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Cadmium: Toxic effects on placental and embryonic development
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 Pregnancy Placenta Embryonic development
Cadmium is a non-essential trace metal that has strong teratogenic and mutagenic effects in living organisms. The content is more highly enriched in women than in men and can enter the embryo through the placenta and destroy the placenta's morphological structure, resulting in fetal growth restriction. In this report, we review published data linking pregnancy exposure to cadmium to placenta and fetal growth and development toxicity 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 development 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 economic 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 concentration 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 longterm, 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 offspring (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 embryophoric 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 function-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 expressed 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: [email protected] (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.
Environmental Toxicology and Pharmacology 67 (2019) 102–107
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placental development. However, proteomic analysis of placental specimens from an e-waste area showed that high cadmium inhibits fumarate hydratase expression, thereby affecting oxidative phosphorylation (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 trophoblast 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).
accumulate in the placenta, where it may impair placental function and affect fetal development (Taylor et al., 2018). During pregnancy, exposure to cadmium increases its concentration in the placenta, but its detailed mechanism still requires elucidation. The adenosine triphosphate (ATP)-binding cassette (ABC) transporter 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 exposure to cadmium, indicating that the expression of membrane proteins 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 histopathology 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 trophoblastic 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 transporter, 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 placental formation and development. S100 P, a member of the calciumbinding protein family, is involved in the regulation of cell proliferation. Studies on human trophoblast-derived cell lines show that exposure to cadmium inhibits the expression of S100 P and thus reduces the proliferation of placental trophoblast cells (Zhou et al., 2016). miR26a 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 transduction process, which reduces the rate of cell migration, resulting in the delaying or slowing of placenta formation and reducing the diameter and weight of the placenta. Then, both mRNA and protein levels of proton-coupled folate transporter (PCFT) in the placenta are downregulated, 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 trophoblast cells, cadmium in the rat placenta can also cause decreased proliferating cell nuclear antigen (PCNA) expression in placental macrophages, 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
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 mineralization 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 embryonic 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 Cdexposed placentas when compared to the normal placentas. The results of bisulfate polymerase chain reaction (PCR) revealed that the methylation patterns of the promoter regions of Cdkn1c and Peg10 were changed, which led to the disturbance of gene expression in the Cdexposed placentas (Xu et al., 2017). Protocadherin (PCDH), a singlestranded transmembrane glycoprotein, is a member of the cadherin superfamily that is involved in the biological processes of cell-cell recognition, adhesion, migration, communication, and tissue differentiation. PCDH genes are primarily known for their functions in early embryonic and central nervous system development, and cause developmental delay and other cerebral abnormalities (Brown et al., 2013; Anitha et al., 2013). The expression of protocadherin alpha subfamilyC1 (PCDHA-C1) is abundant in the placenta and in early embryogenesis, which promotes the growth and development of the placenta and embryo. An increasing number of studies have shown that the expression 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 expression and affecting placenta and embryo development and growth (Everson et al., 2016). The placenta is involved in the development of the fetal hypothalamic-pituitary-adrenal axis (HPA), regulates the expression of glucocorticoid 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, 103
104 4h 8 Days Unclear
Intraperitoneal injection Unclear medium Medium Intraperitoneal injection
CdCl2, Unclear CdCl2
JEG-3 cells Unclear Unclear
Unclear Unclear Unclear
Unclear
Unclear Unclear Unclear Unclear Unclear Unclear
Unclear Unclear
Zebrafish embryo Sprague-Dawley rat Neonate
B6D2 Sperm and embryo
Maternal toenails Maternal serum Maternal urine Maternal serum Maternal urine 57BL/6 mice
Wistar rat CD-1 mice
CdCl2 CdCl2
Unclear Unclear Unclear Unclear Unclear CdCl2
Unclear Unclear Unclear Unclear Unclear 6, 9, and 12 Days 20 Days 9 and 18 Days
Drinking water Intraperitoneal injection, Drinking water
< 84 h
Unclear Unclear Unclear Unclear Unclear Drinking water
Medium
8 and 24 h Unclear 9h
Unclear
Unclear
Unclear
CdCl2 CdCl2 E-waste recycling area Cadmium acetate
48 h 10 Days 21 Days Unclear 6,9 and 12 Days Unclear
Medium Intraperitoneal injection Subcutaneous injection Unclear Drinking water Unclear
CdCl2 CdCl2 CdCl2 E-waste exposure CdCl2 Unclear
ICR mice Wistar rat Maternal placenta C57BL/6 mice Maternal and newborn toenails Maternal and newborn toenails CD-1 mice Maternal placenta Zebrafish embryo Unclear
20 Days 18 Days 24 h
Length of exposure
Gavage Subcutaneous injection Medium
Routes of exposure
CdCl2 CdCl2 CdCl2
Type of cadmium salt
Unclear Unclear HTR-8/SVneo cells JEG-3 cells Unclear Unclear Unclear Unclear Unclear
Sprague-Dawley rat Wistar Hannover rat
Cell lines
Reduced sperm motility, fertilization rate and blastocyst formation rate in vitro Resulted in intrauterine growth restriction Resulted in SGA infants Delayed fetal growth Reduced female neonatal development Reduced female neonatal development Upregulated the DNMT3B/3 L expressions, while downregulating GLUT3 Disrupted zinc transplacental handover Downregulated Znt1 and Znt2 expressions
Induced inflammatory cytokines expression Increased DNAM of inflammatory signaling genes Downregulated XPC and p-regulated UV-DDB2 gene expression Downregulated expression of both RBBP6 and CRYL1 genes Blocked fetal Leydig cell development Reduced female neonate development
Increased DNAM of glucocorticoid receptor
Inhibited trophoblast cell migration Downregulated placental folate transporters Inhibited trophoblast cell proliferation Downregulated fumarate hydratase Dysregulation of DNAM and expression of imprinted genes Downregulated DNAM and expression of PCDHAC1
Down-regulated ABCG2 and ABCB4 transporters Histopathological changes Decreased S100 P expression and cell proliferation
Effects of exposure
(Mikolić et al., 2015) (Wang et al., 2016b)
(Everson et al., 2017) (Wang et al., 2016a) (Cheng et al., 2017) (Taylor and Golding, 2016) (Romano et al., 2016) (Xu et al., 2016b)
(Zhao et al., 2017)
(Scudiero et al., 2017) (Li et al., 2017b) (Zhang et al., 2017)
(Hu et al., 2018) (Everson et al., 2018) (Ling et al., 2017)
(Appleton et al., 2017)
(Brooks and Fry, 2017) (Zhang et al., 2016) (Erboga and Kanter, 2016) (Xu et al., 2016a) (Xu et al., 2017) (Everson et al., 2016)
(Liu et al., 2016) (Yamagishi et al., 2016) (Zhou et al., 2016)
References
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.
Embryo
Placenta
Model
Table 1 Summary table of the difference of cadmium exposure.
H.-X. Geng and L. Wang
Environmental Toxicology and Pharmacology 67 (2019) 102–107
Environmental Toxicology and Pharmacology 67 (2019) 102–107
H.-X. Geng and L. Wang
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 embryonic genome damage and increase the DNA repair process. However, at high concentrations, it results in decreased expression levels 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 increased protein degradation and cell proliferation, and crystallinlambda 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). Embryonic 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 64day-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 gestational day 20 (GD), the results from this study indicated that cadmium 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).
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-tolate 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 dysfunction 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 cadmium 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 gestational day 15 (GD15) (intraperitoneally injected) compared with the control mice. Additional experiments showed that gestational Cd exposure 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 placental function and development (Everson et al., 2018). Cadmium exposure during pregnancy leads to changes in the methylation 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 pregnancy. 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.
3.2. 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 development and dramatically decreased the blastocyst formation rate, indicating that cadmium exposure during pregnancy leads to abnormalities 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, respectively, which demonstrates that maternal exposure to Cd during pregnancy reduces embryo development and results in fetal growth restriction 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 pregnancy, 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 addition, the risk of SGA may be related to the time point of cadmium exposure. 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
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 placenta 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 environmental 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 postfertilization 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 transcription (RT)-PCR in mildly-stressed embryos. With the increase of cadmium concentration, oxidative stress in embryos was further increased with the increase of 8-oxoguanine DNA glycosylase (OGG1) gene expression. However, the expression of genes related to nucleotide 105
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placental metal ions and Zn2+ in Wistar rats and reduces the maintenance 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 embryos is consistent with these results and further research is needed. Secondly, in the process of cadmium-induced embryo growth restriction, the alteration of the methylation patterns of genes in placenta or embryo is also one of its mechanisms (Table 1).
during pregnancy is a crucial factor for fetal growth restriction. However, this correlation is variable due to differences in the number of people surveyed. It also shows that the mechanism of fetal growth restriction 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 reduced neonatal anthropometry (birthweight, birth length, head circumference, 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 diversity 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 exposure dose, time point of cadmium exposure and fetal sex. The difference 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 differences and complexities of embryonic developmental toxicity caused by cadmium exposure during pregnancy.
4. Conclusions The developmental origins of health and disease (DOHaD) emphasize 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 animal 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 cadmium coexist between different species, and the toxicological mechanisms 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 expression of many genes in the embryo, limiting fetal growth and development 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 methyltransferase 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 methylation 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.
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 development, 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 significantly 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 restriction (Xu et al., 2016b). Further studies have shown that cadmiuminduced fetal growth restriction is related to placental levels of cadmium. 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 cadmium exposure during pregnancy leads to disturbed translocation of
Declarations of interest None. 106
Environmental Toxicology and Pharmacology 67 (2019) 102–107
H.-X. Geng and L. Wang
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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 methylation. 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 extension 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-associated 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.
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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 Pregnancy Placenta Embryonic development
Cadmium is a non-essential trace metal that has strong teratogenic and mutagenic effects in living organisms. The content is more highly enriched in women than in men and can enter the embryo through the placenta and destroy the placenta's morphological structure, resulting in fetal growth restriction. In this report, we review published data linking pregnancy exposure to cadmium to placenta and fetal growth and development toxicity 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 development 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 economic 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 concentration 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 longterm, 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 offspring (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 embryophoric 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 function-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 expressed 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: [email protected] (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.
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placental development. However, proteomic analysis of placental specimens from an e-waste area showed that high cadmium inhibits fumarate hydratase expression, thereby affecting oxidative phosphorylation (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 trophoblast 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).
accumulate in the placenta, where it may impair placental function and affect fetal development (Taylor et al., 2018). During pregnancy, exposure to cadmium increases its concentration in the placenta, but its detailed mechanism still requires elucidation. The adenosine triphosphate (ATP)-binding cassette (ABC) transporter 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 exposure to cadmium, indicating that the expression of membrane proteins 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 histopathology 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 trophoblastic 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 transporter, 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 placental formation and development. S100 P, a member of the calciumbinding protein family, is involved in the regulation of cell proliferation. Studies on human trophoblast-derived cell lines show that exposure to cadmium inhibits the expression of S100 P and thus reduces the proliferation of placental trophoblast cells (Zhou et al., 2016). miR26a 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 transduction process, which reduces the rate of cell migration, resulting in the delaying or slowing of placenta formation and reducing the diameter and weight of the placenta. Then, both mRNA and protein levels of proton-coupled folate transporter (PCFT) in the placenta are downregulated, 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 trophoblast cells, cadmium in the rat placenta can also cause decreased proliferating cell nuclear antigen (PCNA) expression in placental macrophages, 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
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 mineralization 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 embryonic 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 Cdexposed placentas when compared to the normal placentas. The results of bisulfate polymerase chain reaction (PCR) revealed that the methylation patterns of the promoter regions of Cdkn1c and Peg10 were changed, which led to the disturbance of gene expression in the Cdexposed placentas (Xu et al., 2017). Protocadherin (PCDH), a singlestranded transmembrane glycoprotein, is a member of the cadherin superfamily that is involved in the biological processes of cell-cell recognition, adhesion, migration, communication, and tissue differentiation. PCDH genes are primarily known for their functions in early embryonic and central nervous system development, and cause developmental delay and other cerebral abnormalities (Brown et al., 2013; Anitha et al., 2013). The expression of protocadherin alpha subfamilyC1 (PCDHA-C1) is abundant in the placenta and in early embryogenesis, which promotes the growth and development of the placenta and embryo. An increasing number of studies have shown that the expression 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 expression and affecting placenta and embryo development and growth (Everson et al., 2016). The placenta is involved in the development of the fetal hypothalamic-pituitary-adrenal axis (HPA), regulates the expression of glucocorticoid 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, 103
104 4h 8 Days Unclear
Intraperitoneal injection Unclear medium Medium Intraperitoneal injection
CdCl2, Unclear CdCl2
JEG-3 cells Unclear Unclear
Unclear Unclear Unclear
Unclear
Unclear Unclear Unclear Unclear Unclear Unclear
Unclear Unclear
Zebrafish embryo Sprague-Dawley rat Neonate
B6D2 Sperm and embryo
Maternal toenails Maternal serum Maternal urine Maternal serum Maternal urine 57BL/6 mice
Wistar rat CD-1 mice
CdCl2 CdCl2
Unclear Unclear Unclear Unclear Unclear CdCl2
Unclear Unclear Unclear Unclear Unclear 6, 9, and 12 Days 20 Days 9 and 18 Days
Drinking water Intraperitoneal injection, Drinking water
< 84 h
Unclear Unclear Unclear Unclear Unclear Drinking water
Medium
8 and 24 h Unclear 9h
Unclear
Unclear
Unclear
CdCl2 CdCl2 E-waste recycling area Cadmium acetate
48 h 10 Days 21 Days Unclear 6,9 and 12 Days Unclear
Medium Intraperitoneal injection Subcutaneous injection Unclear Drinking water Unclear
CdCl2 CdCl2 CdCl2 E-waste exposure CdCl2 Unclear
ICR mice Wistar rat Maternal placenta C57BL/6 mice Maternal and newborn toenails Maternal and newborn toenails CD-1 mice Maternal placenta Zebrafish embryo Unclear
20 Days 18 Days 24 h
Length of exposure
Gavage Subcutaneous injection Medium
Routes of exposure
CdCl2 CdCl2 CdCl2
Type of cadmium salt
Unclear Unclear HTR-8/SVneo cells JEG-3 cells Unclear Unclear Unclear Unclear Unclear
Sprague-Dawley rat Wistar Hannover rat
Cell lines
Reduced sperm motility, fertilization rate and blastocyst formation rate in vitro Resulted in intrauterine growth restriction Resulted in SGA infants Delayed fetal growth Reduced female neonatal development Reduced female neonatal development Upregulated the DNMT3B/3 L expressions, while downregulating GLUT3 Disrupted zinc transplacental handover Downregulated Znt1 and Znt2 expressions
Induced inflammatory cytokines expression Increased DNAM of inflammatory signaling genes Downregulated XPC and p-regulated UV-DDB2 gene expression Downregulated expression of both RBBP6 and CRYL1 genes Blocked fetal Leydig cell development Reduced female neonate development
Increased DNAM of glucocorticoid receptor
Inhibited trophoblast cell migration Downregulated placental folate transporters Inhibited trophoblast cell proliferation Downregulated fumarate hydratase Dysregulation of DNAM and expression of imprinted genes Downregulated DNAM and expression of PCDHAC1
Down-regulated ABCG2 and ABCB4 transporters Histopathological changes Decreased S100 P expression and cell proliferation
Effects of exposure
(Mikolić et al., 2015) (Wang et al., 2016b)
(Everson et al., 2017) (Wang et al., 2016a) (Cheng et al., 2017) (Taylor and Golding, 2016) (Romano et al., 2016) (Xu et al., 2016b)
(Zhao et al., 2017)
(Scudiero et al., 2017) (Li et al., 2017b) (Zhang et al., 2017)
(Hu et al., 2018) (Everson et al., 2018) (Ling et al., 2017)
(Appleton et al., 2017)
(Brooks and Fry, 2017) (Zhang et al., 2016) (Erboga and Kanter, 2016) (Xu et al., 2016a) (Xu et al., 2017) (Everson et al., 2016)
(Liu et al., 2016) (Yamagishi et al., 2016) (Zhou et al., 2016)
References
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.
Embryo
Placenta
Model
Table 1 Summary table of the difference of cadmium exposure.
H.-X. Geng and L. Wang
Environmental Toxicology and Pharmacology 67 (2019) 102–107
Environmental Toxicology and Pharmacology 67 (2019) 102–107
H.-X. Geng and L. Wang
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 embryonic genome damage and increase the DNA repair process. However, at high concentrations, it results in decreased expression levels 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 increased protein degradation and cell proliferation, and crystallinlambda 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). Embryonic 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 64day-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 gestational day 20 (GD), the results from this study indicated that cadmium 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).
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-tolate 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 dysfunction 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 cadmium 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 gestational day 15 (GD15) (intraperitoneally injected) compared with the control mice. Additional experiments showed that gestational Cd exposure 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 placental function and development (Everson et al., 2018). Cadmium exposure during pregnancy leads to changes in the methylation 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 pregnancy. 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.
3.2. 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 development and dramatically decreased the blastocyst formation rate, indicating that cadmium exposure during pregnancy leads to abnormalities 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, respectively, which demonstrates that maternal exposure to Cd during pregnancy reduces embryo development and results in fetal growth restriction 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 pregnancy, 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 addition, the risk of SGA may be related to the time point of cadmium exposure. 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
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 placenta 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 environmental 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 postfertilization 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 transcription (RT)-PCR in mildly-stressed embryos. With the increase of cadmium concentration, oxidative stress in embryos was further increased with the increase of 8-oxoguanine DNA glycosylase (OGG1) gene expression. However, the expression of genes related to nucleotide 105
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placental metal ions and Zn2+ in Wistar rats and reduces the maintenance 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 embryos is consistent with these results and further research is needed. Secondly, in the process of cadmium-induced embryo growth restriction, the alteration of the methylation patterns of genes in placenta or embryo is also one of its mechanisms (Table 1).
during pregnancy is a crucial factor for fetal growth restriction. However, this correlation is variable due to differences in the number of people surveyed. It also shows that the mechanism of fetal growth restriction 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 reduced neonatal anthropometry (birthweight, birth length, head circumference, 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 diversity 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 exposure dose, time point of cadmium exposure and fetal sex. The difference 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 differences and complexities of embryonic developmental toxicity caused by cadmium exposure during pregnancy.
4. Conclusions The developmental origins of health and disease (DOHaD) emphasize 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 animal 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 cadmium coexist between different species, and the toxicological mechanisms 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 expression of many genes in the embryo, limiting fetal growth and development 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 methyltransferase 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 methylation 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.
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 development, 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 significantly 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 restriction (Xu et al., 2016b). Further studies have shown that cadmiuminduced fetal growth restriction is related to placental levels of cadmium. 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 cadmium exposure during pregnancy leads to disturbed translocation of
Declarations of interest None. 106
Environmental Toxicology and Pharmacology 67 (2019) 102–107
H.-X. Geng and L. Wang
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