Environment International 123 (2019) 486–500

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Environment International
journal homepage: www.elsevier.com/locate/envint

Review article

Food advanced glycation end products as potential endocrine disruptors: An T

emerging threat to contemporary and future generation
Guna Ravichandrana, Dinesh Kumar Lakshmanana, Karthik Rajua, Abbirami Elangovana,
⁎
Gayathri Nambirajana, Arul Ananth Devanesanb, Sivasudha Thilagara,
a
Department of Environmental Biotechnology, School of Environmental Sciences, Bharathidasan University, Tiruchirappalli, Tamilnadu, India
b
Department of Food Quality and Safety, Gilat Research Center, Agricultural Research Organization, M.P. Negev 85280, Israel

A R T I C LE I N FO A B S T R A C T

Handling Editor: Robert Letcher Mankind exposure to chemicals in the past century has increased dramatically throughout environment. There is
no question that chemicals interfere with the physiology of biological system. Abundance of chemicals is
Keywords:
documented to be detrimental to human and wildlife. The mammalian endocrine system is comprised of many
Environmental chemicals
Processed foods interacting tissues mediate themselves through hormones that are essential for metabolism, growth and devel-
Advanced glycation end products opment. Humans secrete over fifty different hormones to orchestrate major physiological functions however;
Endocrine disruption these vital functions can be intervened by huge number of internal and external chemical stressors that are
identified as endocrine disruptors. Advanced glycation end products (AGEs), familiarly known as Maillard
products, formed through non-enzymatic glycation whose production is augmented on aging as well as en-
vironmental stressors. Processed foods have become very popular today due to their taste, convenience, and
inexpensiveness. Manufacture of these day-to-day foods involves extreme temperatures on processing results in
the formation of AGEs could independently promote oxidative stress, aging, diabetes, cancer, degenerative
diseases, more fascinatingly hormonal disruption is the subject of interest of this review. Based on some sub-
stantial observations documented till time, we discuss the emergence of dietary AGEs as potential endocrine
disruptors by emphasizing their occurrence, mechanisms and participation in endocrine interruption. Both
economically and in terms of human life, AGEs may represent an enormous cost for the future society. Therefore,
by explicating their novel role in endocrine diseases, the review strives to make an impact on AGEs and their
exposure among public as well as scientific communities.

1. Introduction
Chemicals are extremely heterogeneous, omnipresent, and have
wide application in the manufacture of copious day-to-day products.
Endocrine disruptors (ED) or endocrine disrupting chemicals are de-
fined as exogenous chemicals which are capable of intervening natu-
rally occurring endogenous hormones with their production, release,
transport, metabolism, binding, action, or elimination. Reports from
different scientific models and epidemiological studies implicated EDs
as a significant concern to public health. In its first scientific statement
during 2009, the endocrine society have expressed its serious concerns
over the detrimental role of EDs on reproduction and breast develop-
ment (Elisa et al., 2011), cancer (Ana and Carlos, 2015), prostate cancer
(Eduardo et al., 2017), thyroid (Ullafeldt and Katharina, 2012), and
obesity (Philippa, 2017) and cardiovascular endocrinology
(Fairweather, 2016). EDs represent a broad class of stuffs including
pesticides, plasticizers, surfactants, fuels, pharmaceutical agents, per-
sonal care products and even plenty of food products. Most of the foods
consumed nowadays by developed societies are processed. The di-
versity of processed food products have increased exponentially during
the last century, along with the need for more safe and convenient.
However, these foods also contain potential EDs as their processing

Abbreviations: 3-DG, 3-deoxyglucosone; AGE, advanced glycation end product; AMH, anti-mullerian hormone; AT, adipose tissue; CEL, carboxyethyl-lysine; CML,
carboxymethyl-lysine; ECM, extra cellular matrix; ED, endocrine disruptor; FSH, follicle stimulating hormone; GH, growth hormone; GO, glyoxal; IR, insulin re-
sistance; IS, insulin sensitivity; LH, luteinizing hormone; MG, methylglyoxal; MMP, matrix metallo protein; MRP, Maillard reaction products; NFκB, nuclear factor
kappa-light-chain-enhancer of activated B cells; PCOS, polycystic ovary syndrome; RAGE, receptor for advanced glycation end product
⁎
Corresponding author at: Department of Environmental Biotechnology, School of Environmental Sciences, Bharathidasan University, Tiruchirappalli 620024,
Tamilnadu, India.
E-mail address: sudha@bdu.ac.in (S. Thilagar).

https://doi.org/10.1016/j.envint.2018.12.032
Received 3 October 2018; Received in revised form 14 December 2018; Accepted 15 December 2018
Available online 05 January 2019
0160-4120/ © 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
G. Ravichandran et al.
methods involve numerous undesirable compounds that are added de-
liberately to maintain the quality of foods that ultimately become ha-
zardous to the consumers health (Kandarakis et al., 2009). Moreover,
food contact materials are also lay foundation to the migration of sev-
eral toxic substances with endocrine acting properties into food.
Nevertheless, there are plenty of evidences framed on advanced gly-
cation end products (AGEs), a distinctive class of compounds, com-
monly specified as Maillard reaction products (MRP) which are in-
stinctively formed in foods. They are hypothesized for their endocrine
disrupting properties. Evidences from humans and experimental ani-
mals show AGEs in food sources get absorbed and increased in circu-
lating tissues and further exacerbate their endogenous production
(Koschinsky et al., 1997). They tend to accumulate with long lived
blood and tissue structural proteins such as albumin, collagen, elastin,
and lens crystallin and contribute to the development of complications
in aging, diabetes, Alzheimer's disease, heart diseases etc. (Vlassara,
1994). Crosslink formation between these long living proteins make
extra cellular matrix (ECM) rigid and collapse the integral framework of
tissues. Not only diabetics and aged communities but, children and
adolescents with diabetes also have more impacts from glycemic con-
trol to micro and macrovascular complications on exposure to AGEs
(Monnier et al., 1996; Yozgatli et al., 2018; Jaisson et al., 2016). En-
thrallingly, AGEs also exhibit oxidative stress and inflammation in
several tissues by interfering vital hormones involving numerous phy-
siological obligations. Though the role of AGEs on the pathology of
several illnesses had been well documented, emphasis on endocrine
disruption is not studied much. Such an emergence of AGEs with this
special characteristic should have incited the endocrine society to
consider and project them in the list of endocrine disruptors.
‘How chemicals often affect us?’, ‘Toxic and hormone-disrupting
chemicals tied to $340 billion in U.S. health costs’, ‘Health costs of
hormone disrupting chemicals over €150 billion a year in Europe’, ‘UN
report examines link between hormone-disrupting chemicals and health
problems’, ‘Eating out may strike your hormones’, ‘Essential oils make
male breasts develop’, ‘Is America's sperm crippled by chemicals?’,
‘Eggs in India carry high levels of dioxins’. This is nothing but, just a
collection of recent headlines by BBC, CNN, NY times and Reuters that
have hit around the globe, warning the growing incidence of endocrine
disruption and prevalence in many developed and developing nations
(BBC, 2018; NY Times, 2012, 2017; Reuters, 2016; The guardian, 2015;
The times, 2018; UN news, 2013; The Hindu, 2005). It was estimated
that 451 million people are with diabetes worldwide in 2017. This is
expected to increase up to 693 million by 2045. Almost half of the
world population live with diabetes is still undiagnosed (Cho et al.,
2018). International Diabetes Federation says globally 80,000–100,000
children and adolescents with type 1 diabetes (TID) are in urgent need
of assistance (The Lancet-Diabetes and Endocrinology, 2013). 200
million people with thyroid disease around the world undergo treat-
ment. In developing countries such as India, the incidence of diabetes,
obesity, thyroid, parathyroid, pituitary, adrenal and metabolic dis-
orders is increased for past three decades (Kumar and Patnaik, 2017).
Growing number of all these endocrine related incidents denotes that
people are in exposure to various environmental toxins and develop
diseases apart from their diverse genetic backgrounds. Furthermore, the
list of EDs is still hastily growing. According to the TEDX (The Endo-
crine Disruption Exchange) database, 881 suspected as EDs in 2011
have been increased to 1419 in 2017 (TEDX report, 2017). Along with
air, water and consumer products, humans are also continuously ex-
posed to EDs through a variety of food stuffs. A recent expert panel
estimated the economic burden of diabetes, obesity, and infertility with
high probability causation by EDs to be €157 billion annually in the
European Union (Trasande et al., 2015). Though there is an extensive
research conducted for past decade on this ground, the knowledge on
EDs is still limited. Therefore, addressing food EDs exposure will be an
opportunity to help reducing public health costs. With this crucial
motto, with discussing the exposure and effects of other existing
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Environment International 123 (2019) 486–500
significant endocrine disruptors in addition, the review will deeply
address the pathology of AGEs as a potential endocrine disruptor by
magnifying certain endocrine toxicological reports which will instigate
individual and scientific society to communicate and implement pre-
cautionary principles against the consequences of AGEs.
2. Endocrine disrupting chemicals
Endocrine disruptors are gang of either natural or synthetic che-
micals which interfere with hormones of the living system and possess
deleterious health defects. It is estimated that about thousand out of
hundred thousand manufactured chemicals have endocrine disrupting
properties. Biomonitoring shows nearly all humans of the con-
temporary world have a chemical burden. In addition to the known
EDs, there are countless suspected EDs or chemicals that have never
been tested. Although most of the EDs are man-made, some of the EDs
are naturally or accidentally formed in the human diet (Diamanti-
Kandarakis et al., 2009; Gore et al., 2015). Great amounts of these
chemicals are improperly released into the environment every day by
human activities throughout the world. Moreover, EDs astoundingly
cause adverse effects even with low concentrations. Several nuclear
receptors (NRs) are identified as mediators of EDs (Lazzati et al., 2010)
and number of human tissues have been reported the presence of such
receptor expression in brain, immune system, cardiovascular system,
lungs, mammary glands, liver, kidneys, reproductive tracts, bones,
adipose and other connective tissues (Mueller, 2004).
3. Endocrine disruptors and day-to-day environments
Most of the chemicals released directly or indirectly into the en-
vironment have been detected in sediments, wastewaters, surface wa-
ters, and ground waters as well as in human food (Mnif et al., 2010;
Ferrara et al., 2008). Exposures to known EDs are relatively high in
contaminated environments where industrial chemicals leach into soil
and water that are taken up by microorganisms, algae, and plants, and
move into food chain of the animal kingdom. Since the discovery of
dichloro diphenyl trichloroethane (DDT), numerous other pesticides
have been used extensively worldwide during the green revolution
(Briggs, 2009; Cooper and Dobson, 2007). The World Health Organi-
zation (WHO) has claimed that synthetic pesticide exposure lead de-
clined reproductive functions ranging from poor sperm count to re-
duced organ size. In addition, a whopping 220,000 deaths had recorded
worldwide against cancers, allergies, and neurological disorders due to
pesticide poisoning (WHO annual report, 1992). Over hundreds of
pesticides have been found to disrupt several endocrine hormones (Mnif
et al., 2011). Well-known plasticizers such as bisphenol A (BPA) and
phthalates are recognized as high-profile EDs whose endocrine inter-
ference have been highly ascribed in human and wild life reproductive
and thyroid systems. They are used in the production of food and
beverage cans, flame retardants, plastics, water supply pipes, plastic
wrap, vinyl flooring and printing inks (Roy et al., 2004; Meeker and
Ferguson, 2011; Colón et al., 2000; Main et al., 2006), which can easily
seep out and migrate into the environment during the manufacture,
consumption and disposal processes (Staples et al., 1997). Researchers
also reported hormonal disruption of personal care products (PCP) such
as fragrances and cosmetics in aquatic environments and macroorgan-
isms (Fent et al., 2010; Poiger et al., 2004), human urine and milk (Felix
et al., 2008; Schlumpf et al., 2010). PCPs have shown to exert estro-
genic effects in in vitro studies (Mnif et al., 2007; Schlumpf et al.,
2001). They also inhibit iodide uptake by thyroid gland, thus interfere
with the biosynthesis of thyroid hormones in in vivo systems
(Schmutzler et al., 2006; Schmutzler et al., 2007). Various surfactants
are reported to bind with estrogen receptors and block or alter en-
dogenous estrogen functions in reproductive and developmental stages
(Hong et al., 2004). Similarly, several poly aromatic hydrocarbons have
reported for their endocrine disrupting properties (Lee et al., 2007;
G. Ravichandran et al.
Gozgit et al., 2004; Santonado et al., 1997).
All among these factors, food matrix has become a major source of
introducing EDs to human. Food is a crucial contributor that affects the
health of the individual in many ways. During the last century, in many
western countries, the food system had a major transition from a sus-
tained green system to commercially efficient, highly processed, and
readily available, which is however susceptible towards contamina-
tions. Foods that have deliberately added additives and extensively
processed for maintaining the quality and safety can unfortunately
contain several EDs. Especially, external factors such as packing or
coating materials made with several plasticizers and slipping agents in
combination with foods can migrate into foods and whose deleterious
effects have been widely documented (Marsh and Bugusu, 2007;
Geueke et al., 2014; Ehlert et al., 2005; Buculei et al., 2012; Cabado
et al., 2008).
4. Food processing contamination and endocrine disruption
Food preparation undergoes a long chain of processing includes
heating, roasting, grilling, baking, canning, and fermentation, where
each stage has invasion of potential source of chemicals into the food.
Food contamination is defined as the presence of harmful microbes in
food which can cause a variety of illness to consumers. Depending upon
the food preparation process, chemicals that are mixed as additives or
chemicals that are formed accidentally during food processing are ac-
tually lead negative impacts to human health. Methods used for food
processing can be categorized into two types, conventional thermal
methods including pasteurization, sterilization, drying and roasting
(Peng et al., 2017; Halpin et al., 2014) and non-thermal novel methods
such as high pressure treatment (Roberts, 2014), electric field treatment
(Thirumdas et al., 2015) and irradiation etc. (Tong et al., 2012). Among
these, thermal processing is vastly applied in the domestic as well as
industry to inactivate microbes and improve their sensory qualities such
as flavor, texture, taste, and shelf life. However, from a biochemical
perspective, thermal processing promotes series of chemical and phy-
sical changes to food proteins and affects protein conformation by
promoting interactions of food proteins with other components present
in the food stuffs. Maillard reaction is the quintessential for this in-
stinctive modification of food components where temperature and time
are the most significant factors influence the formation of numerous of
toxic products are called AGEs. While scrutinizing the pathological
impacts of AGEs in degenerative diseases ascribed in wide range of
reports, the disruptive endocrine activities also noted down in certain
studies dealt AGEs mediated disease progression. Based on some direct
and indirect studies on this platform till now, along with other degen-
erative mechanism, AGEs are also speculated to intervene with hor-
mones such as insulin, leptin, adiponectin, parathyroid hormone, tes-
tosterone, androgen, estrogen, progesterone, anti-mullerian hormone,
gonadotropins and CNS hormones will be discussed in this review.
5. Historical perspectives of AGEs
Louis Camille Maillard (1878–1936), a French chemist, who was
engaged in peptide synthesis in 1912, had proposed the reason for food
browning (Maillard, 1912). However, his finding was validated only
after 50 years, when studies found AGEs involvement in food browning
during thermal processing. Enzymatic browning was already explained
but, non-enzymatic darkening was first published only in 1941 by re-
searchers of California University (Weast and Mackinney, 1941). Years
before, several studies had shown that heating food proteins such as
casein, bread crust and meat at high temperature (100–200 °C) led to
loss of nutritional value. Greaves et al. (1938) found that the nutritional
value of heated casein was restored by fortification with lysine. Doob
et al. (1942) reported the influence of moisture on browning of dried
whey and skim milk however; none of these publications were men-
tioned and given credits to Maillard reactions. Only then in earlier
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Environment International 123 (2019) 486–500
1950s, consequences of Maillard reaction were explained in milk and
egg powder, canned fish and bread. They also stated that Maillard re-
action was also responsible for the production of aromas in beer, car-
amel, bread, maple sugar, fried potatoes and cheese. However, they
were dealt only chemical, nutritional, and safety aspects of the Maillard
reaction in foods (Patron, 1950; Patron, 1951).
Only by later, it was predicted that the Maillard reaction also ensues
in vivo, a process generally described as glycation. In 1990s, the
binding of AGEs to receptor advanced glycation end product (RAGE)
was proposed and subsequently the rate of AGEs formation was found
to hasten diabetes and aging (Schmidt et al., 1992). Interestingly, ad-
ministration of AGE-modified albumin (exogenous) to experimental
animals resulted in similar vascular complications those seen in dia-
betes and aging (Vlassara et al., 1992; Brownlee et al., 1985). AGE-
RAGE signaling cascades directed cellular dysfunction and localized
tissue destruction were also observed postliminary (Ulrich and Cerami,
2001; Bierhaus et al., 2005). Howbeit, the significance of exogenous
AGEs was largely dismissed until 1997, when Koschinsky et al., de-
monstrated the absorption of dietary AGEs by human intestine. Most
clinical studies then have diagnosed AGEs in patients with arterial
stiffness (Semba et al., 2010a, 2010b), chronic kidney disease (Semba
et al., 2010a, 2010b), anemia (Semba et al., 2008), poor skeletal muscle
strength (Dalal et al., 2009) and physical performance (Semba et al.,
2010a, 2010b), cardiovascular disease (CVD) mortality (Semba et al.,
2009a, 2009b). Not all but, most AGEs have characteristic auto-fluor-
escence, which simplify their identification in vivo. Heterogeneously,
till date 20 types of AGEs have been elucidated and major AGEs include
pyralline, N-carboxymethyl-lysine (CML) and pentosidine (Semba et al.,
2010a, 2010b).
6. Recent progress on AGEs research
Researchers found that high intake of dietary AGEs are associated
with increased arterial stiffness and inflammation in T2D (Di Pino et al.,
2017). Recent cardiac studies on AGEs clarified their multifaceted roles
in CVDs. Lutgers et al. (2006) and De Vos et al. (2016) explained the
accumulation of AGEs and formation of cross-links lead stiffness of
interstitial tissue, RAGE binding and mitochondrial dysfunction which
contribute to vascular dysfunction and accelerated atherosclerotic
processes. Studies also validate MG-derived AGE as an early signs of
atherosclerosis in childhood diabetes (Heier et al., 2015). The correla-
tion is revealed between CML and diabetes among individuals with
impaired fasting glucose where higher AGE levels in their later phases
predicted to develop diabetes. (Luft et al., 2015). Moreover, high-AGEs
diet contributed to the high-AGE and ROS levels and low levels of SOD
in heart with upregulated RAGE expression influence AGEs/RAGE/ROS
pathway in the pathogenesis of vascular complications in diabetes (Xing
et al., 2016).
Studies in human subjects revealed that CML-AGE accumulation
mediated RAGE expression in obese adipose tissue suggests that RAGE
expression and adipocytokines elevation denotes the independent effect
of AGEs on developing obesity pathology (Gaens et al., 2014). Re-
searchers demonstrate the pro-tumorigenic effects of AGEs on estrogen-
breast cancer cell lines. RAGE up-regulation is likely increase the sen-
sitivity of ER-breast cancer cells to AGEs for breast cancer development
(Sabine et al., 2017; Lee et al., 2018). Moreover, CML also promote
pancreatic cancer in type 2 diabetes (Menini et al., 2017). Recently, it
was found that AGE-albumin are excreted by macrophages in microglial
cells and develop neurodegenerative diseases (Kyunghee et al., 2017).
In a longitudinal study, AGEs levels are associated with development of
paratonia in AD (Hans et al., 2017).
7. Production of endogenous AGEs
Rate of protein turnover, degree of hyperglycemia and extent of
oxidative stress are the key regulators of generation of AGEs involving
G. Ravichandran et al.
glycation of cellular and tissue proteins (Peppa and Vlassara, 2005).
There are three different phases in which AGEs formation occurs in vivo
are discussed below.
7.1. Initial phase
The Maillard reaction begins with the reaction between carbonyl
group of reducing sugars (either glucose or fructose or ribose) and
amino groups (mostly lysine and arginine residues) of proteins to form
schiff base which is also be formed through polyol pathway. This un-
stable schiff base is further rearranged to become more stable keto-
amines, called amadori products (AP) which can form irreversible
crosslink with proteins and peptides and generate free radicals.
However, depending upon the minimal substrate concentration and
time, APs are still reversible (Suzuki et al., 1999; Bonnefont-Rousselot,
2002).
7.2. Proliferation phase
Amadori products undergo further chemical rearrangements in
presence of transitional metal ions to form active carbonyl intermediate
groups known as dicarbonyls include Glyoxal (GO), methylglyoxal
(MG) and 3-deoxyglucosone (3-DG) become precursors for AGEs pro-
duction at advanced stage. Glucose, fructose, and schiff base from the
previous phase can also be converted and accumulated into dicarbo-
nyls, termed as “carbonyl stress” and they tend to react with amino and
sulfhydryl groups of proteins results in browning, and cross-linking.
(Suzuki et al., 1999; Thornalley et al., 1999).
7.3. Advanced phase
Eventually, dicarbonyls are directly rearranged with amadori pro-
ducts and proteins through various chemical modifications including
oxidation, non-oxidation, hydration, dehydration, glycation, glycosy-
lation, fructosylation, acid hydrolysis and form stable, irreversible AGEs
including N-(carboxymethyl)lysine (CML), N-(carboxyethyl)lysine
(CEL), deoxyglucosone lysine dimer (DOLD), glyoxal-lysine dimer
(GOLD), methylglyoxal-lysine dimer (MOLD), glyoxal derived imida-
zolium crosslinking (GODIC), methylglyoxal derived imidazolium
crosslinking (MODIC), 3-deoxyglucosone derived imidazolium cross-
linking (DODIC), glucosepane, pentosidine, pyralline, fructose-lysine,
and hydroimidazolones etc. (Thorpe and Baynes, 2003) (Fig. 1). The
salient properties, source and mode of generation and pathophysiology
of different types of AGEs is portrayed in the Table 1.
8. Effect of crosslinking and RAGE mediated orchestrations by
AGEs
Numerous studies have proposed two foremost mechanisms through
which AGEs contribute to cellular pathology include crosslink forma-
tion and RAGE interaction. Accumulation of AGEs in the extra cellular
matrix (ECM) proteins leads to formation of cross-links which perma-
nently alter the properties of matrix metallo proteins (MMPs) such as
collagen and elastin and also other serum and tissue proteins including
albumin, myelin, tubulin, fibrinogen, and laminin through AGE-AGE
intermolecular covalent bonds (Fig. 2) (Jeanethe et al., 2013). This
increases stiffness and expands ECM leading to the increased deposition
MMPs thus, ECM become rigid towards proteolytic cleavage. AGEs here
bind to the non-collagenous part of the helix-rich domain of MMPs and
inhibit the formation of a matrix structure which would affect the
mechanical properties (elastic, brittleness, elongation, tensile strength
etc.) of tissue that ultimately leads to organ dysfunction (Sims et al.,
1996; Paul and Bailey, 1999). On the other hand, although AGEs found
to interact with multiple receptors, they recognize RAGE as their most
favorite functional receptor which belongs to immunoglobulin super-
family that expressed in variety of tissues where AGEs accumulate.
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Environment International 123 (2019) 486–500
Though recognizes a range of other ligands, RAGE has highest binding
potential for AGEs and brings effective cellular responses. AGE-RAGE
interaction generally involves activation of transcription factor, nuclear
factor kappa-light-chain-enhancer of activated B cells (NFκB) through
generating intracellular oxidative stress and the ras/MAP kinase
pathway. Secretion of various cytokines such as TNFα, interleukin 1β
(IL1β), IL6, endothelin-1, vascular endothelial growth factor, E-selectin
and etc. Interestingly, AGE-RAGE interaction promotes its own tran-
scriptional upregulation via activating NFκB (Neeper et al., 1992). In
addition to this, downstream signaling molecules such as extracellular
signal-regulated kinase (ERK), mitogen-activated protein kinases
(MAPK), and c-Jun N terminal kinases (JNK3) are also demonstrated in
AGE-RAGE mediated oxidative stress and consecutive inflammatory
responses (Fig. 2) (Tanaka et al., 2000a, 2000b).
9. Production of exogenous AGEs and their consequences
Humans cook food since the discovery of fire. Different cooking
methods (boiling, grilling, roasting, and frying) result in destruction of
bacteria and heat-sensitive toxins. However, ingredients in food stuffs
are glycated under high heat medium. Apart from protein turnover and
hyperglycemia, rate of AGEs formation can also be influenced exo-
genously by different styles of diet. AGEs accumulate in healthy elderly
persons as well as people with chronic diseases. Researchers quantify
AGEs in food and in human to identify mechanisms that would explain
their pathology. For last two decades, bulk of evidences shown AGEs
role in the development of chronic degenerative diseases. Meanwhile,
results of human studies show that restriction of Food AGEs (FAGEs)
has posted positive effects on insulin resistance (IR) and cardiovascular
disease CVD (Estifanos et al., 2016).
Regardless of the heterogeneity of AGEs, CML and MG have been
reported as most abundant AGEs acquired from competitive foods.
Uribarri et al., 2007 investigated whether AGEs intake is correlated
with markers of inflammation and oxidative stress by comparing older
(60–80 years) versus younger (18–45 years) healthy adults. Volunteers
given thermally processed oral AGE challenge beverage that contained
1.8 × 106 AGE units (mostly of CML and MG derivatives) and found
higher serum AGEs levels in older group were correlated with levels of
inflammation markers and oxidative stress (OS). In another study,
healthy subjects were given meat and meat-derived products processed
under high and dry heat including broiling, grilling, frying, and roasting
and found significant hike in plasma CML levels (Ames, 2008). An acute
dietary intervention study found that urinary excretion of pentosidine
and pyralline for three days was recorded in healthy volunteers who
received pretzels sticks, processed at 300 °C (Forster et al., 2005). Si-
milarly, patients with renal failure but not on dialysis and patients
following dialysis had consumed low AGE pretzel sticks, coffee and
custard for 5 days. Analysis of their urine samples showed that l2% of
pentosidine was excreted by non-dialysis whereas dialysis patients
cleared only 1% (Miyata et al., 1998). Interestingly, studies have
monitored the effect of western diet versus prudent diet where the
western diet rich in red and processed meats, sweets, deserts, potato
chips and refined grains apply grilling, roasting, and frying under
higher temperature in dry medium. Whereas, the prudent diet that
characterized with fruits, vegetables, legumes, fish, poultry and whole
grains mostly entail boiling at medium temperature. Positive correla-
tions were eventually reported between western diet and proin-
flammatory markers such as TNF-α (tumor necrosis factor-alpha), ILs
(interleukin) and C-reactive protein (CRP) (Lopez-Garcia et al., 2004).
Early MRPs, CEL, pyralline, and pentosidine are highly formed
through lysine and arginine modifications in processed milk, bakery
products, bread crust and roasted coffee. Among these, pyralline
quantification ranging 150–3700 mg/kg protein in these foods indicates
that it represents one of the dominating AGEs in foods (Henle et al.,
1997). And, MG, GO and 3-DG derived AGEs are highly formed during
manufacture of bakery products, carbonated soft drinks sweetened with
G. Ravichandran et al. Environment International 123 (2019) 486–500

Fig. 1. Schematic pathway of endogenous production of advanced glycation end products. Nonenzymatic reactions of reducing sugars with amino groups of proteins
produce respective schiff bases, which undergo Amadori rearrangement to raise amadori products. Along with amadori products, further chemical modifications
through polyol and non-amadori pathways, highly reactive carbonyl compounds (GO MG and 3-DG) which further react with protein amino groups forming a variety
of AGEs such as CML, CEL, pyralline, pentosidine, crossline, glucosepene, hydroimidazole, GOLD, MOLD, DOLD, GODIC, MODIC, DODIC etc.

high fructose corn syrup and fermented foods such as yoghurt, wine, analysis, AGEs content found to range 1–27,000 kU per serving shows
beer (Lo et al., 2008; Degen et al., 2012). In addition, GOLD, MOLD, people are in greater risk of exposure on their each and every dining
DOLD, MODIC, DODIC and GODIC were detected in enzymatic hydro- (Uribarri et al., 2010).
lysates of bakery products found crosslinked between arginine and ly-
sine (Biemel et al., 2001).
10. AGEs as potential endocrine disruptors
In a longitudinal study, AGE content in hundreds food samples was
analyzed during 2003–2008. Totally 549 day-to-day foods including
The human body is comprised of many interacting tissues. They
almonds, butter, margarine, peanuts, soybeans, sunflower seeds,
communicate each other as well as with rest of the body through se-
pumpkin seeds, walnuts, cooking oils, beef, chicken, turkey, pork, lamb,
creting bountiful of signalers including hormones. Hormones regulate
veal, fish, cheese, egg, bread, beans, pasta, rice, corn, potato, snacks
metabolism, growth and development, tissue function, sexual and re-
and crackers, sandwich, soup, coffee, tea, wine, bear and sweet bev-
production functions etc. The endocrine system is made up of pituitary,
erages were selected based on the frequent choices of healthy American
thyroid and parathyroid, adrenal glands, pancreas, ovaries and testicles
multiethnic urban population. Foods were prepared following standard
and affects almost every organ and cell in the body via hormone
cooking methods such as boiling (100 °C), roasting (177 °C), deep-frying
mediated signals. By secreting the ‘stimulating hormones’, hypotha-
(180 °C), oven-frying (230 °C), and broiling (225 °C). At the end of
lamus stimulates anterior and posterior pituitary glands to secrete

490
 Table 1
Source, characteristic features and pathological impacts of AGEs.
Type of AGEs Source Mode of generation Fluorescence or non- Crosslink or non- Target Pathophysiology References
fluorescence crosslink

AGE-1 (glucose-derived) Exogenous & Oxidation Fluorescence Crosslink Human gastric Cancer metastasis (Singh et al., 2001)
G. Ravichandran et al.

endogenous (Dengl et al., 2017)

Pentosidine Exogenous & Glycoxidation Fluorescence Crosslink Bone collagen Bone damage (Singh et al., 2001)
endogenous (Mitome et al., 2011)
(John and Lamb,
1993)
Dermis & epidermis of aged and Increased skin stiffness, loss of skin (Beisswenger et al.,
diabetic skin collagen flexibility, susceptibility to mechanical 2001)
stimuli and MMP degradation
Kidney collagen Sclerosis of renal glomeruli (Horie et al., 1997)
Aorta collagen Aorta stiffness (Kusunoki et al.,
2003)
Brunescent cataractous lens Development of cataractous lenses (Nagaraj et al., 1991)
CML Exogenous & Glycoxidation Non-fluorescence Non-crosslink Dermis & epidermis of aged and Decreased elasticity and is resistant to (Singh et al., 2001)
endogenous diabetic skin of collagen, vimentin proteolytic degradation (Wang et al., 2012)
and elastin (Beisswenger et al.,
2001)
(Monnier et al., 2005)
Eye-lens proteins Development of both senile and diabetic (Dunn et al., 1989)
cataracts and acidification of lens proteins
Pyralline Exogenous & Non-oxidative Non-fluorescence Crosslink Antioxidant enzymes of aortic Oxidative stress (Singh et al., 2001)
endogenous smooth muscle cells (Obayashi et al.,
1996)
Crossline Endogenous Glycation Fluorescence Crosslink Kidney collagen Sclerosis of renal glomeruli (Bidasee et al., 2003)

491
AGE-2 (glyceraldehyde Endogenous Oxidation Fluorescence Crosslink Blood vessels Increased CVD risk (Kitahara et al., 2008)
derived) (Nama et al., 2015)
Pancreatic duct Pancreatic ductal adenocarcinoma (Takata et al., 2017)
AGE-3 (glycolaldehyde- Endogenous Oxidation Fluorescence Crosslink Lens-Bruch's membrane & choroidal Dysfunction of retinal pigment epithelium (Nagai et al., 2002)
derived) ECM (John and Lamb,
1993)
Vascular muscle Vascular smooth muscle cell dysfunction (Nama et al., 2015)
GA-pyridine Endogenous Glycation Non-fluorescence Crosslink Microvascular arteries Atherosclerosis lesions (Greven et al., 2005)
(Wetzels et al., 2017)
AGE-4 (MGO derived AGE) Exogenous & Oxidation Non-fluorescence Crosslink Blood-fibrinogen Vascular dysfunction and atherosclerosis (Van Eupen et al.,
endogenous 2013)
CNS Multiple sclerosis (Wetzels et al., 2017)
CEL Exogenous & Hydration and dehydration Non-fluorescence Non-crosslink Aged dermis collagen Increased skin stiffness, loss of skin (Ahmed et al., 1997)
endogenous flexibility, susceptibility to mechanical (Beisswenger et al.,
stimuli and MMP degradation 2001)
Aged eye-lens protein Development of both senile and diabetic (Dunn et al., 1989)
cataracts and acidification of lens proteins
MOLD (methyl-glyoxal lysine Exogenous & Non-oxidation Non-fluorescence Crosslink Aged dermis collagen Increased skin stiffness, loss of skin (Van Eupen et al.,
dimer) endogenous flexibility, susceptibility to mechanical 2013)
stimuli and MMP degradation (Beisswenger et al.,
2001)
Lens, RBC, kidney Decreased GSH levels (Linetsky and
Shipova, 2007)
Argpyrimidine Exogenous & Oxidation Fluorescence Cross-link Nervous system-spinal cord-amyloid Familial amyloidotic polyneuropathy (FAP) (Teruyuki et al., 2008)
endogenous deposits (Gomes et al., 2005)
CEHL Endogenous Oxidation Non-fluorescence Non-crosslink Dermis collagen Increased skin stiffness, loss of skin (Dunn et al., 1991)
flexibility, susceptibility to mechanical (Beisswenger et al.,
stimuli and MMP degradation 2001)
(continued on next page)
Environment International 123 (2019) 486–500
G. Ravichandran et al. Environment International 123 (2019) 486–500

‘releasing hormones’ which then recognize target tissues to release their

(Konishi et al., 1994)

(Brings et al., 2017)

(Brings et al., 2017)

(Brings et al., 2017)

(Odani et al., 1998)
(Leone et al., 2017)

(Zyzak et al., 1995)

(Beisswenger et al.,
respective hormones to accomplish the instructions. Humans secrete

(Price et al., 2010)

(Karachalias et al.,
(Thornalley et al.,

(Sell et al., 2005)

over 50 different hormones in which most of them are involved in the
regulation of major physiological functions. Insulin, a well character-
References

ized metabolic hormone regulates glucose uptake, glycogen synthesis

1999)

2001)

2003)
and lipolysis whereas its counterpart, glucagon hormone regulates
gluconeogenesis and glycogenolysis. Calcitonin hormone, thyroxin

complications-nephropathy, retinopathy and

hormone, and triiodothyronine hormone of thyroid gland involved in
basal metabolism, brain growth and development and calcium regula-
Free radical generation, oxidative stress

flexibility, susceptibility to mechanical

tion. Gastric hormones including gastrin and ghrelin maintain gastric

Retinopathy, cataract and blindness

Increased skin stiffness, loss of skin
acid secretion and appetite stimulation. Adrenal hormones such as al-

Development of microvascular
stimuli and MMP degradation
dosterone, cartisol, epinephrine and, norepinephrin regulate mineral
Dialysis related amyloidosis

reabsorption and inflammatory and stress responses. Estrogen, proges-

Diabetic complications

Diabetic complications

peripheral neuropathy
terone, testosterone and androgen are essential for the growth and
Immune suppression

development of reproductive organs. In addition, adiponectin and

Vascular damage
Pathophysiology

leptin from adipose tissue regulate glucose levels as well as fatty acid
breakdown, food intake and metabolic rate etc. Moreover, pituitary
hormones such as growth hormone (GH), follicle stimulating hormone
(FSH), luteinizing hormone (LH), prolactin, vasopressin and oxytocin
have significant role in maintaining physical growth, sex hormone se-
Glomeruli, retina, nerve and plasma

Glomeruli, retina, nerve and plasma

cretion, breast growth and milk production, water excretion and blood
pressure (Krista et al., 2012). However, all these vital functions can be
Enzymes of glyoxalase system
Muscle-IgG collagen chains in

affected while hormones meddled by the so called endocrine disruptors

(ED) (Fig. 3).
Aged dermis collagen

In day-to-day life, humans are exposed to wide variety of chemicals

Β2-microglobulin

either due to occupations or through environment. Glyphosate (pesti-

Lens crystalline
Serum proteins
muscular-type

cides), atrazine, lead, cadmium, phthalates (Children product), bi-

sphenol-A, (food packages), brominated flame retardants, poly-
Arterioles

protein

protein
Target

chlorinated biphenyls (electronic and building materials), triclosan

(antibaterials), perfluorochemicals (textiles and clothings), parabens,
glycol ethers, phthalates, cyclosiloxanes (cleansers, cosmetics and per-
Crosslink or non-

sonal care products), tributylin (Paints), nonylphenol (detergents),

Non-crosslink

ethinyl estradiol (synthetic steroins) are reported to interrupt the hor-

Crosslink

Crosslink

Crosslink

Crosslink

Crosslink

Crosslink
crosslink

mones involved in metabolism, reproduction, and other vital functions

through increased inflammation, oxidative stress, adipogenesis, accu-
mulation of lipids etc. (Dodson et al., 2009; Gore, 2014; Polyzos et al.,
Fluorescence or non-

2012). Although reports on endocrine disruption in wild life have been

published from 1940s, the field has acquired drastic interest only by last
Non-fluorescence

Non-fluorescence

Non-fluorescence

Non-fluorescence

Non-fluorescence

Non-fluorescence

decade (Marty et al., 2011).

Fluorescence
fluorescence

The mechanisms through which EDs may interrupt the endocrine

system were predicted by many studies. EDs usually imitate or partly
imitate naturally occurring hormones in the body and lead to over-
stimulation. Then, they act as antagonists, where they bind to the cell
degradation/autoxidation

receptors hence, the normal endogenous hormone cannot bind to the

Non-oxidative/oxidative/

Oxidative degradation or

receptors and no signal occurs (Fig. 3). Apart these, they can also in-
Mode of generation

terfere or block the natural hormones or their receptors or specific

transport proteins or the appropriate sites where the delivery of hor-
Fructosylation
Non-oxidation
Non-oxidative
autoxidation

mones takes place (NIEHS, 2010; UNEP and WHO, 2012).

Oxidation

Oxidation

From the beginning, it is well understood that predisposition of

AGEs accomplishes serious of biomolecules modifications lead to tissue
damage through salient mechanisms such as crosslinking and AGE-
RAGE signaling. Not restraining, scientists on the other hand were also
observed the impacts of AGEs on other crucial molecules, especially
Exogenous &

Exogenous &

Exogenous &

Exogenous &
Endogenous

Endogenous

Endogenous
endogenous

endogenous

endogenous

endogenous

hormones. Among the heterogeneity, some well characterized en-

Source

dogenous and exogenous AGEs have been recognized to disrupt hor-

mone functions. Ironically, mechanisms by which other EDs been well
established though, identifying such disrupting mechanisms behind
AGEs is still obscure. Therefore, it is assumed that AGEs may either
GOLD (glyoxal lysine dimer)
Hydroimidazolones (MGO

directly or indirectly interfere with hormones or their receptors or

AGE-5 (glyoxal derived)

transport or delivery and even they might exclusively organize sig-

AGE-6 (3DG-derived)
Table 1 (continued)

naling pathways. Therefore, disclosing the feasible route of execution

Fructosyl-lysine

will be highly helpful to understand the novel role of AGEs. Herein,

Type of AGEs

Gluco-sepane
derived)

based on some substantial evidences made so far, we discuss the

emergence of AGEs as endocrine disruptors.
MGO

492
G. Ravichandran et al. Environment International 123 (2019) 486–500

Fig. 2. Schematic representation of AGEs accomplishments in ECM and cellular level. AGEs form covalent cross-links with proteins, increase oxidative stress, and
upregulate inflammation. Proteins that constitute the extracellular matrix are among the longest lived and most susceptible to AGE modification. Here, thick and thin
pinky fibers in left represent collagen and elastin respectively and cyan fibers in right corresponds proteoglycan fibers. Matrix modification is achieved by stiffening
of tissues by crosslinking with collagen, elastin, and proteoglycan and affects the mechanical properties of matrices of skeletal muscle, tendons, joints, bone, heart,
arteries, lung, skin, and lens. On the other hand, AGEs have potential attraction towards its receptor, RAGE. Activated RAGE upregulates cellular apoptosis,
inflammatory cytokines, adhesion molecules, and its own receptor via NF-kB. (For interpretation of the references to color in this figure legend, the reader is referred
to the web version of this article.)

10.1. AGEs and insulin disruption
Insulin is a peptide hormone, produced by beta cells of the pan-
creatic islets that regulates whole body metabolism by promoting the
uptake of sugar into cells. Among the multiple cell types, pancreatic β
cells are highly vulnerable to AGE induced toxicity in mice (Zhao et al.,
2009). Recently, the role of dietary AGEs in the development of IR and
type 2 diabetes (T2D) has been proposed by Cai et al. (2012), who fed
isocaloric diet with and without synthetic MG to mice. MG (+) mice
developed premature IR, adiposity and inflammatory phenotypic shift
than MG (−) mice. In a study, the standard mouse diet, AIN-93G with
high (Prepared in 100 °C × 20–60 s and 125 °C × 20–30 min) and low
AGEs (subjected to 100 °C × 20–60 s) promote pancreatic islet in-
flammation and cell destruction, though the diet contains low fat and
adequate antioxidants (Zheng et al., 2002). Additionally, Katarína et al.
(2012) showed that high dietary intake of CML directly induced IR in
rat muscle.
Exposure to high AGEs during fetal development and early child-
hood could lead proinflammation at young age. This speculation is
herein supported by the relationship between high maternal AGEs and
infant plasma insulin levels (Veronica et al., 2010). Maternal
transmission of disease risk has been raised nowadays as a serious
contributing factor which increasingly affects younger adults and
children. Children of obese, diabetic, and pre-diabetic mothers are more
susceptible to develop diabetes is pointing to maternal transmission of
pro-diabetic risk (Dabelea, 2009). Studies have proposed that exo-
genous AGEs such as CML and MG are able to predispose individuals to
an abnormal increase in oxidative stress and inflammation. CML-BSA
(bovine serum albumin) and MG-BSA derived AGEs shown to promote
T2D as well as T1D via early autoimmune cytotoxic T-cell activation,
high-fat–fed and aging in mice models (Melpomeni et al., 2003; Sandu
et al., 2005; Cai et al., 2008).
10.2. AGEs and reproductive hormones disruption
10.2.1. Testosterone and Androstenedione disruption
Testosterone is the primary male reproductive hormone, plays a key
role in the development of testes and prostate and promotes secondary
sexual characteristics such as muscle, bone, and hair growth.
Androstenedione is a precursor of testosterone, androgens, and estro-
gens synthesis and also has androgenic activity. Tantalaki et al. (2014)
studied the role of dietary AGEs and their effect on metabolic and

493
G. Ravichandran et al. Environment International 123 (2019) 486–500

Fig. 3. Illustration of endocrine disruption by AGEs and their possible mechanism of action. Humans have vulnerability towards degree of AGEs that have been
identified endogenously as well as exogenously are accumulated in the system and interfere with the hormones of physiological significance including, insulin, leptin,
adiponectin, testosterone, androgen, androstenedione, progesterone, estradiol, AMH etc. In addition, the possible mechanism through which AGEs may interrupt the
endocrine system is sketched out based on the mechanisms by other EDs predicted by studies. AGEs may block or entrap the natural hormones in the body and affect
their target actions. And they may imitate or partly imitate our hormones and lead to overstimulation. Apart these, by acting as an antagonist, they may also bind to
cell surface or nuclear receptors hence, the normal endogenous hormone cannot signal.

hormonal derangements in 23 women with polycystic ovary syndrome
(PCOS). The low AGE diet group who consumed hypocaloric diet with
ad-libitum prepared using normal diet composition (20%, 50% and
30% of protein, carbohydrate, and fat respectively) under ordinary
cooking temperature (60 to 80 °C) whereas the high-AGE diet group
was advised to have more frequently isocaloric diet (roasted, grilled,
broiled and baked foods, beef, pork, poultry, fish and baked cheese)
prepared applying high temperature (over 220 °C). At the end, the high
AGEs diet showed elevated levels of insulin, total testosterone, an-
drostenedione and abnormal estrous cycles leading to ovulatory dys-
function. Kandarakis et al. (2007) investigated the exposure of dietary
AGEs affects metabolic and hormonal functions of female rats. They
assigned rats to access thermally processed AGE diet consists of high
and low CML, fructosyllysine, and furosine levels for six months in
which high-AGE diet had increased deposition of AGEs, higher RAGE
expression and elevated plasma testosterone levels in theca cells of
ovaries, compared to animals fed on low-AGE.
10.2.2. Estradiol and progesterone disruption
In another study, female wistar rats were fed high-AGE diet had
declined levels of the estradiol and progesterone. These female sex
hormones are crucial for implanting the fertilized egg in the uterus,
maintaining pregnancy and also to regulate the estrous and menstrual
cycles. The peripheral blood mononuclear cells of rats were isolated
from high-AGE diet-fed rats in which increased expression of RAGE,
glucose, insulin and testosterone levels indicate deregulated metabolic
and hormonal functions compared with the low-AGE diet-fed rats
(Chatzigeorgiou et al., 2013).
10.2.3. Androgen and anti-mullerian hormone (AMH) disruption
AMH is also known as mullerian inhibiting substance, synthesized
by primary follicles and elevated in women with PCOS as an indicator
of disturbed ovulatory process. AMH has an inhibitory effect on FSH
sensitivity and thus interfered with anovulation. In a study involving
normal and PCOS women fed with AGE-enriched diet, significantly up
regulated testosterone and androgens levels (Kandarakis et al., 2006).
Group of another authors demonstrated that ovulatory and anovulatory
women with PCOS have higher serum levels of AMH and AGEs, com-
pared with Non-PCOS women. And interestingly, inhibition of AGE-
RAGE system in D-galactose induced PCOS animal model brought back
the AMH and testosterone levels (Park and Choi, 2012). Taking these
results altogether, it could be concluded that AGEs have absolute role in
reproductive endocrine disruption.

494
G. Ravichandran et al.
10.3. AGEs and gonadotropins disruption
Eleni et al., 2018 shown that AGEs are capable to interfere with
gonadotropins. Interference of glycated human albumin with LH and
FSH signaling in human granulosa KGN cells was investigated. Reg-
ulation of MAPK/ERK signaling pathway by LH has been implicated in
cell proliferation and differentiation, maturation of oocytes, follicle
development and initiation of the ovulation process (Su et al., 2002).
Since, direct effect of AGEs over LH deranges its pathway and con-
tributes to the pathophysiology of anovulation. Moreover, FSH has been
shown to act through ERK pathway to increase granulosa cell pro-
liferation (Kandaraki et al., 2017; Kayampilly and Menon, 2009). After
all, AGEs accumulation impedes with FSH and the resultant disruption
of mitogenesis and further ovarian functions suggest that AGEs can
potentially impact gonadotropins.
10.4. AGEs and thyroid and parathyroid hormones disruption
Thyroid hormones are essential for growth and development. They
regulate carbohydrate, protein, fat, vitamin metabolism, bone growth,
and neural maturation. Parathyroid hormone is involved in absorption
and regulation of calcium, production of vitamin D etc. Researchers
investigated the impact of thyroglobulin (Tg) modification by AGE
(AGE-Tg) and found that AGE-Tg shown neither antigenicity nor im-
munogenicity in sera of healthy and women with Hashimoto's thyr-
oiditis (Hatzioannou et al., 2015). Although immunologically AGE-Tg
has no obvious effects and correspondingly no reports on thyroid hor-
mone disruption by AGE till now, it could be assumed that increased
AGEs accumulation in thyroid gland may able to interfere with thyr-
oglobulins and affect the biosynthesis of thyroid hormones which in-
volves thyroglobulin as precursor. Such reports in near future will be
highly welcomed which will incite researchers to shed more light on
AGEs participation in thyroid gland pathology.
10.5. Impact of AGEs on adipose tissue hormones
Adipose tissue (AT) plays a central role in regulating whole-body
energy homeostasis. AT stores energy in the form of lipid and controls
the lipid mobilization and distribution. AT also performs as an endo-
crine organ and produces adipokines which communicate with other
organs and modulate a range of metabolic activities. Thus, AT dys-
function plays a prominent role in the development of obesity and its
related disorders such as IR, CVD, and diabetes (Hajer et al., 2008).
AGE-albumin is related with macrophage activation by promoting a
greater secretion of adipocytokines. Studies show that with extortion by
S100β - a calcium-binding protein, AGE-albumin induces macrophage
activated inflammation which stimulates the RAGE pathway in adipo-
cytes (Okuda et al., 2012). This was supported by a recent study sug-
gests that adipocyte derived S100β can act as an inflammatory cytokine
via RAGE and stimulate M1 polarization of macrophages in an in vitro
co-culture system (Fujisaka et al., 2009). Moreover, the RAGE pathway
also found to be involved in mouse adipocyte hypertrophy (Fujiya et al.,
2014). Researchers also compared the AGE-albumin accumulations,
level of S100β, and RAGE expressions in different adipocytes. Kui et al.
(2016) investigated the impacts of age-related AGE-albumin accumu-
lation in AT and found that RAGE expression mediated NFκB signaling
pathways were higher in the visceral fat of old rats (28 weeks) than in
that of young (3 weeks), but no different in RAGE expression was seen
in subcutaneous fat. Furthermore, activated macrophage infiltration in
subcutaneous fat was also no different in young and old rats but sur-
prisingly, it was more prominent in visceral fat of old than young rats.
Taking these observations in account, it is concluded that age-related
AGE-albumin accumulation in adipose tissue could significantly or-
chestrate inflammation and IR.
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Environment International 123 (2019) 486–500
10.5.1. Leptin and adiponectin disruption
Leptin is an adipocyte specific hormone, the key regulator of food
intake, IS and glucose tolerance whose levels are correlated with the
amount of body fat (Masuzaki et al., 1999). Mice with lack of leptin
develop obesity and IR and treatment of those mice with recombinant
leptin results in restoration of IS (Halaas et al., 1995). Ohgami et al.
(2001) found that AGE-proteins can be recognized by CD36 (a surface
scavenger receptor of adipocytes) as effective ligands. This finding
paves the way Kuniyasu et al. (2003) to demonstrate the pathological
impact of AGE proteins-CD36 interaction on the synthesis and secretion
of adipocytokines. To test this hypothesis, Yuka et al. (2004) then ex-
amined this phenomenon in mouse adipocytes and returned with in-
teresting finding that CD36 mediated pathway by AGE-proteins results
in the down regulation of leptin expression.
Adiponectin is another adipokine produced exclusively by adipo-
cytes involved in the regulation of glucose metabolism and fatty acid
oxidation. Consonance to this, adiponectin gene expression and protein
levels are higher in subcutaneous than in intra-abdominal AT
(Katherine et al., 2010). The association between endogenous AGEs and
adiponectin causing IR in obese people is documented (Masayo et al.,
2013). On the other hand, the association of maternal and food-derived
AGEs (CML and MG) between circulating AGEs and adipose hormones
of newborn and infant children was addressed by Veronica et al.
(2010). They assessed the relationship between maternal blood and
food AGEs to circulating AGEs, inflammatory markers, leptin, adipo-
nectin, and insulin levels in maternal and infants. They found circu-
lating levels of AGEs in infants increase with age. In addition, lower
adiponectin and leptin levels in infants correlated with higher maternal
AGE levels (Luo et al., 2013). Therefore, since these two hormones
dynamically regulate integrative energy metabolism, above observa-
tions postulate that both endogenous and exogenous AGEs may po-
tentially contribute to the increased incidence of diseases in the young
ones.
10.6. Impact of AGEs on CNS hormones and diseases
The consequences of AGEs have been well explained in diseases of
central nervous system (CNS). Autism is a disorder of atypical social,
cognitive and verbal behaviors along with self-injurious actions
(American Psychiatric Association, 2013). Though, inheritance by
most, patients develop also via environmental factors (Loke et al.,
2015). Spontaneous protein modifications by AGEs are reported in
adult and children with autism (Thornalley and Rabbani, 2014;
Rossignol and Frye, 2012). Importantly, MG directly impacted mi-
tochondrial dysfunction and increased oxidative stress by significantly
downregulating blood GSH to lead neuropathological changes in mice
and patients with autism (Ankrah and Appiah-Opong, 1999; Sims et al.,
2004; Maher, 2012). Interestingly, AGE accumulation is independently
associated with higher levels of depressive symptoms. Researchers
suggest that pentosidine is involved in the development of depressive
symptoms including mood, sleep, behavior and cognition through
vascular stiffening, inflammation, and oxidative stress induced neuro-
degeneration (Guerrero et al., 2013).
Parkinson's disease (PD) is another very common disease caused by
resting tremors, rigidity, slow movements, and autonomic instability
due to degeneration of dopaminergic neurons. α-synuclein, a type of
neurotransmitter controlling voluntary and involuntary movements, is
found to cross linked with other AGEs form protein aggregates in var-
ious brain regions of PD patients (Vicente and Outeiro, 2010). Glycated
α-syn interacts with RAGE and triggers the release of NF-kB lead to
neuronal cell death. Similarly, in Huntington's disease, the accumula-
tion of amyloid-beta induced RAGE expression lead to medium spiny
projection neurons and astrocytes damage (Goate et al., 1990; Vitek
et al., 1994). Furthermore, AGEs also play an important role in AD.
amyloid β peptide, an extracellular deposit generated by the amyloid
precursor protein (Kim et al., 2015). The higher Aβ-AGEs crosslinks of
G. Ravichandran et al.
brain plaques along with RAGE expression interfere with axonal and
intracellular protein traffic in neurons leads to neural death and loss of
cognitive function (Kazantsev et al., 1999; Srikanth et al., 2013).
Amyotrophic lateral sclerosis (ALS), a very common motor neuron
disease where a mutation in an antioxidant enzyme, copper–zinc su-
peroxide dismutase 1 affects the steady-state concentration of super-
oxide which promotes OS in brain neural cells (Takamiya et al., 2003).
Strikingly, its glycation by CML in neurons and higher serum and cer-
ebrospinal fluid CML levels in ALS patients reported by Kaufmann et al.
(2004) suggests AGEs role in culmination of ALS. Additionally, familial
amyloidotic polyneuropathy (FAP), an another neurodegenerative dis-
ease characterized by transthyretin (TTR) composed amyloid fibril de-
posits (TTR) (Sousa et al., 2001). Similarly, Shorter and Lindquist
(2005) and Southern et al. (2016) showed that glycated TTR con-
tributes cytotoxicity via oxidative stress and RAGE suggests that AGEs
could progress FAP.
Hormones play an important role in mediating between environ-
ment and structure and function of the brain during throughout life.
Hormonal effects on the brain are classified as organizational impacts
that occur during development and maturity whereas experiential im-
pacts depend on personal life events. Hormones have significant role on
brain function from genes to behavior. Notably, earlier brain functions
are exponentially sensitive to even the slightest shift in the hormonal
milieu (Perz, 1997).
The physiological significance of hormones on CNS has elaborately
reviewed by Andrea et al., 2002. Notably, in various neurodegenerative
diseases such as Alzheimer's, Parkinson's and Huntington's disease, re-
searchers implicated the declined levels of numerous hormones. Simi-
larly, studies have also witnessed role of EDs in CNS diseases (Weiss,
2011). Cohesively, though AGEs pathways been well defined in CNS
diseases, their direct participation on hormonal intervention has not
been explored. However by scrutinizing the AGEs phenomenon, it is
hypothesized that AGEs may possess ancillary effects on CNS by dis-
rupting the key hormones involved in the CNS functions. Hypothala-
mic–pituitary–gonadal (HPG) axis deregulations are implicated in CNS
disease symptoms of post menopause. Gonadotropin-release hormone
secretes LH and FSH which then promote the synthesis of sex steroids,
such as androgens and estrogens. However, drastic estrogen decline
during menopause affects the negative feedback by sex steroids on
gonadotropin production result in increased peripheral LH. The sub-
sequent alteration affects HPG axis leads to anxiety, depression and
modulates learning and memory (Cummings et al., 1998; Daniel et al.,
2006). Thereby, based on Eleni et al. (2002) and Chatzigeorgiou et al.
(2013) observations, it can be hypothesized that AGEs may indirectly
induce CNS pathology through disrupting LH and FSH as well as by
interfering estrogen lead LH and FSH regulations.
In addition sex differentiation and reproductive functions, estrogens
regulate the release of neurotransmitters by interacting with their
abundant receptors on various parts of the brain. By acting as choli-
nergic agonists, they also induce rate-limiting enzymes during neuro-
transmitters formation. Therefore, estrogen disruption by AGEs at this
context, can lead to many common CNS symptoms such as hot flashes,
headaches, and depression (Lawrence and Sahakian, 1995; Sherwin,
1996). Menopause induced changes in the synthesis and secretion of
estrogen contribute to mood, behavior and nociceptive perception
changes in woman's life (Sherwin, 1996). A study by Etgen and
Karkanias (1994) revealed hiking estrogen levels during proestrus in-
fluenced the norepinephrine and dopamine turnover suggest their sig-
nificance in regulation of catecholaminergic system. Moreover, Amin
et al. (2005) portrayed estrogens as serotoninergic agonists by reporting
increased serotonin synthesis in women who shown positive mood and
behavior. EDCs such as 2,4-dichlorophenoxacetic acid and bisphenol A
have been found to disrupt dopamine synthesis, release and turnover by
intervening estrogen or with estrogen receptors (Suzuki et al., 2003).
Therefore, the indirect disruption of the dopaminergic system by AGEs
is hypothesized with their potential estrogen interference.
496
Environment International 123 (2019) 486–500
11. Summary and conclusion
FAGEs which can be considered as potent unstable candidates are
accumulated during aging and chronic degenerative diseases. More
dangerously they are wide spread in westernized as well as highly
processed prudent diets that has shown to disrupt and or exacerbate the
metabolic and hormonal profile of individuals whoever prone to over-
exposure. Since extrapolating different study designs from animals to
humans become more pragmatic nowadays, still we are insufficient of
evidences to develop the efficient methods and guidelines to predict
and mitigate the vulnerability of AGEs.
In this ground, as discussed earlier, AGEs causing damage to bio-
molecules has proved by substantial evidences. However, only small
ratios of publications have dealt with their hormone interfering sce-
narios and among them (except some reports in adipose tissue), hardly
very few publications had discussed the possible mechanisms and at-
tributions. In fact, notwithstanding adverse effects of AGEs been noted
down since past two decades, the necessary measures to limit their
exposure are still underprivileged. Therefore, researchers and scientific
communities are in critical need to reveal the additional features of
AGEs in course of endocrine disruption through clinical as well as ex-
perimental aspects which will hopefully provoke policy makers to
frame strong guidelines and recommendations to overcome AGEs con-
sequences.
Conflict of interest
All the authors declare that there are no conflicts of interest.
Acknowledgement
The authors are thankful to UGC SAP and DST- FIST for providing
the infrastructure facility.
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