function

vascular tone, kidney function

317
. Potassium is important for maintaining intracellular fluid volume, acid-base-balance,
normal functioning of the cell and transmembrane electrochemical gradients. Since
and anti-microbial agent

sodium is the main regulator of extracellular fluid volume, including plasma volume,
potassium and sodium exhibit a strong relationship. Intracellular potassium is about 30
Potentially toxic

Potentially toxic
Potentially toxic
Table 3: Nutritional sources and principal functions of elements7,142,315-317

times higher than its extracellular concentration, and together with extracellular sodium,
this difference creates a transmembrane electrochemical gradient that is maintained by
the sodium-potassium (Na+/K+)-ATPase transporter. About 20% of our basal energy is
consumed by this Na+-K+-ATPase and our brain and kidneys invest 50-70% of their energy
Grain products, vegetables, nuts, dairy and meat

Shellfish, vegetables, fruits, meat, grain products

Grain products, nuts, legumes, vegetables and

expenditure in this process. The K/Na intra/extra cellular distribution is notably required for
Grain products, vegetables, nuts, pulses, meat
Vegetables, fruits, meat, fish, nuts, dairy, grain

nerve transmission, muscle contraction and kidney function. As mentioned above, sodium
Dairy, fish, meat, legumes, grain products

Grain products, dairy and drinking water

Commonly found in nature: fresh water

is the main regulator of extracellular fluid volume in the body, and consequently it is also
Meat, fish, vegetables, grain products
Meat, grain products, nuts, shellfish

important for the regulation of blood pressure and plays a key role in normal nerve and
Grain products, nuts, legumes

muscle function. High intracellular sodium stimulates the influx of calcium142,315-317.

Fish, eggs, dairy, seaweed
Artificially added to food
Dairy, vegetables, nuts

Fish, meat, dairy, nuts

The best-known function of calcium is in bone metabolism, where it is important for

Element Nutritional source

homeostasis and bone formation. Bone (ileac crest) contains per dry weight: 16.90 g%
calcium, 7.96 g% phosphate, 0.496 g% sodium, 0.183 g% potassium and 0.149 g% chloride319.
vegetables

and cacao
products

Calcium, as signal transducer, is required for vascular contraction and vasodilation, muscle
fruits

function, nerve transmission, intracellular signalling and hormone secretion142,315-317.

Phosphorus is a ubiquitous mineral and has important and diverse functions in the
human, as it is a structural component of bone and teeth and an essential component
Mg

Mn

Mo
Na

Cd
Cu
Zn
Ca

As
Se
Fe
Br
K

P
S

40 41
Chapter 1
of nucleic acids and phospholipids. Among others, phosphorus is involved in the critical
pathway that produce and store energy as high-energy phosphates320 such as ATP and
creatine phosphate. Phosphate is also a major component of our genetic material: DNA
and RNA. Sulphur is at the molecular basis of some amino acids, vitamins and enzymes.
Magnesium is involved as a cofactor in hundreds of enzymatic reactions in the body, with
functions in e.g. energy metabolism, protein and amino acid syntheses. It is the counter-ion
of the aforementioned energy rich phosphates in ATP and creatine phosphate, but also
of the phosphate in DNA/RNA. Because of its association with ATP, all energy producing
and consuming reactions with ATP are dependent on magnesium. Furthermore, it has
a stabilizing and protective function for the cell membrane. Since it is also involved in
the homeostasis of calcium, phosphorus and sodium, magnesium has a function in the
regulation of blood pressure142,315-317 and in bone health321.
Essential elements: zinc, copper and iron
Among the richest sources of zinc, iron and copper are shellfish (all), meat (all three), grain
products (all), nuts (all), vegetables (iron and copper), legumes (iron) and cacao (copper)
(Table 3). Dietary iron exists as haem and non-haem iron. Animal products contain both
iron forms, whereas plant-based products only contain non-haem iron322.
The roles of zinc can be divided into catalytic, structural and regulatory functions. It is
an integral component in over 300 zinc metallo-enzymes, which find their function
in metabolism of carbohydrates, fat and protein, and the clearance of reactive oxygen
species. Most well-known operational in the latter function is the copper and zinc
containing superoxide dismutase (SOD). Furthermore, zinc has a structural role in proteins
(e.g. zinc fingers), cell membranes, nucleic acids and ribosomes and it is involved in gene
transcription, cell signalling, hormone release and apoptosis323. Zinc has therefore an
important role in growth, brain development, tissue maintenance and wound healing324,325.
Copper is a cofactor for several metallo-enzymes that are involved in energy production,
iron metabolism, activation of neuropeptides, and the synthesis of connective tissue
and neurotransmitters. It is thereby involved in many processes such as angiogenesis,
homeostasis of neurohormones, gene expression, brain development, immune function
and clearance of reactive oxygen species (e.g. afore mentioned SOD)322.
Iron is an essential component of haemoglobin (Hb) and myoglobin. Haem-iron functions
as the binding site of oxygen and its transport from lungs to tissues. It thereby supports
e.g. muscle contraction and brain functioning because of the need of oxygen in electron
transport/oxidative phosphorylation322. Likewise, iron is essential for physical growth, brain
42
General introduction: Brain-selective nutrients
development through neural and glial energy metabolism, neurotransmitter metabolism
and myelination322,326.
1
Essential elements: iodine and selenium
Seaweed, fish, eggs and dairy are rich natural sources of iodine (Table 3). At present, about
60% of our iodine intake does not derive from a natural source327, but from iodized salt
in bread, and iodized salt added during cooking and at the table. In 2008 the maximally
permitted iodine content of bakery salt in The Netherlands was reduced from 70-85 to
50-65 mg/kg, while it was simultaneously allowed to add iodized salt to almost all foods328.
Since then the Dutch iodine intake has decreased with 20-25%327. The biogeochemical
cycle of iodine329,330 explains why iodine accumulates in the sea. Like EPA and DHA, our
current low intake of iodine, because of the low consumption of fish, seaweed and shellfish,
clearly illustrates our abandonment of the land-water ecosystem.
Selenium is mostly found in meat, fish, vegetables and grain product (Table 3). Selenium
exists in two forms: inorganic (selenite and selenite) and organic (selenomethionine and
selenocysteine). Selenium is an abundant element in the earth’s crust. Erosion of rocks is
considered a main source of selenium deposition in soil331. The global selenium levels of
the soil exhibit a patchy picture with some locations producing selenium deficiency and
others toxicity through the consumption of locally grown vegetables and fruits and raised
cattle, such as in China332.
Iodine and selenium are important brain-selective nutrients. Iodine is indispensable for the
synthesis of thyroid hormone (T3). Thyroid hormone is of utmost importance for both the
developing and developed brain. The function of iodide as an ancient antioxidant (2I- →
I2 + 2e) is as yet poorly appreciated333-336. This function is fully operational in e.g. seaweed
and because of the evolutionary unity of life, iodide’s function as antioxidant is likely to be
operational in us as well. Among the common halides, iodine is the least electronegative,
which explains the property of iodine to act as an electron donor. It is universally known
that iodine is important in thyroid hormone synthesis, but it may be of equal importance
to understand the widespread anti-microbial function of iodine in (exocrine) gland
epithelial cells residing in e.g. the salivary glands, gastric mucosa, breasts, intestine and
prostate. Like the thyroid endocrine gland, those cells accumulate iodide via the high
affinity sodium/iodide symporter (NIS) located at their basolateral side337-339. This iodide
is subsequently secreted at the apical side and together with locally synthesized H2O2
oxidized to hypoiodite (IO-). Hypoiodite is an unstable potent oxidant with powerful anti-
microbial, antiviral and antifungal properties336. Derangement of this potentially harmful
system with numerous reactive oxygen species may be at the basis of the relation between
autoimmune thyroiditis and cancers of the stomach, breast, prostate and others336,340.
43
Chapter 1
Dysbalances between iodine and selenium may underlie this derangement, since selenium
is a cofactor of the selenoenzymes involved in the detoxification of redundant reactive
oxygen species. Interestingly, the choroid plexus, where cerebrospinal fluid is produced,
also accumulates iodide, which may be another link of iodine with brain health.
As mentioned above, the physiological roles of selenium is via several selenium-containing
proteins (selenoproteins) of which mainly serve oxidoreductase functions. Although the
identity and function of several selenoproteins is as yet unknown341, selenoproteins play
critical roles in reproduction, thyroid hormone metabolism, DNA synthesis and protection
from oxidative damage and infection342.
Essential elements: manganese and molybdenum
Important sources for manganese and molybdenum are grain products, nuts and
legumes142,315-317. Manganese is a cofactor for many enzymes, including those with functions
in amino acid-, cholesterol-, and glucose- and carbohydrate- metabolism343. Furthermore
manganese plays a role as co-factor in the formation of bone cartilage, bone collagen and
in bone mineralization344. Molybdenum in combination with molybdopterin, is a cofactor
required for the function of four enzymes: sulphite oxidase, xanthine oxidase, aldehyde
oxidase and mitochondrial amidoxime reducing component. These enzymes metabolize
sulphur containing amino acids and are also involved in metabolizing drugs and toxins345.
Elements in pregnancy and lactation.
Minerals: potassium, calcium, phosphorus, sulphur, sodium and magnesium
Potassium deficiency, presenting as hypokalaemia, resulting from insufficient dietary
intake is rare. Hypokalaemia leads to intracellular potassium shortage and the replacement
by sodium to maintain electro-neutrality, osmotic pressure and cell volume346. Sodium
deficiency is uncommon in the Western world347. Likewise, in the general population,
calcium deficiency during pregnancy and lactation is rare348. Decreasing circulating calcium
is widely known to cause mobilization of calcium from bone, but that may also occur
for decreasing circulating sodium349,350. Adequate calcium intake during pregnancy may
be important in the prevention of pre-eclampsia351. During pregnancy the placenta and
later the mammary gland produce parathyroid-hormone related peptide (PTHrP). PTHrP is
involved in the mobilisation of calcium from the skeleton and thereby maintains calcium
levels despite increased transfer to the fetus or to the breast milk.348. Phosphorus deficiency
is rare320 and detailed information on sulphur deficiency is lacking352-354. Magnesium
deficiency during pregnancy has been associated to pre-eclampsia355, and magnesium
sulphate infusion is used as a treatment. Animal studies have shown associations of
maternal magnesium deficiency with altered maternal and fetal fatty acid metabolism,
44
General introduction: Brain-selective nutrients
fetal growth, fetal survival356 and behavioural deficits of the offspring at adult age357. After
birth, magnesium shortage may lead to the sudden infant death syndrome358.
1
Essential elements: zinc, copper and iron
Severe zinc deficiency is rare. Mild-to-moderate zinc deficiency has been estimated to
effect 4-73% of the world’s population359. Zinc deficiency is related to inadequate intake
or absorption of zinc from the diet. People with gastrointestinal- or related diseases,
vegetarians, elderly people, pregnant- and lactating women and exclusively breastfed
infants over 7 months are at risk. Due to the large number of processes in which zinc is
involved, the consequences of zinc deficiency are diverse323. Worldwide zinc deficiency
is predicted to be responsible for 1% of all deaths and 4.4% of deaths of infants and
children aged 6 months to 5 years325. Although associations have been found between
maternal zinc status and pregnancy complications including pregnancy hypertension,
gestational diabetes, preterm birth, and infant birth weight, more confirmative studies are
needed325. Copper deficiency in humans is also rare360. There have been some associations
between low copper status and pathological pregnancies and miscarriages, whereas high
copper levels are associated with better fertility and embryo differentiation, but also with
preeclampsia and abortions326.
The first stage of iron deficiency is depletion of iron stores, followed by iron-deficiency
erythropoiesis and ultimately iron deficiency anaemia322. The worldwide prevalence of
anaemia is high361,362 and it is suggested that iron deficiency is the cause in about 50%
of such cases363. Populations at risk of iron deficiency are: pregnant women, infants and
children, women with heavy menstrual bleeding, frequent blood donors, people with
cancer, gastrointestinal disorders/surgery or with heart failure322. Analysis of 1999-2006 data
from the US NHANES study found that 6.9%, 14.3% and 29.7% of pregnant women in their
1st, 2nd and 3rd trimester, respectively, were iron deficient364. Iron deficiency anaemia during
pregnancy has been associated with low birth weight, premature birth, low maternal
and fetal/infant iron stores, impaired infant cognitive and behavioural developments and
higher lead concentrations, which may increase the risk of neurotoxicity365,366. RCTs with
iron supplements in women found a lower risk of anaemia at term, higher Hb levels during
lactation, more frequent occurrence of high Hb during pregnancy, lower risk of low birth
weight infants, and lower risk of preterm delivery than in the un-supplemented or placebo
groups. Positive effects of iron supplementation on other maternal and infant outcomes
are less clear367,368.
Essential elements: iodine and selenium
Iodine deficiency is no longer ‘just a third world issue’. It is currently the world’s most
prevalent, yet easily preventable, cause of (developmental) brain damage369. Developmental
45
Chapter 1
iodine deficiency may interact with selenium deficiency and sufficiency to cause
myxoedematous cretinism and neurological cretinism, respectively370. Several European
countries exhibit a high prevalence of mild iodine deficiency as shown in Figure 5.
Figure 5: Iodine nutrition during pregnancy in the countries of the WHO European Region and Kosovo,
based on urinary iodine excretion (μg/L). This figure was published in Lancet Diabetes and Endocrinology,
3(9), Zimmermann M.B., Gizak, M., Abbott, K., Anderson, M., Lazarus, J.H., Iodine deficiency in pregnant
women in Europe, 672-674, Copyright Elsevier (2015)371.
Mild iodine deficiency during pregnancy may cause maternal (subclinical) hypo-
thyroxinaemia and elevated thyroid-stimulating hormone (TSH) in the fetus, which
relates to mild and subclinical cognitive and psychomotor deficits in neonates, infants
and children372. For instance, 8 years old children of women with first trimester urinary
iodine-to-creatinine ratios of less than 150 μg/g were more likely to have scores in the
lowest quartile of verbal IQ, reading accuracy and reading comprehension, compared
with counterparts of mothers with ratios of 150 μg/g or higher373.
Selenium deficiency has been associated with heart disease, neuromuscular disorders,
cancer, male infertility and inflammation341. Selenium-containing proteins, especially
glutathione peroxidases, play important roles in the destruction of endogenous reactive
oxygen species. Accordingly, during pregnancy, insufficient status may contribute to
preterm birth, miscarriage, intrauterine growth retardation and other conditions that
are related to increased oxidative stress374. The role of selenium in brain development is
related to that of iodine (see above), since selenium is a cofactor in three enzymes involved
in thyroid hormone metabolism375. The serious effects of mutations in selenocysteine
synthase to brain development may be a clear indication of the central role of selenium in
the protection from neurodegeneration376. The maternal selenium status in the 1st trimester
46
General introduction: Brain-selective nutrients
of pregnancy shows positive relationships with motor development and language and
cognitive developments at 1 and 2 years of age377. In addition, lower scores on total-,
problem solving-, personal social- and fine motor- functioning are observed in infants 1
born to mothers with selenium levels ≤0.9 μmol/L in the 2nd trimester of pregnancy, when
compared to mothers with higher selenium levels378. Selenium may be important in female
fertility and pregnancy induced hypertensive disorders379.
Essential elements: manganese and molybdenum
Manganese and molybdenum deficiency are rare345,380-382. Deficiency of manganese results
in impaired growth, poor bone formation and skeletal defects, and abnormal metabolism
of macronutrients. Furthermore insufficient manganese concentrations are associated with
negative effects on reproductive health and development381. A rare metabolic disorder,
known as ‘molybdenum cofactor deficiency’ prevents the biosynthesis of molybdopterin.
This metabolic disorder causes impairments in the functioning of enzymes that metabolize
sulphite, leading to encephalopathy and seizures, and death within days after birth345,382.
AI/RDA during pregnancy and lactation
During pregnancy potassium and magnesium requirements are higher to maintain
maternal status and meanwhile provide the fetus with adequate amounts. During lactation
the required intakes of these elements were comparable to non-pregnant intakes (Table
2). The IOM-RDAs for potassium and magnesium increase from 2,600 and 320 mg/day to
2,900 and 350-360 mg/day, respectively, during pregnancy and then decrease to 2,800
and 310-320 mg/day in lactation. The IOM-AIs for 0-6-month-old infants are based on
median breast milk concentrations of apparently healthy lactating women. For potassium
and magnesium these are 13.1 and 1.6 mmol/L (400 and 30 mg/day), respectively. For
calcium, phosphorus and sodium there is no evidence that higher intakes are needed
during pregnancy and lactation (Table 2) and the RDAs are 1,000, 1,500 and 700 mg/day
respectively. The IOM-AIs for 0-6-month-old infants for calcium, sodium and phosphorus
translate to 6.4, 6.7 and 4.1 mmol/L, respectively (200, 110 and 100 mg/day).
The iron IOM-RDAs for pregnant and lactating women amount to 27 and 9 mg/day,
respectively. As previously mentioned, mother-to-child iron transport in pregnancy
is preferred over lactation, resulting in the building of adequate infant stores during
pregnancy. Breast milk iron is low; the IOM-AI for 0-6-month-old infants is 6.3 μmol/L
(0.27 mg/day).
For zinc, copper, iodine, selenium and manganese, the required intakes increase during
pregnancy and are even higher during lactation (Table 2). Fetal zinc accretion occurs from
the 24th week of gestation. Zinc storage takes place in the fetal liver. Placental zinc transfer
47
Chapter 1
is an active process and circulating fetal zinc concentrations are consistently higher than
maternal levels383. The same is true for zinc transport during lactation, where breast milk
zinc concentrations remain higher than those in maternal plasma for at least the first 4 to
6 months384,385. The RDAs of the IOM for pregnant and lactating women amount to 11 and
12 mg/day, respectively. The zinc IOM-AI for 0-6-month-old infants is 39.2 μmol/L (2 mg/
day). Copper and zinc are stored in the fetal liver386,387. The RDAs of the IOM for copper for
pregnant and lactating women amount to 1,000 and 1,300 μg/day, respectively. About
30% of assimilated copper bypasses the liver and is absorbed in the mammary gland
during lactation388. The copper IOM-AI for 0-6 month-old infants is 4.0 μmol/L (200 μg/day).
During the first trimester of pregnancy, the fetus is not able to use iodine to synthesize
thyroid hormone and therefore depends on maternal thyroid hormone supply. Via
placental uptake by the NIS, the fetus will accumulate iodine in the first trimester,
most likely to prevent iodine deficiency and to contribute to redox homeostasis via its
antioxidant properties. From the second trimester, the fetus uses transported iodine to
synthesize thyroid hormone. During lactation, iodine becomes actively concentrated into
the lactating breast, via uptake by NIS, causing 20-50 times higher concentrations in human
milk compared with plasma155. The RDAs of the IOM for pregnant and lactating women
amount to 220 and 290 μg/day, respectively, while the iodine AIs for 0-6-month-old infants
are 1.1 μmol/L (110 μg; IOM-AI) and 0.5 μmol/L (50 μg; Nordic-AI). Selenium requirements
are elevated during pregnancy due to the increased fetal needs142. In regions with low
dietary selenium intake, maternal selenium status decreases during pregnancy, whereas
this is not the case in regions with adequate dietary selenium intake389. During lactation
maternal selenium status is lower or similar to non-pregnant controls and correlates with
breast milk concentrations378. The selenium RDAs of the IOM for pregnant and lactating
women amount to 60 and 70 μg/day, respectively. The selenium IOM-AI for 0-6-month-old
infants has been established at 0.24 μmol/L (15 μg/day).
For manganese the RDAs for pregnant and lactating women amount to 2.0 and 2.6 μg/
day, respectively whereas for molybdenum the RDA increases from 43-45 μg/day for
non-pregnant women to 50 μg/day during pregnancy and lactation. The IOM-AIs for 0-6
months infants for manganese and molybdenum are established at 0.07 and 0.03 μmol/L
(0.03 and 2 μg/day), respectively.
Toxic elements during pregnancy and lactation
The developing brain is also susceptible to toxic elements such as bromine, cadmium
and arsenic. Maternal exposure to these toxic elements may occur through the diet,
air, drinking water or (passive) smoking390. Bromine exposure can occur by drinking
contaminated water, eating contaminated food and breathing bromine gas in the air391.
48
General introduction: Brain-selective nutrients
Tobacco smoke, inhalation by workers in the non-ferrous metal industry and consumption
of contaminated food, notably organ-meat and shellfish, are the main cadmium sources of
humans392. Drinking-water containing naturally high levels of arsenic and consequently the 1
food prepared and irrigated with this water, are the main sources of arsenic exposure393.
High bromine exposure can lead to respiratory problems and low blood pressure, which
can in its turn cause kidney or brain damage391. High cadmium exposure has negative
effects on the kidneys, skeleton and respiratory system, while cadmium is also classified
as a human carcinogen392. High (long term) arsenic exposure leads to arsenic poisoning.
Acute arsenic poisoning symptoms are of gastrointestinal nature and can even cause
death in extreme cases. Long-term exposure to arsenic can cause skin lesions, peripheral
neuropathy, gastrointestinal symptoms, conjunctivitis, enlarged liver, bone marrow
depression, erythrocyte destruction, metabolic syndrome and cancer393.
There are no IOM-ULs available for bromine, cadmium and arsenic. The WHO has set
drinking water guideline values (DWGV). For bromine the WHO-DWGV was set at an
acceptable daily intake of 0.4 mg/kg body weight. For cadmium the provisional tolerable
monthly intake is 25 µg/kg and for arsenic the DWGV was set at 10 µg/L394. The United
States Environmental Protection Agency (EPA) has set the reference dose for toxic elements
in drinking water at 0.0003 and 0.0005 mg/kg/day for arsenic and cadmium, respectively395.
Although it seems that the placenta can act as a barrier for fetal arsenic and cadmium
exposures396,397, toxic elements do cross the placenta398. Not only can these elements
accumulate in the placenta and cause damage; there is also increasing evidence that they are
involved in epigenetic alterations, which could lead to cognitive and neurodevelopmental
risk in later life398. During pregnancy, maternal exposure to bromine is associated to still
birth defects399, low birth weight and preterm delivery400,401. Maternal exposure during
pregnancy to arsenic has been associated with gestational diabetes risk402, spontaneous
abortion403,404, stillbirth403,404, sexually dimorphic birth outcomes402 and increased infant
infections405. Both arsenic and cadmium associate with low birth weight403,404,406, congenital
heart defects in infants407, and disturbed neurodevelopment408,409. Also the mammary
gland has a protective function to some degree, since breastfed infants have lower arsenic
exposure than formula fed infants410,411. Cadmium is presumably actively transported into
the mammary gland by iron and manganese transporters412. Childhood exposure to arsenic
has been associated with decreased IQ413.
Element interaction
As shown above, many elements do not operate in isolation but exhibit interaction, e.g.
by competition414. Examples are potassium and sodium415,416, calcium and magnesium417,418,
copper and zinc419,420, and iodine and bromine421,422. They may also exhibit synergy e.g.
49
Chapter 1 General introduction: Brain-selective nutrients

calcium, phosphorus and magnesium in bone health, and iodine and selenium in thyroid the brain; they are used elsewhere in the body as well. If the requirement for any one of
function and extra-thyroidal processes336,338,423. Many interactions are described in plants the brain selective nutrients is not met at the correct stage of development, permanent
and animals but relatively little is known on interaction in humans424. retardation results’. In view of the fact that all nutrients are important to brain development, 1
brain selective nutrients have been defined by Georgieff375 as ‘nutrients with particularly
Aim of the element studies in this thesis large effect on developing brain circuits during the last trimester and early neonatal period
The introduction of ‘inductively coupled plasma-mass spectrometry’ (ICP-MS) provided and of whom the importance has been established primarily through nutrient deficit
the possibility to simultaneously measure low concentrations of many elements at studies and through knowledge of their role in the specific biochemical pathways that
high accuracy. Only few studies examined a broad range of milk elements using ICP- underlie neuronal and glial growth and function’.
MS. To provide updated information on element concentrations and their variations, we
determined 16 elements by ICP-MS in breast milk samples from mothers living in the Table 4: Brain-selective nutrients and their function in brain development7,114,151,157-159,179,235,289-291,375,378,425-430
Netherlands, Curaçao, Vietnam, Malaysia and Tanzania. The current IOM-AIs for 0-6-month- Brain-selective Important in brain for: Deficiency increases risk of:
old infants are based on the average breast milk compositions. Most of these studies nutrient
derive from small subject numbers and date from 1976-1998. In Chapter 5.1, we describe, Vitamin B12 Myelin formation Neural tube defects
Neurotropic and neurotoxic cytokines Microcephaly
the comparison of our results with the outcomes of other studies using ICP-MS. We
Neurological symptoms:
also compared the outcomes with the IOM-AIs, and the available WHO Drinking Water • Irritability
Guideline Values (WHO-DWGV) and the guidelines of the United States Environmental • Failure to thrive

Protection Agency (US-EPA). Furthermore, in an attempt to find regulation of element • Apathy

• Hypotonia
interactions by the lactating gland, we calculated ratios of some milk elements and also • Developmental delay
relative percentages of the four quantitatively major milk elements (Na, K, Ca and Mg). Since Vitamin D As neurosteroid modulates multiple brain functions: Altered brain structure (animal studies)
no upper limits for 0-6-month-old infants have been established for the toxic elements, • Neurotransmission;
• Neuroprotection;
we used the WHO-DWGV to compare the outcomes of bromine and cadmium, and the
• Immunomodulation
Reference Dose as set by the United States Environmental Protection Agency (EPA) for EPA+DHA As a structural constituent of membranes specifically in the Impaired neurodevelopment
cadmium and arsenic. CNS on
• Neuronal growth and differentiation;
• Neuronal signaling
As mentioned above, in 2008 the maximally permitted iodine content of bakery salt in
Vitamin A Potential signaling molecule in the brains (animal studies) Night blindness
The Netherlands was reduced from 70-85 to 50-65 mg/kg salt, while it was simultaneously (RAE)375,428 • Regulates numerous gene products
allowed to add iodized salt to almost all foods328. Since then the Dutch iodine intake has • Modulates neurogenesis

decreased with 20-25%327, but there is no information on the current iodine status of • Neuronal survival
• Synaptic plasticity
pregnant and lactating Dutch women. In Chapter 5.2 we investigated the iodine status Folate Neural Tube Closure Neural tube defects
at 20 and 36 weeks of pregnancy and during lactation, and also the breast milk iodine Neuronal Structure Impaired neurodevelopment
content, following the use of an iodine-containing multivitamin supplement. Choline Neurotransmitter Neural tube defects
Myelination Impaired neurodevelopment
Zinc DNA synthesis Cognitive impairment (animal studies)
Summary of arguments for brain selective nutrients Concentrated in mossy fibers in the hippocampus: Impaired metabolism of LCP (notably AA)
Table 4 summarizes the arguments in favour of the existence of brain selective nutrients. • Encephalin binding to opiate receptors
Vitamin A, and the combination of folate, choline and betaine have not been discussed Neurotransmitter release
Iron Myelin synthesis Neurodevelopment delay & emotional
in this introduction, since they have not been studied in the current thesis. We repeat
Monoamine synthesis fragility
the already mentioned definition of brain selective nutrients by Cunnane7 as being ‘a Neuronal and glial energy metabolism
collective term encompassing those nutrients needed especially for normal human brain Uptake of oxygen by the brain

development, and although they are important for brain, these nutrients aren’t specific to

50 51
Chapter 1 General introduction: Brain-selective nutrients

Table 4: (Continued) The close relation between maternal and infant nutritional status implies that the
Brain-selective Important in brain for: Deficiency increases risk of: requirement for 0-6-month-old infants could derive best from (breast milk and blood)
nutrient
Copper Myelin synthesis Deficiency is seen in Menke’s disease, with
samples of life-long adequately fed mothers. To find clues for the optimization of maternal 1
status and intake, infant status and human milk, and for the optimal formula composition,
Involved in neurotransmitter synthesis and degradation as symptoms like:
cofactor • Progressive mental retardation we studied maternal nutrient status and milk compositions in various geographical regions
Neuronal and glial energy metabolism • Hypothermia with different cultural backgrounds. We conducted our studies in The Netherlands,
Combined with iron for cellular energy metabolism • Seizures Curaçao, in several locations in Vietnam (Halong Bay, Phu Tho, Tien Giang, Ho Chi Minh
Synthesis of collagen and elastin  used in vessel structure • Death during infancy
Antioxidant function
City and Hanoi), Malaysia (Kuala Lumpur) and in three populations in Tanzania (Sengerema,
Iodine Essential role in thyroid hormone production, thyroid Mental retardation Ukerewe and Maasai). We hypothesized that studying the worldwide variation of nutrients
hormones are important metabolism of cells and brain Cretinism in breastmilk collected from ‘apparently healthy and well-fed mothers’ might get us closer
development
to more reliable DRIs, or at least confirm the existing ones.
Selenium Role in the normal activity of glutathione peroxidases Impaired neurodevelopment
Heme-production is iron- and selenium-dependent
Essential role for the activity of iodothyronin deioninase, We focused on the above defined brain-selective nutrients vitamin B12, vitamin D, fish oil
which is important for iodine metabolism fatty acids and (trace) elements during pregnancy and lactation. The selected populations
exhibit, occasionally profound, differences in their life-long lifestyles. For instance, there is
Aim of this thesis huge difference in exposure to sunlight, ranging from mostly low in the Netherlands to life-
long high in Tanzania. The selected populations also had different diets: typically Western
Despite existing recommendations, the optimal intakes and/or status of vitamin B12, in the Netherlands and Curaçao, Asian diets in Malaysia and Vietnam, and diets determined
vitamin D, LCP and (trace) elements by pregnant- and lactating women and their infants by culture or the availability of food in Tanzania, such as low- (Maasai), high- (Sengerema)
are currently uncertain. Establishment of optimal dietary intakes or status is complicated and very high- (Ukerewe) intakes of freshwater fish. We expected that such studies might
and occasionally unethical, the latter notably in 0-6-month-old children. Even for adults, provide us with data on similarities and differences in maternal nutrient status and breast
establishing DRIs is not easy, due to the difficulty to provide solid evidence of benefits, milk composition to find clues for nutrient optimality from an evolutionary perspective.
such as those from (long term) RCTs. Furthermore, dietary reference intakes (DRIs), notably
adequate intakes (AIs), derive from populations living in Western countries, and might The specific aims have been discussed above, but can be summarized as follows:
not reflect ‘optimal values’. In addition, they are almost exclusively based on the study
of single nutrients, that is, by neglecting interactions. Lifestyle has changed drastically • In Chapter 2 we established a ‘functionally adequate’ milk vitamin B12 concentration
during the past 200 years, and reference value data could be polluted by data from and used the outcome to evaluate the ‘adequacy’ of the milk vitamin B12 concentrations
subjects with unhealthy dietary habits and subclinical deficiencies. Apparently healthy in various populations.
subjects may suffer from the metabolic syndrome (pre-diabetes, insulin resistance • In Chapter 3 we studied:
syndrome), which changes many hormonal axes431. DRIs for pregnant women are usually 1. Whether the milk antirachitic activity (ARA) of mothers with ‘adequate’ vitamin D
extrapolated from estimates for non-pregnant counterparts, adjusted for estimated fetal status reaches the IOM-AI for 0-6-month-old infants (Chapter 3.1),
and changing maternal demands. The same approach is used to assess DRIs for lactating 2. The supplemental vitamin D dose needed to reach ‘adequate’ maternal vitamin
women with adjustments for the average amounts of nutrients excreted via the breast D status and the corresponding milk ARA (Chapter 3.2), and
milk. For infants, average intakes by full-term infants who are exclusively breastfed and 3. The ‘parent’ vitamin D concentrations in plasma and adipose tissue of traditionally
are born to ‘apparently healthy and well nourished mothers’, are used to establish the AIs. living non-pregnant, pregnant and lactating women and their infants in Tanzania
It is uncertain to which extent this approach results in the establishment of the genuine (Chapter 3.3).
nutrients requirements. • In Chapter 4 we describe a dose-response trial to investigate what dosage of
supplemental DHA+EPA is needed to reach ‘adequate’ maternal EPA+DHA status

52 53
Chapter 1
at the pregnancy’s end and what dosage is needed to reach ‘adequate’ DHA+EPA
concentrations in mature milk.
• In Chapter 5 we:
4. Evaluated the milk element concentrations of various populations by using the
IOM-AI and data from other studies employing the same analytical technique
(Chapter 5.1), and
5. Studied the iodine status of Dutch women during pregnancy and lactation,
and also their breast milk iodine concentration following the use of an iodine-
containing multivitamin supplement (Chapter 5.2).
54
General introduction: Brain-selective nutrients
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