Environmental Toxicology and Pharmacology 67 (2019) 102–107

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Environmental Toxicology and Pharmacology

journal homepage: www.elsevier.com/locate/etap

Cadmium: Toxic effects on placental and embryonic development T

⁎
Hui-Xia Geng, Lai Wang
Institute of Chronic Disease Risks Assessment, School of Nursing and Health Sciences, Henan University, Kaifeng, 475004, Henan Province, PR China

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

Keywords: Cadmium is a non-essential trace metal that has strong teratogenic and mutagenic effects in living organisms.
Cadmium The content is more highly enriched in women than in men and can enter the embryo through the placenta and
Pregnancy destroy the placenta's morphological structure, resulting in fetal growth restriction. In this report, we review
Placenta published data linking pregnancy exposure to cadmium to placenta and fetal growth and development toxicity
Embryonic development
and summarize the related mechanisms. An understanding of how cadmium exposure contributes to placental
and fetal development is necessary for the development of prevention and control strategies for fetal develop-
ment defects caused by cadmium exposure during pregnancy.

1. Introduction
Cadmium is a ubiquitous heavy metal with multiple organ toxicity
that is constantly released into the environment through human eco-
nomic activities, causing great harm to human health. Cadmium enters
the human body mainly through occupational exposure, diet,
breathing, smoking, or drinking water. In recent years, diet has been
verified as the main source of human exposure to cadmium pollution.
An investigation in southern Jiangsu Province, China, showed that
approximately 14.89% of cadmium in the soil was transferred into rice
grains, and up to 3.19% could be transferred from rice grains to the
human body through rice consumption (Li et al., 2017a). However, the
survey of pregnant women also showed that the blood cadmium con-
centration was related to diet, and this correlation with the offspring of
serum cadmium concentration was consistent (Moynihan et al., 2017).
Cadmium causes damage to multiple organs and tissues, such as the
kidneys, liver, lungs, bones and brain, and leads to cells carcinogenesis
in these organs. The United States Environmental Protection Agency
(USEPA) classifies cadmium as a probable human carcinogen (Group
B1). In recent years, a number of studies have shown that female body
cadmium enrichment is higher than that in men, and cadmium can
cross the placenta, affecting the placental development and function,
and into the fetus, gathering in multiple organs and systems, resulting
in fetal body-related gene expression disorder. Its short-term effect is to
interfere with the normal process of fetal development, while long-
term, it leads to a variety of systemic diseases in adults. During
breastfeeding, cadmium can be secreted into the milk, which aggregates
in the offspring’s body, and destroys the learning and memory ability of
the offspring (Dharmadasa and Kim, 2017; Halder et al., 2016). Thus,
exposure to cadmium during pregnancy not only causes damage to
women themselves, but also causes placental and fetal development
disorders and may cause long-term functional impairment of the off-
spring (Jacobo-Estrada et al., 2017).
2. Toxicity of cadmium in placental development
2.1. Cadmium placenta enrichment and toxicity
The placenta develops between the endometrium and the embry-
ophoric membrane after female pregnancy. The placenta is the main
location for maternal and fetal material and energy exchange. The
placenta can synthesize and secrete some hormones, filter out harmful
substances in the blood, and provide nutrition and functional support
for the development of the embryo. Therefore, during pregnancy, when
the normal placenta formation process is destroyed or placental func-
tion-related gene expression levels are changed, placental function may
be damaged, which ultimately affects the normal development of the
fetus. Cadmium can pass through the placenta during pregnancy and

Abbreviations: Cd, cadmium; ABC, adenosine triphosphate (ATP)-binding cassette; ABCG2, ATP-binding cassette transporter G2; ABCB4, ATP-binding cassette
transporter B4; LA-ICP-MS, laser ablation inductively coupled plasma mass spectrometry; TGF-β, transforming growth factor-β; PCFT, proton-coupled folate
transporter; PCNA, proliferating cell nuclear antigen; OXPHOS, oxidative phosphorylation; CDkn-1c, cyclin dependent kinase inhibitor-1c; Peg-10, paternally ex-
pressed gene -10; PCDH, protocadherin; NR3C1, glucocorticoid receptor; IL, interleukin; FGR, fetal growth restriction; IUGR, intrauterine growth restriction; DOHaD,
developmental origins of health and disease
⁎
Corresponding author.
E-mail address: wanglai@henu.edu.cn (L. Wang).

https://doi.org/10.1016/j.etap.2019.02.006
Received 4 August 2018; Received in revised form 12 February 2019; Accepted 14 February 2019
Available online 15 February 2019
1382-6689/ © 2019 Elsevier B.V. All rights reserved.
H.-X. Geng and L. Wang
accumulate in the placenta, where it may impair placental function and
affect fetal development (Taylor et al., 2018). During pregnancy, ex-
posure to cadmium increases its concentration in the placenta, but its
detailed mechanism still requires elucidation.
The adenosine triphosphate (ATP)-binding cassette (ABC) trans-
porter receptor protein is a member of the superfamily of membrane
proteins. It widely participates in the transport of various substrates,
heavy metals, and other substances through the cell membrane, which
must hydrolyze ATP to supply energy. ATP-binding cassette transporter
G2 (ABCG2) and B4 (ABCB4), an important metal transporter, mediate
the transport of divalent heavy metal ions across cell membranes. The
expression levels of ABCG2 and ABCG4 were found to be significantly
lower in the placenta in Sprague-Dawley rats during pregnancy ex-
posure to cadmium, indicating that the expression of membrane pro-
teins involved in heavy metal transport in the placenta after cadmium
exposure was reduced, thereby decreasing their transport function and
increasing the intracellular accumulation of cadmium in the placenta of
cadmium-treated rats (Liu et al., 2016).The research of placenta his-
topathology of the rats with a single cadmium exposure on gestation
day 18 showed that the trophoblasts in the labyrinth zone were swelling
at 1 h and had vacuolar degeneration at 2 and 3 h. After 6 and 24 h,
syncytiotrophoblast-selective necrosis or apoptosis resulted in a drastic
decrease in cell number. In the trophoblastic septa, the expression of
matrix metalloproteinase was significantly increased, particularly in
cytotrophoblasts at 24 h after exposure. The localization of cadmium in
the placenta was detected by the laser ablation inductively coupled
plasma mass spectrometry (LA-ICP-MS), which was prominent in the
labyrinth zone and tended to increase with the progression of tropho-
blastic septa damages (Yamagishi et al., 2016). In the case of the same
cadmium salt (CdCl2), although there were differences in animal
models, routes and length of cadmium exposure, it was observed that
cadmium exposure resulted in decreased expression of metal trans-
porter, cadmium ion accumulation, apoptosis and placental structure
destruction in the placenta of cadmium exposure during pregnancy in
mice (Table 1).
Cadmium reduces the expression of related functional genes in the
placenta, affecting the morphology and function of cells in different
functional regions of the placenta, such as reducing the proliferation
and migration of trophoblast cells, thereby affecting the normal pla-
cental formation and development. S100 P, a member of the calcium-
binding protein family, is involved in the regulation of cell prolifera-
tion. Studies on human trophoblast-derived cell lines show that ex-
posure to cadmium inhibits the expression of S100 P and thus reduces
the proliferation of placental trophoblast cells (Zhou et al., 2016). miR-
26a is an important regulator of trophoblast cell migration. Cadmium
reduces the expression of miR-26a in trophoblast cells and inhibits the
expression of the transforming growth factor-β (TGF-β) signal trans-
duction process, which reduces the rate of cell migration, resulting in
the delaying or slowing of placenta formation and reducing the dia-
meter and weight of the placenta. Then, both mRNA and protein levels
of proton-coupled folate transporter (PCFT) in the placenta are down-
regulated, which limits the normal development of the fetus, leading to
increased neural tube defects (Brooks and Fry, 2017; Zhang et al.,
2016).
In addition to inhibiting the proliferation and migration of tropho-
blast cells, cadmium in the rat placenta can also cause decreased pro-
liferating cell nuclear antigen (PCNA) expression in placental macro-
phages, spongiotrophoblast cells, trophoblast giant cells, and labyrinth
trophoblast cells, thereby promoting apoptosis, significantly decreasing
the size of the placental layer, reducing the quality of the placenta, and
delaying placental development as compared with the control group
(Erboga and Kanter, 2016). Thus, the cadmium ions in the placenta can
reduce trophoblast cell proliferation, promote its apoptosis, inhibit its
migration, and ultimately delay the placental development process.
Then, the formation of placental size and quality is lower than the
normal developmental process, which is the toxicity of cadmium in
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Environmental Toxicology and Pharmacology 67 (2019) 102–107
placental development. However, proteomic analysis of placental spe-
cimens from an e-waste area showed that high cadmium inhibits fu-
marate hydratase expression, thereby affecting oxidative phosphoryla-
tion (OXPHOS) of cells, decreasing mitochondrial function, and
affecting energy utilization, which delays placental development. This
study suggests that the toxicity of cadmium in placental development
not only reduces trophoblast cell proliferation, promotes apoptosis, and
inhibits migration, but also reduces the process of placental cell energy
production (Xu et al., 2016a).Studies on human chorionic and tropho-
blast cell lines, such as HTR-8/SVneo cells, JEG-3 cells, have shown that
cadmium causes a decrease in the activity, proliferation and migration
of these cells. These results are consistent the toxicological effects of
cell apoptosis and placental structure destruction in mice exposure to
cadmium during pregnancy. However, if the selected cell lines derive
from the animal species in the in vivo experiment, these results will be
mutually verified, complement each other, and be more scientific,
strictness and accuracy (Table 1).
2.2. The mechanisms of cadmium placental developmental toxicity
Epigenetics are broadly described as heritable alterations in gene
function, which do not involve variations in DNA sequence, genomic
imprinting, and DNA methylation as the major form of epigenetic
modification (Bitto et al., 2014). In recent years, the effects of cadmium
exposure on an organism’s epigenetic signatures have become one of its
toxicological mechanisms. The epigenetic mechanism of cadmium on
placental development is mainly DNA methylation changes (Vilahur
et al., 2015). However, cadmium exposure in early life alters DNA
methylation differently in girls and boys. The methylation changes of
genes are associated with organ development, morphology, and mi-
neralization of bone in girls, whereas changes in boys were found in cell
death-related genes (Kippler et al., 2013).
Studies of 13 imprinted genes associated with placenta and em-
bryonic development in C57BL/6 mice indicate that the maternally
expressed gene, cyclin-dependent kinase inhibitor-1c (CDkn-1c), and
paternally expressed gene, paternally expressed gene-10 (Peg-10), were
significantly upregulated and downregulated, respectively, in the Cd-
exposed placentas when compared to the normal placentas. The results
of bisulfate polymerase chain reaction (PCR) revealed that the methy-
lation patterns of the promoter regions of Cdkn1c and Peg10 were
changed, which led to the disturbance of gene expression in the Cd-
exposed placentas (Xu et al., 2017). Protocadherin (PCDH), a single-
stranded transmembrane glycoprotein, is a member of the cadherin
superfamily that is involved in the biological processes of cell-cell re-
cognition, adhesion, migration, communication, and tissue differ-
entiation. PCDH genes are primarily known for their functions in early
embryonic and central nervous system development, and cause devel-
opmental delay and other cerebral abnormalities (Brown et al., 2013;
Anitha et al., 2013). The expression of protocadherin alpha subfamily-
C1 (PCDHA-C1) is abundant in the placenta and in early embryogen-
esis, which promotes the growth and development of the placenta and
embryo. An increasing number of studies have shown that the expres-
sion level of PCDHA-C1 in the placenta was inversely correlated with
cadmium concentrations in the mother's toenail. The mechanism was
strongest amongst those with low levels of DNA methylation in the
promoter region of placental PCDHAC1, downregulating gene expres-
sion and affecting placenta and embryo development and growth
(Everson et al., 2016).
The placenta is involved in the development of the fetal hypotha-
lamic-pituitary-adrenal axis (HPA), regulates the expression of gluco-
corticoid receptor (NR3C1) and downstream target genes, and controls
the endogenous stability of cortisol levels in the fetal body or easily
leads to abnormal fetal development and the emergence of long-term
cognitive and neurobehavioral problems in children. Cohort studies
have shown that maternal cadmium exposure during pregnancy leads
to increased methylation of the NR3C1 promoter in the placenta,
 H.-X. Geng and L. Wang

Table 1
Summary table of the difference of cadmium exposure.
Model Cell lines Type of cadmium salt Routes of exposure Length of Effects of exposure References
exposure

Placenta Sprague-Dawley rat Unclear CdCl2 Gavage 20 Days Down-regulated ABCG2 and ABCB4 transporters (Liu et al., 2016)
Wistar Hannover rat Unclear CdCl2 Subcutaneous injection 18 Days Histopathological changes (Yamagishi et al., 2016)
HTR-8/SVneo CdCl2 Medium 24 h Decreased S100 P expression and cell proliferation (Zhou et al., 2016)
cells
JEG-3 cells CdCl2 Medium 48 h Inhibited trophoblast cell migration (Brooks and Fry, 2017)
ICR mice Unclear CdCl2 Intraperitoneal injection 10 Days Downregulated placental folate transporters (Zhang et al., 2016)
Wistar rat Unclear CdCl2 Subcutaneous injection 21 Days Inhibited trophoblast cell proliferation (Erboga and Kanter, 2016)
Maternal placenta Unclear E-waste exposure Unclear Unclear Downregulated fumarate hydratase (Xu et al., 2016a)
C57BL/6 mice Unclear CdCl2 Drinking water 6,9 and 12 Days Dysregulation of DNAM and expression of imprinted genes (Xu et al., 2017)
Maternal and newborn Unclear Unclear Unclear Unclear Downregulated DNAM and expression of PCDHAC1 (Everson et al., 2016)
toenails
Maternal and newborn Unclear Unclear Unclear Unclear Increased DNAM of glucocorticoid receptor (Appleton et al., 2017)
toenails
CD-1 mice JEG-3 cells CdCl2, Intraperitoneal injection 8 and 24 h Induced inflammatory cytokines expression (Hu et al., 2018)
Maternal placenta Unclear Unclear Unclear Unclear Increased DNAM of inflammatory signaling genes (Everson et al., 2018)
Embryo Zebrafish embryo Unclear CdCl2 medium 9h Downregulated XPC and p-regulated UV-DDB2 gene (Ling et al., 2017)

104
expression
Zebrafish embryo Unclear CdCl2 Medium 4h Downregulated expression of both RBBP6 and CRYL1 genes (Scudiero et al., 2017)
Sprague-Dawley rat Unclear CdCl2 Intraperitoneal injection 8 Days Blocked fetal Leydig cell development (Li et al., 2017b)
Neonate Unclear E-waste recycling Unclear Reduced female neonate development (Zhang et al., 2017)
area
B6D2 Sperm and embryo Unclear Cadmium acetate Medium < 84 h Reduced sperm motility, fertilization rate and blastocyst (Zhao et al., 2017)
formation rate in vitro
Maternal toenails Unclear Unclear Unclear Unclear Resulted in intrauterine growth restriction (Everson et al., 2017)
Maternal serum Unclear Unclear Unclear Unclear Resulted in SGA infants (Wang et al., 2016a)
Maternal urine Unclear Unclear Unclear Unclear Delayed fetal growth (Cheng et al., 2017)
Maternal serum Unclear Unclear Unclear Unclear Reduced female neonatal development (Taylor and Golding, 2016)
Maternal urine Unclear Unclear Unclear Unclear Reduced female neonatal development (Romano et al., 2016)
57BL/6 mice Unclear CdCl2 Drinking water 6, 9, and 12 Days Upregulated the DNMT3B/3 L expressions, while (Xu et al., 2016b)
downregulating GLUT3
Wistar rat Unclear CdCl2 Drinking water 20 Days Disrupted zinc transplacental handover (Mikolić et al., 2015)
CD-1 mice Unclear CdCl2 Intraperitoneal injection, Drinking 9 and 18 Days Downregulated Znt1 and Znt2 expressions (Wang et al., 2016b)
water

CdCl2: Cadmium chloride; S100P: Ca2+-binding S100 protein family; DNAM: DNA methylation; XPC: xeroderma pigmentosum C; UV-DDB2: UV-damaged DNA-binding protein 2; RBBP6: retinoblastoma binding protein
6; CRYL1 :crystallin-lambda 1; B6D2:C57BL/6 × DBA/2; SGA: small for gestational age; DNMT: DNA methyltransferase; GLUT3: glucose transporters 3; Znt: zinc transporters.
Environmental Toxicology and Pharmacology 67 (2019) 102–107
H.-X. Geng and L. Wang
decreased NR3C1 expression and function, and fetal development at
abnormal cortisol concentrations. Taken together, these results indicate
that prenatal exposure to cadmium may affect the offspring's NR3C1
activity, which may help explain cognitive and neurodevelopmental
abnormalities and other mechanisms of long-term toxicological effects
in life (Appleton et al., 2017).
These are various inflammatory gene expression throughout mid-to-
late gestation in rat placenta and warrant further the placenta and fetus
development (Vaswani et al., 2018).Nevertheless, pro-inflammatory
cytokine expression disorders may be associated with placental dys-
function and impaired fetal growth, which lead to preeclampsia and
fetal growth restriction (Cotechini et al., 2014; Liang et al., 2018 Jun;
Zenerino et al., 2017). A growing body of evidence suggests that cad-
mium has pro-inflammatory activities. Several inflammatory cytokines,
tumor necrosis factor-α (TNF-α), interleukin (IL)-8, and IL-6, were
upregulated in the placentas of mice with CdCl2 (3.0 mg/kg) on ge-
stational day 15 (GD15) (intraperitoneally injected) compared with the
control mice. Additional experiments showed that gestational Cd ex-
posure activated Akt signaling in the mouse placenta, and LY294002, a
specific inhibitor of PI3K, blocked CdCl2-evoked Akt phosphorylation
and inhibited CdCl2-induced inflammatory cytokine expression (Hu
et al., 2018). An epigenome-wide association study (EWAS) between
cadmium concentrations and DNA methylation (DNAM) from human
placentae showed that higher cadmium was associated with increased
DNAM levels in inflammatory signaling genes (TNFAIP2, ACOT7, and
RORA), which disturbed inflammatory processes, and impaired pla-
cental function and development (Everson et al., 2018).
Cadmium exposure during pregnancy leads to changes in the me-
thylation pattern of imprinted genes, protocadherin, glucocorticoid
receptors and genes governing placental development, which affects the
development of the placenta and exerts a toxicological effect
(Table 1).Although these studies have different cadmium exposure
animal models, types of cadmium salts, routes and length of cadmium
exposure, the changes in the methylation patterns of related genes have
all been observed, especially in the study of human placenta, which
provide a scientific basis for prevention and treatment of placental or
fetal developmental defects due to cadmium exposure during preg-
nancy. However, there are many types of genes involved in placental
development. If it can prove that the changes of methylation profile of
placental development genes caused by cadmium exposure during
pregnancy, it can reveal the extensiveness and consistency of cadmium
placental developmental toxicity.
3. Embryonic developmental toxicity of cadmium
3.1. Cadmium causes abnormal expression of related genes in embryos
In addition to affecting the formation and development of the pla-
centa during pregnancy, cadmium exposure during pregnancy can also
be enriched in the embryo, reducing the expression of related genes in
the fetus, leading to abnormal embryonic development and congenital
disorders of the structure and function of some tissues and organs in the
offspring. Zebrafish are the best model organism for studying the en-
vironmental toxicity in vertebrates due to its advantages of small size,
convenient breeding, strong fertility, transparent embryonic body, and
nearly 90% homology with human genes. The expression profile of
nucleotide excision repair genes (NER) was altered when the zebrafish
embryos were exposed to cadmium. Exposure of embryos at 1 h post-
fertilization to 3–5 μM of cadmium induced a 2- to 3-fold increase of
oxidative stress. The expression of xeroderma pigmentosum C (XPC)
was downregulated, while the expression of DNA-damage-binding
protein 2 (UV-DDB2) was upregulated by real-time reverse transcrip-
tion (RT)-PCR in mildly-stressed embryos. With the increase of cad-
mium concentration, oxidative stress in embryos was further increased
with the increase of 8-oxoguanine DNA glycosylase (OGG1) gene ex-
pression. However, the expression of genes related to nucleotide
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Environmental Toxicology and Pharmacology 67 (2019) 102–107
excision repair was downregulated. This study showed that cadmium
exposure easily leads to increased intra-embryonic oxidative status, and
at lower concentrations, showed increased DNA repair-related gene
expression, indicating that at low concentrations, it can cause em-
bryonic genome damage and increase the DNA repair process.
However, at high concentrations, it results in decreased expression le-
vels of nucleotide excision repair genes, which affects the DNA repair
process, resulting in embryonic development abnormalities (Ling et al.,
2017).
Retinoblastoma binding protein 6 (RBBP6) is associated with in-
creased protein degradation and cell proliferation, and crystallin-
lambda 1 (CRYL1) is a lens protein with redox activity. Some studies
have also shown that exposure to cadmium upregulates the expression
of both RBBP6 and CRYL1 genes in a dose-dependent manner at the
gastrula stage, the early phases of zebrafish development. Eventually,
the retinal morphology in adult zebrafish retinas are altered due to
exposure to cadmium during pregnancy (Scudiero et al., 2017). Em-
bryonic interstitial Leydig cells are the main source of production and
secretion of male hormones, which are the critical factors for testis
descent and the development of the male reproductive tract. Adult 64-
day-old Sprague-Dawley rats received a single intraperitoneal injection
of 0, 0.25, 0.5, and 1.0 mg/kg cadmium on gestational day 12. On ge-
stational day 20 (GD), the results from this study indicated that cad-
mium dose-dependently reduced testosterone production of fetal testis
and downregulated protein expression levels of Leydig (LHCGR,
SCARB1, STAR, CYP11A1, HSD3B1, and CYP17A1) and Sertoli cells
(HSD17B3, DHH, and FSHR). Thereby, maternal exposure to cadmium
during the pregnancy reduced the formation of testosterone in fetal
rats, lowered fetal Leydig cell numbers, and interfered with normal
male fetal development (Li et al., 2017b).
3.2. Cadmium causes fetal growth restriction
In addition to disrupting the expression of certain genes in the fetus,
cadmium that enters the embryo through the placenta affects normal
fetal development, resulting in intrauterine growth restriction (IUGR)
or fetal growth restriction (FGR) to lower fetal development below
normal months of age and reduce birth anthropometry, such as birth
weight, birth height, head circumference, and Apgar scores in the
newborn (Zhang et al., 2017). Mouse fertilized egg in vitro experiments
confirmed that cadmium exposure inhibits early embryonic develop-
ment and dramatically decreased the blastocyst formation rate, in-
dicating that cadmium exposure during pregnancy leads to abnormal-
ities in embryonic development, but also shows that cadmium exposure
during pregnancy is more hazardous to fetal development than to the
mother (Zhao et al., 2017).
A population-based survey of the associations between maternal
toenail cadmium and fetal development showed that Cd concentrations
in maternal toenails increase intrauterine growth restriction (IUGR) and
small for gestational age (SGA) births by 1.95 and 1.46 times, respec-
tively, which demonstrates that maternal exposure to Cd during preg-
nancy reduces embryo development and results in fetal growth re-
striction or limited functional development (Everson et al., 2017). A
prospective cohort study based on a population of 3254 pregnancies
also showed similar results, such as maternal serum Cd level in preg-
nancy, with an approximately 10.6% risk of small for gestational age
(SGA) infants in the high cadmium group (≥1.06 μg/L), significantly
higher than 7.5% among subjects in the low cadmium group
(< 1.06 μg/L). However, the study also pointed out that exposure to
cadmium during pregnancy leads to fetal growth restriction. In addi-
tion, the risk of SGA may be related to the time point of cadmium ex-
posure. In the middle gestational stage, SGA elevates the risk in contrast
to the early gestational stage (Wang et al., 2016a). However, a cohort
study of maternal urinary Cd levels showed that increases in cadmium
concentrations in maternal blood in the first trimester of pregnancy are
related to fetal growth restriction, suggesting that Cd exposure time
H.-X. Geng and L. Wang
during pregnancy is a crucial factor for fetal growth restriction. How-
ever, this correlation is variable due to differences in the number of
people surveyed. It also shows that the mechanism of fetal growth re-
striction caused by exposure to cadmium during pregnancy would
change with the development of the embryo (Cheng et al., 2017). In a
large prospective pregnancy cohort, prenatal exposure to cadmium re-
duced neonatal anthropometry (birthweight, birth length, head cir-
cumference, and ponderal index) had a sex-specific effect, in which
embryotoxicity was associated with girls but not boys. These results
indicate that the effects of prenatal cadmium exposure on fetal growth
restriction are gender-specific, and also reflect the complexity and di-
versity of embryonic developmental toxicity of cadmium (Taylor and
Golding, 2016; Romano et al., 2016).
It can be seen from the above discussion that cadmium exposure
during pregnancy causes the expression levels of multiple genes in
zebrafish and mouse embryos to be disordered, leading to abnormal
embryonic development, especially fetal growth restriction. However,
population-based investigations show that cadmium-induced fetal
growth restriction during pregnancy exposure is connected with ex-
posure dose, time point of cadmium exposure and fetal sex. The dif-
ference of these studies between different species indicate differences in
embryonic developmental toxicity after the exposure to Cd during
pregnancy (Table 1). Therefore, a large number of studies on animal
models and population-based are needed to refine cadmium dose, time
points, length of exposure and other factors to further clarify the dif-
ferences and complexities of embryonic developmental toxicity caused
by cadmium exposure during pregnancy.
3.3. The mechanism of embryonic developmental toxicity of cadmium
3.3.1. Reduced nutrient supply
The detailed mechanism by which cadmium causes fetal growth
restriction remains to be elucidated, but cadmium exposure leads to a
decrease in the expression of carrier proteins associated with nutrient
transport in the placenta. Reducing the nutritional supply of embryos
may be involved in this process. In the early stage of embryonic de-
velopment, there is a large amount of cell proliferation and growth. The
process requires the consumption of large amounts of glucose and other
energy substances, and the lack of energy molecules may interfere with
cell division and growth processes, delaying embryonic development.
In the placenta, a large number of nutrient transporters, such as
glucose transporters (GLUTs), can provide a variety of nutrients needed
during fetal development. Some studies have shown that
the expression of DNA methyltransferase (DNMT) 3B was sig-
nificantly upregulated, and GLUT3 was significantly downregulated in
cadmium-exposed mice when compared to the normal placentas. Data
from bisulfite PCR demonstrated the hypermethylation of the promoter
region of GLUT3. Therefore, maternal exposure to Cd during pregnancy
downregulates the expression of GLUT3, reduces placenta glucose
transport, decreases embryonic nutrient and energy supply, affects the
growth and development of the fetus, and leads to fetal growth re-
striction (Xu et al., 2016b). Further studies have shown that cadmium-
induced fetal growth restriction is related to placental levels of cad-
mium. At low doses, cadmium has no significant association with
neonatal indices, such as birth weight, head circumference, and body
length, while at high doses, cadmium causes fetal growth restriction
(Guo et al., 2016).
3.3.2. Zinc ion (Zn2+) disorder
Zn2+ is a trace metal element necessary for organisms and plays a
key role in many proteins involved in enzymatic reactions, signal
transduction, and DNA repair in vivo, especially in the early stages of
embryo development. Appropriate Zn2+ concentrations determine the
differentiation of nerves, the formation of neuroblasts, and the growth
and development of embryos (Chowanadisai et al., 2013). Oral cad-
mium exposure during pregnancy leads to disturbed translocation of
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Environmental Toxicology and Pharmacology 67 (2019) 102–107
placental metal ions and Zn2+ in Wistar rats and reduces the main-
tenance of fetal nutrition and viability (Mikolić et al., 2015). Studies on
cadmium-caused placenta and fetal metal ion transport disorder have
shown that maternal exposure to cadmium during pregnancy increased
placental zinc ion concentrations and reduced the concentration within
the embryo. Moreover, placental Znt1 and Znt2, two zinc transporters,
were downregulated in cadmium -exposed mice. These results suggest
that maternal Cd exposure during pregnancy reduces Zn transport
across the placenta, resulting in the enrichment of zinc ions in the
placenta and the reduction in the fetus body, inducing fetal growth
restriction due to the lack of zinc ions (Wang et al., 2016b).
In summary, the mechanism for cadmium-induced embryo growth
restriction may be related to the reduction of nutrient supply. These
studies in rats and mice indicate that decreased expression of glucose
transporter and Znt1/2 may be one of its mechanisms. However, the
animal models used in these studies are all rodents, and the mechanism
by which cadmium-induced embryo growth restriction in primate em-
bryos is consistent with these results and further research is needed.
Secondly, in the process of cadmium-induced embryo growth restric-
tion, the alteration of the methylation patterns of genes in placenta or
embryo is also one of its mechanisms (Table 1).
4. Conclusions
The developmental origins of health and disease (DOHaD) empha-
size the impact of the uterine environment on childhood and lifelong
health, suggesting that destruction of embryonic development in early
life and the disturbance of endogenous biological function may lead to
premature death of the fetus and a variety of systemic diseases in
adulthood, such as hypertension, obesity, and diabetes. The low doses
of environmental pollutant exposure in early embryo development is a
causative factor of DOHaD outcomes, which have different types of
epigenetic change in the genome (Hoffman et al., 2017). In this paper,
we review the effects of cadmium exposure on placental and embryonic
development during pregnancy. Although there are differences in an-
imal models, cell lines, routes and length of exposure, type of cadmium
salt and so on in each study, all studies have shown cadmium exposure
during pregnancy. It causes abnormal development in placentas and
embryos, indicating that the placental and embryonic toxicity of cad-
mium coexist between different species, and the toxicological me-
chanisms are similar, such as abnormal changes in gene methylation
(Table 1). In summary, exposure to cadmium during pregnancy affects
not only placental formation and function, but also changes in the ex-
pression of many genes in the embryo, limiting fetal growth and de-
velopment and long-term harmful effects on the function of certain
organs and tissues in offspring, and these processes are associated with
cadmium exposure, leading to aberrant methylation of genes within the
placenta and embryo. Changes in the epigenetic modification patterns
induced by cadmium, such as aberrant methylation, have been linked to
their ability to easily bind to thiols. Cadmium-thiol interactions may
lead to depletion of the methyl donor S-adenosyl-methionine, resulting
in methylome alterations, and subsequently altered DNA methyl-
transferase activity, altering the critical developmental process in early
embryonic stages, causing blockages in fetal development, or changes
in certain functions of the body (Ruiter et al., 2016). Reduced exposure
to cadmium during pregnancy inhibited the abnormal changes of me-
thylation patterns in the promoter region of the genes in placentas or
embryos. This has important theoretical and practical significance in
reducing placental and embryonic developmental toxicity of cadmium,
maintaining the normal intrauterine growth environment of the fetus,
and elucidating the developmental origins of health and disease.
Declarations of interest
None.
H.-X. Geng and L. Wang
Transparency document
The Transparency document associated with this article can be
found in the online version.
Acknowledgments
This work was supported by grants from the Science and
Technology Projects of Henan province (172102310001), Henan
Province Foundation for University Key Teacher (16A330001)
References
Anitha, A., Thanseem, I., Nakamura, K., et al., 2013. Protocadherin α (PCDHA) as a novel
susceptibility gene for autism. J. Psychiatry Neurosci. 38 (3), 192–198.
Appleton, A.A., Jackson, B.P., Karagas, M., et al., 2017. Prenatal exposure to neurotoxic
metals is associated with increased placental glucocorticoid receptor DNA methyla-
tion. Epigenetics 12 (8), 607–615.
Bitto, A., Pizzino, G., Irrera, N., Galfo, F., Squadrito, F., 2014. Epigenetic modifications
due to heavy metals exposure in children living in polluted areas. Curr. Genomics 15
(December (6)), 464–468.
Brooks, S.A., Fry, R.C., 2017. Cadmium inhibits placental trophoblast cell migration via
miRNA regulation of the transforming growth factor beta (TGF-β) pathway. Food
Chem. Toxicol. 109 (Pt 1), 721–726.
Brown, N., Burgess, T., Forbes, R., et al., 2013. 5q31.3 Microdeletion syndrome: clinical
and molecular characterization of two further cases. Am. J. Med. Genet. A 161A (10),
2604–2608.
Cheng, L., Zhang, B., Zheng, T., et al., 2017. Critical windows of prenatal exposure to
cadmium and size at birth. Int. J. Environ. Res. Public Health 14 (1) pii: E58.
Chowanadisai, W., Graham, D.M., Keen, C.L., et al., 2013. Neurulation and neurite ex-
tension require the zinc transporter ZIP12 (slc39a12). Proc. Natl. Acad. Sci. U. S. A.
110 (24), 9903–9908.
Cotechini, T., Komisarenko, M., Sperou, A., Macdonald-Goodfellow, S., Adams, M.A.,
Graham, C.H., 2014. Inflammation in rat pregnancy inhibits spiral artery remodeling
leading to fetal growth restriction and features of preeclampsia. J. Exp. Med. 211
(January (1)), 165–179.
Dharmadasa, P., Kim, N., Thunders, M., 2017. Maternal cadmium exposure and impact on
foetal gene expression through methylation changes. Food Chem. Toxicol. 109 (Pt 1),
714–720.
Erboga, M., Kanter, M., 2016. Effect of cadmium on trophoblast cell proliferation and
apoptosis in different gestation periods of rat placenta. Biol. Trace Elem. Res. 169 (2),
285–293.
Everson, T.M., Armstrong, D.A., Jackson, B.P., et al., 2016. Maternal cadmium, placental
PCDHAC1, and fetal development. Reprod. Toxicol. 65, 263–271.
Everson, T.M., Kappil, M., Hao, K., et al., 2017. Maternal exposure to selenium and
cadmium, fetal growth, and placental expression of steroidogenic and apoptotic
genes. Environ. Res. 158, 233–244.
Everson, T.M., Punshon, T., Jackson, B.P., Hao, K., Lambertini, L., 2018. Cadmium-as-
sociated differential methylation throughout the placental genome: epigenome-wide
association study of two U.S. Birth cohorts. Environ. Health Perspect. 126 (January
(1)), 017010.
Guo, J., Wu, C., Qi, X., et al., 2016. Adverse associations between maternal and neonatal
cadmium exposure and birth outcomes. Sci. Total Environ. 16, 31934–31939.
Halder, S., Kar, R., Galav, V., et al., 2016. Cadmium exposure during lactation causes
learning and memory-impairment in F1 generation mice: amelioration by quercetin.
Drug Chem. Toxicol. 39 (3), 272–278.
Hoffman, D.J., Reynolds, R.M., Hardy, D.B., 2017. Developmental origins of health and
disease: current knowledge and potential mechanisms. Nutr. Rev. 75 (12), 951–970.
Hu, J., Wang, H., Hu, Y.F., Xu, X.F., Chen, Y.H., Xia, M.Z., Zhang, C., Xu, D.X., 2018.
Cadmium induces inflammatory cytokines through activating Akt signaling in mouse
placenta and human trophoblast cells. Placenta 65, 7–14.
Jacobo-Estrada, T., Santoyo-Sánchez, M., Thévenod, F., Barbier, O.C., 2017. Admium
handling, toxicity and molecular targets involved during pregnancy: lessons from
experimental models. Int. J. Mol. Sci. 18 (July (7)) pii: E1590.
Kippler, M., Engström, K., Mlakar, S.J., Bottai, M., Ahmed, S., 2013. Sex-specific effects of
early life cadmium exposure on DNA methylation and implications for birth weight.
107
Environmental Toxicology and Pharmacology 67 (2019) 102–107
Epigenetics 8 (May (5)), 494–503.
Li, T., Chang, Q., Yuan, X., et al., 2017a. Cadmium transfer from contaminated soils to the
human body through rice consumption in southern Jiangsu Province, China. Environ.
Sci. Process Impacts 19 (6), 843–850.
Li, X., Liu, J., Wu, S., et al., 2017b. In utero single low-dose exposure of cadmium induces
rat fetal Leydig cell dysfunction. Chemosphere 194, 57–66.
Liang, T., Jinglong, X., Shusheng, D., Aiyou, W., 2018 Jun. Maternal obesity stimulates
lipotoxicity and up-regulates inflammatory signaling pathways in the full-term swine
placenta. Anim. Sci. J.(June 26). https://doi.org/10.1111/asj.13064.
Ling, L.B., Chang, Y., Liu, C.W., et al., 2017. Oxidative stress intensity-related effects of
cadmium (Cd) and paraquat (PQ) on UV-damaged-DNA binding and excision repair
activities in zebrafish (Danio rerio) embryos. Chemosphere 167, 10–18.
Liu, L., Zhou, L., Hu, S., et al., 2016. Down-regulation of ABCG2 and ABCB4 transporters
in the placenta of rats exposed to cadmium. Oncotarget 7 (25), 38154–38163.
Mikolić, A., Piasek, M., Sulimanec Grgec, A., et al., 2015. Oral cadmium exposure during
rat pregnancy: assessment of transplacental micronutrient transport and ster-
oidogenesis at term. J. Appl. Toxicol. 35 (5), 508–519.
Moynihan, M., Peterson, K.E., Cantoral, A., et al., 2017. Dietary predictors of urinary
cadmium among pregnant women and children. Sci. Total Environ. 575, 1255–1262.
Romano, M.E., Enquobahrie, D.A., Simpson, C., et al., 2016. Maternal body burden of
cadmium and offspring size at birth. Environ. Res. 147, 461–468.
Ruiter, S., Sippel, J., Bouwmeester, M.C., et al., 2016. Programmed effects in neurobe-
havior and antioxidative physiology in zebrafish embryonically exposed to cadmium:
observations and hypothesized adverse outcome pathway framework. Int. J. Mol. Sci.
17 (11) pii: E1830.
Scudiero, R., Esposito, M.G., Simoniello, P., et al., 2017. Retinoblastoma binding protein
6 and crystallin lambda 1 are cadmium-responsive genes in zebrafish embryos and
adults retinae. C. R. Biol. 340 (4), 197–203.
Taylor, C.M., Golding, J., 2016. EmondAM.Moderate Prenatal Cadmium Exposure and
Adverse Birth Outcomes: a Role for Sex-Specific Differences? Paediatr. Perinat.
Epidemiol. 30 (6), 603–611.
Taylor, C.M., Emond, A.M., Lingam, R., Golding, J.P., 2018. Renatal lead, cadmium and
mercury exposure and associations with motor skills at age 7 years in a UK ob-
servational birth cohort. Environ. Int. 117, 40–47.
Vaswani, K., Dekker Nitert, M., Chan, H.W., Almughlliq F, B., 2018. Mid-to-Late gesta-
tional changes in inflammatory gene expression in the rat placenta. Reprod. Sci. 25
(February (2)), 222–229.
Vilahur, N., Vahter, M., Broberg, K., 2015. The epigenetic effects of prenatal cadmium
exposure. Curr. Environ. Health Rep. 2 (2), 195–203.
Wang, H., Liu, L., Hu, Y.F., et al., 2016a. Maternal serum cadmium level during preg-
nancy and its association with small for gestational age infants: a population-based
birth cohort study. Sci. Rep. 6, 22631.
Wang, H., Wang, Y., Bo, Q.L., et al., 2016b. Maternal cadmium exposure reduces pla-
cental zinc transport and induces fetal growth restriction in mice. Reprod. Toxicol.
63, 174–182.
Xu, L., Ge, J., Huo, X., et al., 2016a. Differential proteomic expression of human placenta
and fetal development following e-waste lead and cadmium exposure in utero. Sci.
Total Environ. 550, 1163–1170.
Xu, P., Wu, Z., Xi, Y., et al., 2016b. Epigenetic regulation of placental glucose transporters
mediates maternal cadmium-induced fetal growth restriction. Toxicology 372,
34–41.
Xu, P., Wu, Z., Yang, W., et al., 2017. Dysregulation of DNA methylation and expression
of imprinted genes in mouse placentas of fetal growth restriction induced by maternal
cadmium exposure. Toxicology 390, 109–116.
Yamagishi, Y., Furukawa, S., Tanaka, A., et al., 2016. Histopathological localization of
cadmium in rat placenta by LA-ICP-MS analysis. J. Toxicol. Pathol. 29 (4), 279–283.
Zenerino, C., Nuzzo, A.M., Giuffrida, D., Biolcati, M., Zicari, A., Todros, T., Rolfo, A.,
2017. The HMGB1/RAGE pro-inflammatory Axis in the human placenta: modulating
effect of low molecular weight heparin. Molecules 22 (11) pii: E1997.
Zhang, G.B., Wang, H., Hu, J., et al., 2016. Cadmium-induced neural tube defects and
fetal growth restriction: association with disturbance of placental folate transport.
Toxicol. Appl. Pharmacol. 306, 79–85.
Zhang, Y., Xu, X., Chen, A., et al., 2017. Maternal urinary cadmium levels during preg-
nancy associated with risk of sex-dependent birth outcomes from an e-waste pollution
site in China. Reprod. Toxicol. 75, 49–55.
Zhao, L.L., Ru, Y.F., Liu, M., et al., 2017. Reproductive effects of cadmium on sperm
function and early embryonic development in vitro. PLoS One 12 (11), e0186727.
Zhou, T., Wang, H., Zhang, S., et al., 2016. S100P is a potential molecular target of
cadmium-induced inhibition of human placental trophoblast cell proliferation. Exp.
Toxicol. Pathol. 68 (10), 565–570.