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Abstract

To understand the effects of endocrine-disrupting chemicals (EDCs), the mechanism(s) by which EDCs exert their harmful effects on humans and their offspring needs careful examination and clarification. Epigenetic modification, including DNA methylation, expression of aberrant microRNA (miRNA), and histone modification, is one mechanism assumed to be a primary pathway leading to the untoward effects of endocrine disruptors. However, it remains unclear whether such epigenetic changes caused by EDCs are truly predicting adverse outcomes. Therefore, it is important to understand the relationship between epigenetic changes and various endocrine endpoints or markers. This paper highlights the possibility that certain chemicals (Cd, As, Pb, bisphenol A, phthalate, polychlorinated biphenyls) reported having ED properties may adversely affect the epigenome. Electronic database sources PubMed, SCOPUS, JSTOR, and the Google Scholar web browser were used to search the literature. The search was based on keywords from existing theories and basic knowledge of endocrine disorders and epigenetic effects, well-known EDCs, and previous search results. Unclear and often conflicting results regarding the effects of EDCs indicate the need for further research to support better risk assessments and management of these chemicals.

Graphical Abstract

Keywords

epigenetic modification toxic metals bisphenol A phthalate polychlorinated biphenyls

Introduction

Endocrine-disrupting chemicals (EDCs) are defined by the United Nations World Health Organization (UN WHO) as ‘an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse effects in an intact organism, or its progeny, or (sub)populations.^1,2 The topic of EDCs is related to many heated debates. As recently stated in a review by Goumenou et al. (2021), a huge effort has been already made in this field but also is still needed and essential to tackle all hot topics such as low-dose effects of EDCs, critical windows of exposure, nonmonotonic dose-response phenomena, improvement of testing strategies for EDCs identification, appropriateness of the use of threshold or adversity concepts, etc.³ Furthermore, the introduction the of exposome concept by Wild (2005), as a summation of all exposures and individual experiences over the lifetime, from the moment of conception to advanced age complements the genome, definitely adds another additional layer of complexity to epidemiological studies aiming to derive association between ECDs exposure and particular disease.⁴ Another point is disease transmission to future generations and the relations between EDC exposure of ancestors and disease development in future generations.

The mechanism by which EDCs cause disease transmission to future generations has been hypothesized to include epigenetic modifications.^5,6 Epigenetic changes are defined as a long-term change in gene expression that persists even when the initial trigger is no longer present and which does not involve a change in gene sequence or structure.⁷ The three major epigenetic modifications are DNA (CpG) methylation, aberrant microRNA (miRNA) expression, and histone modification. Various environmental exposures can affect the epigenome.^8,9 However, more work is needed to strengthen the link between exposure-associated epigenetic changes and adverse health outcomes. Exposure to EDCs has been intensively investigated concerning global methylation, while less information is available for gene-specific CpG methylation and miRNA expression. A recent review concluded that perinatal exposure to certain EDCs affects the epigenetic machinery and alters the developmental trajectory of the reproductive and neuroendocrine systems in a sex-specific manner, identifying the female brain as more sensitive to disruption by perinatal EDC exposure than the male brain.¹⁰ This difference could provide a possible explanation for why the female reproductive system is more susceptible to EDCs. Rattan and Flaws (2019) have pointed to epidemiological and experimental evidence of a link between EDCs exposure and adverse ovarian and uterine health outcomes in females across generations.¹¹

One of the important roles of epigenomes in human health is its potential use as a site of action of drugs. Aberrant epigenetic signaling is known to be an important component of disease development, and the reversibility of epigenetic modifications allows for the development of clinically effective drugs. Epigenetic therapies, which are currently being developed, affect the disruption of DNA methyltransferase or histone deacetylase. The use of epigenetic therapy can have a positive effect on drug delivery, optimize the dosing schedule and improve the effectiveness of existing treatment patterns, especially when it comes to chemotherapy, radiation and immunotherapy.¹²

Indeed, epigenetics is considered the link that connects genetics and the environment in shaping endocrine function.¹³ Nevertheless, it remains unclear whether such EDC-induced epigenetic changes are genuinely predictive of adverse outcomes.⁷ Hence, it is of the utmost importance to understand the link between epigenetic changes and endocrine-related endpoints. This review highlights the possible effects that specific chemicals considered to have ED properties can affect the epigenome.

The primary literature was considered in this review. Web-based electronic sources of the databases PubMed, SCOPUS, JSTOR, and the web-based search engine Google Scholar were used for the literature search. The search was based on keywords from existing theories and basic knowledge of endocrine-disrupting and epigenetic effects, well-known EDCs, and previous search results. Specific topics or ideas were not targeted; offhand discovery, snowballing, reference chasing, and tracking citations were not included. The authors have highlighted major EDCs, relevant routes of exposure and possible effects of exposure to these chemicals on the epigenome to drive future research. Other significant considerations, e.g. transgenerational or sex-specific effects and potential application in risk assessment, have been considered.

Cadmium

Cadmium (Cd) is a metal without any significant biological function. It is found in the environment as a standard component of the earth’s crust. Still, Cd also occurs as an environmental pollutant due to human activities (batteries, electronic waste, industrial processes, phosphate fertilizers, pesticides). However, the primary route of exposure of the general population to cadmium is through consumption of food and tobacco smoke.¹⁴ The latest data provided by the European Food Safety Authority (EFSA) regarding the intake of Cd is that the intake should not exceed 2.5 μg/kg body mass per week.¹⁵

It has long been known that chronic exposure to cadmium can lead to a variety of disorders of the lungs, kidneys, liver, bones, brain, and other organs.¹⁶ Because of Cd’s ability to alter hormone homeostasis, Cd is classified as an endocrine disruptor. Its metalloestrogenic activity has been confirmed by Silva and colleagues.¹⁷ Cd is a risk factor for the development of insulin resistance,¹⁸ can harm the thyroid gland,¹⁹ and can negatively affect the male reproductive system.²⁰ Cd has been reported to cause several epigenetic changes, namely DNA methylation, histone modification, and miRNA. These changes can result in altered gene expression and have been observed both in vitro and in vivo.²¹

Cd is classified as a known human carcinogen (Group 1) by the Internacional Agency for Research on Cancer (IARC).²² Cd causes several types of cancer, but the mechanism by which it causes cancer is not entirely understood. However, experimental and epidemiological studies indicate that Cd-induced cancers involve epigenetic modifications.²¹ There is an established link between Cd and kidney and prostate cancer,²² pancreatic cancer,²³ and thyroid cancer,²⁴ and the role of miRNA is involved in the development of these cancers. A study conducted by Liang et al. (2020) reported a link between epigenetic regulation of signaling pathways such as Wnt and several metabolic pathways. The study supported the findings of previous studies relating to the metabolic properties of normal and cancerous breast tissue. Changes have been associated with faster growth, proliferation, and migration of cancer cells (e.g. faster energy production in the cell). Cadmium-induced epigenome changes are essential in detecting and understanding the cause of breast cancer. Genes such as TXNRD1 and CCT3 have been identified that may be important for both cancer therapy and detection.²⁵ An understanding of the impact of Cd on the epigenome may well contribute to the improvement of treatment for such cancers.

Several studies have shown that Cd can affect the growth and development of the fetus. Because Cd can accumulate in the placenta, it has been suggested that the accumulation of Cd in the placenta may lead to dysfunctional growth and development of the embryo. The impaired function may be associated with a disorder in DNA methylation. Everson et al. (2018) showed that the presence of Cd in the placenta was associated with DNA methylation, affecting growth processes, metabolism, and the development of inflammation. Genes involved in the immune and inflammatory signaling pathways (RORA, ACOT7, and TNFAIP2) are associated with a child’s size at birth. This study showed that epigenetic regulation of cell growth and inflammatory or immune pathways in the placenta might contribute to cadmium-mediated reproductive toxicity.²⁶ It has been reported that DNA methylation can lead to changes in sperm levels in mice.²⁷ Further research, however, is needed to assess the impact of epigenetic changes induced by Cd on future generations.

Arsenic

Arsenic (As) is a toxic element widely present in the earth’s crust. The primary use of arsenic is in alloys of lead (batteries and ammunition) and semiconductor electronic devices. Arsenic trioxide has been used to produce pesticides and treat wood products; however, these applications, for the most part, have been phased out following the recognition of the toxicity of arsenic. People are most often exposed to arsenic by consuming polluted water, a severe problem for public health, especially in areas such as Bangladesh. In 2009, the Scientific Panel on Contaminants in the Food Chain (CONTAM Panel) within EFSA adopted the opinion that the provisional tolerable weekly intake (PTWI) established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), which was 15 μg/kg body mass, was not adequate. Adverse effects have been found to occur when exposed to lower doses than those suggested by JECFA. The CONTAM Panel concluded that the Benchmark dose lower confidence limit (BMDL₀₁) is between 0.3 and 8 μg As/kg body mass per day.²⁸

Due to arsenic exposure, health problems such as kidney and liver disorders, neurological problems, skin problems, and reproductive and cardiovascular toxicity can occur. In addition, arsenic has been reported to have mutagenic, genotoxic, and carcinogenic properties.²⁹ Because arsenic stimulates the formation of DNA adducts and cross-links,³⁰ its genotoxicity stems primarily from the ability of arsenic to produce reactive oxygen species.³¹ Similar to Cd, As acts through DNA methylation, histone modification, and miRNA. Exposure to this metalloid has also been reported to affect telomerase function, potentially leading to cancer or cell death.³²

According to its IARC classification, the inorganic compounds of As are Group 1 human carcinogens. Chronic exposure to arsenic can act on oncogene or tumor suppressor genes because of the action of arsenic on miRNA, and As has been linked to lung, skin, bladder, and several other types of cancer.³³ miR-182-5p is suppressed in the presence of arsenic, which contributes to the overexpression of hypoxia factors, and the overexpression of these factors has been suggested to contribute to the carcinogenic potential of arsenic.³⁴ As is involved in miRNA carcinogenesis through its effect on the regulation of the p53 gene. As affects miR-200-b, which can lead to reduced transcription of the p 53 gene. At the same time, growth factors such as TNF-alpha are released.³⁵ Zhou and Xi (2018) have reported a link between changes in histone levels, such as acetylation and methylation, with cancer development.³⁶ A small number of studies have suggested that histone phosphorylation may contribute to this effect. For example, arsenic can induce histone three phosphorylation, which increases the expression of specific oncogenic proteins.³⁷

Other harmful effects can occur because of the action of As on the epigenome. One example is the relationship between placental DNA methylation and arsenic exposure, especially LYRM2 methylation. These results need to be evaluated further to better explain the placenta’s role in protecting the embryo/fetus from arsenic exposure.³⁸ Wallace and colleagues (2020) have recently reported a link between miRNA expression changes and neurodegenerative diseases (Alzheimer’s and Parkinson’s disease).³⁹

Lead

Lead (Pb) is found naturally in the earth’s crust. Significant sources of lead in the environment are from mines and metal smelters. Numerous health disorders occur following lead exposure,^40,41 including diseases of the nervous, hematopoietic, reproductive, and gastrointestinal systems. According to IARC, inorganic lead is a Group 2A carcinogen, probably carcinogenic to humans.⁴² The U.S. Food and Drug Administration (FDA) has set a maximum daily intake of lead in food, the Interim Reference Level (IRL). The IRL is 3 μg/day for children and 12.5 μg/day for adults.⁴³

Exposure to Pb can lead to changes in the epigenome. The influence of Pb on the epigenetic regulation of genes that affect the development of neurons has been investigated by Masoud et al. (2016) who reported the effect of Pb on the expression of genes encoding specific miRNAs. Their study showed that exposure to lead at an early age could adversely affect miRNA expression, which has been linked to the overexpression of neurotoxic proteins and the potential development of Alzheimer’s disease.⁴⁴ A case-control study conducted in China suggested a link between increased miRNA21 expression, urine Pb levels, and the occurrence of microalbuminuria, which suggested that miRNA21 may be a mediator in the development of lead-induced albuminuria.⁴⁵ Pb has also been reported to increase the expression of certain forms of miRNA and decrease other miRNAs. Li et al. (2015) suggested that Pb interacts with the placenta via miRNA, adversely affecting development and cognitive function.⁴⁶

Bisphenol A

Bisphenol A (BPA) was first synthesized in 1891, but it was not until 1936 that it was reported to have estrogenic activity.⁴⁷ In 2013, the global production of BPA was approximately 6.7 million tons.⁴⁸ Its use in plastics, food packaging, and toys has resulted in ubiquitous and long-term human exposure to BPA. Bisphenol A is one of the most thoroughly investigated endocrine-disrupting chemicals. Fortunately, BPA is rapidly metabolized into non-bioactive metabolites, such as glucuronide conjugates, with a short half-life of approximately 4–5 h. The U.S. Environmental Protection Agency (EPA) has set the safe limit for BPA exposure at 50 μg/kg body mass daily. In comparison, the European Food Safety Authority (EFSA) had a lower limit of 4 μg/kg body mass daily.⁴⁹ However, in February 2022 the EFSA Panel on Food Contact Materials, Enzymes, and Processing Aids recommended a limit of 0.04 ng BPA/kg/day.

The significant pathways for BPA endocrine disruption involve ER and PPARγ.⁵⁰ The timing of BPA exposure and the developmental phase of the exposed organism are of significant importance.⁵¹ As with many EDCs, the earlier the exposure during development, the more permanent and far-reaching are the effects.⁴⁹ For example, UDP-glucuronosyltransferase (UGT), the primary enzyme responsible for BPA conjugation and excretion, displays altered isoform expression during pregnancy. Consequently, with maternal BPA elimination capacity altered, the fetus is potentially more vulnerable to BPA exposure. Additionally, the lack or reduced fetal BPA elimination, possibly from a poor expression of liver UGT in the fetus, may be another factor contributing to increased fetal vulnerability to epigenetic changes induced by BPA.⁵⁰

Prenatal exposure to BPA increased hypermethylation of CAPS2, TNFRSF25, and HKR1 genes by promoting hypermethylation of relevant cytosine-phosphate-guanine (CpG) sites, often resulting in obesity.^52,53 There is evidence that even low BPA levels can affect the epigenome and that the effect is sex-specific. A cross-sectional study of prenatal BPA exposure suggested that DNA hypermethylation, a primary epigenetic mechanism, was the predominant effect of BPA exposure among male infants. In contrast, the female infants mainly showed DNA hypomethylation.⁵⁴ Another study suggested that male rats exposed to BPA expressed the free fatty acid uptake gene Fat/Cd36 more than females or controls. At the same time, the expression of genes involved in triglyceride synthesis and β-oxidation, such as Dgat, Agpat6, Cebpα, Cebpβ, Pck1, Acox1, Cpt1a, and Cybb, was decreased. These changes subsequently led to an increase in hepatic steatosis in male rats.

The exposure to BPA also led to the hypermethylation of the gene for carnitine palmitoyl transferase 1A (CPTA1), an enzyme enabling long-chain fatty acids to enter the mitochondria and further promoting their oxidation by transferring acyl groups, originating from fatty acids, from coenzyme A to carnitine.⁵⁵ Further evidence supporting the hypothesis that BPA favors epigenetically induced metabolic disorders, indicating the promotion of obesity and possibly insulin resistance following BPA exposure, was highlighted in a study by Junge et al. (2018). These authors investigated epigenetic changes induced by BPA in infant cord blood. Their results were confirmed in experimental animals and on human adipocyte-derived mesenchymal stem cells. The human mesoderm-specific transcript (MEST) promoter was the target affected by BPA. This gene codes α/β hydrolases, a family of enzymes linked to obesity, adipocyte size, and preadipocyte proliferation, and was found to be hypomethylated, which could result in altered expression and could contribute to the onset of the metabolic disorder.⁵⁶

Although BPA is a commonly studied EDC, only a few studies on its transgenerational effects were found in the literature. One study, concerning the exposure of pregnant rats to BPA, concluded that exposure to the chemical promoted infertility in male descendants of female rats exposed to BPA during pregnancy. The androgen receptor expression, ERβ, steroid receptor co-regulator 1, and nuclear co-repressor protein were diminished in male rats.^57,58 The effect was transgenerational, affecting phenotypes of the F1-F3 generations. When interpreting the results of such studies on females, it is essential to keep in mind – if F0 exposure took place during pregnancy, F1 ova (which would become F2) were also exposed. To be genuinely transgenerational, it has to affect at least the F3 generation.⁵⁹ Interestingly, BPA was also found to decrease DNA methylation in rats, involving enzymes such as PDE type 4 variant 4 and coat color.^60,61

Phthalates

Phthalates and phthalate esters are liquid plasticizers used to produce floor tiles, vinyl flooring, wall coverings, furniture upholstery and mattresses, textiles, personal care products, household supplies, toys, pacifiers, teethers, nipples, and medical equipment.⁶² Within a decade of their initial use in the 1920s, the use of phthalates and phthalate esters was widespread with the expansion of polyvinyl chloride plastics. Phthalates are usually not chemically bound to the plastic, making them easier to absorb, which is why they are often detected in human urine, serum, and breast milk. The daily exposure to di (2-ethylhexyl)phthalate (DEHP) is estimated to be between three (3) and 30 μg/kg.⁴⁹ According to EFSA, the tolerable daily intake (TDI) for DEHP is 50 μg/kg body mass/day.⁶³

Exposure to phthalates has been reported to have various untoward effects on the ovary, uterus, anterior pituitary gland, reproductive cycle, fertility in females, and steroidogenesis. Phthalates are also known for their weak affinity for estrogen receptors and induction of peroxisome proliferator-activated receptor (PPARβ) in adipose tissue.⁴⁹ The hypothesis that some of these adverse effects are realized at least partly through the PPAR pathway is supported by the fact that stressors, such as the PPARγ antagonist T0070907, have a significantly stronger effect when administered after prior exposure to phthalates. Lee et al. (2017) explained the impact of phthalates in low doses as a “first hit” against the fetal endocrine system that renders them vulnerable to “second hits” in adulthood, represented by a PPARγ antagonist. Furthermore, retinoid X receptors were associated with decreased aldosterone levels in their study, complementing the hypothesis that the effect was realized through PPARs. Interestingly, the phthalate “first hit” also affected the Kcnk5 potassium channels, and their deregulation was observed in animal adrenal glands.⁶⁴

Lu et al. (2020) identified several differentially methylated CpG sites associated with phthalate urine concentrations. Many of the sites were linked to genes associated with metabolic syndrome, hypertension, obesity, type 2 diabetes, insulin resistance, and other glycemic traits.⁶⁵ Physical traits such as larger waist circumference, higher BMI, or thicker skinfolds, were suggested to be associated with or predict metabolic syndrome or disorders linked to the syndrome in adults,⁶⁶ adolescents,^67–69 and children (McCArthy 2007, Liang et al. 2015).^70,71 At the same time, adipogenesis was reported by Gore and his colleagues.⁴⁹

Phthalates were also found to disrupt oocyte development and maturation and have been linked to differentially methylated regions of genes associated with metabolic processes and early growth and tumorigenesis.^72,73 Although the effects of EDCs are often more pronounced when the exposure occurs early in life, epigenetic changes following phthalate exposure are not exclusive to exposure during early development. Differentially methylated thyroid receptor-interacting protein 6 (TRIP6) gene promoters were found in peripubertal children exposed to phthalates.⁷⁴

Wei et al. (2020) suggested that phthalates could contribute to the onset of metabolic disorders by modulating microRNAs (miRNAs). di (2- Ethylhexyl) phthalate was used to trigger insulin resistance in mice. The methylation of the Dnmt3a-dependent promoter and long non-coding RNAs (lncRNAs) downregulated miR-17 in skeletal muscle cells. The authors proposed that miR-17 then disrupted the Keap1-Nrf2 redox system and activated Txnip in response to the oxidative stress, which then upregulated miR-200a, targeting directly the 3′ untranslated region (UTR) of Insr and Irs1 genes, which could consequently disrupt insulin signaling and hinder glucose uptake. To support this hypothesis, the authors found that miR-17 overexpression resulted in miR-200a silencing and mitigated insulin resistance in the exposed mice.⁷⁵ An association of phthalates with miRNAs targeting mRNAs linked to processes characteristic for adverse events, such as angiogenesis, apoptosis, and proliferation of connective tissues, was found in human subjects.⁷⁶ Another group has suggested that EDCs could realize their effects through mechanisms involving epigenetic changes of mitochondrial DNA (mtDNA).⁷⁷

The transgenerational effects of phthalates were also considered in a recent murine study. The authors found that prenatal exposure to phthalates resulted in changes in the epigenetic regulation of several genes, including Dmnt1, Tet1, and Tet2, spanning several generations, with some encompassing the F1-F3 generations.⁷⁸ The increasing number of studies on the epigenetic effects of phthalates in recent years warrants a better understanding of these effects and a better rationale for phthalate regulation in the future.

Polychlorinated biphenyls

Although no longer commercially available, polychlorinated biphenyls (PCBs) are still present in the environment due to their long-standing persistence. For dioxin-like PCBs, EFSA has recommended a tolerable weekly intake of 2 pg TEQ/kg body mass.⁷⁹ The active transport of the PCBs across the placenta ⁸⁰ can result in in utero exposure, in addition to a potential release from lipid storage during pregnancy.⁸¹ PCBs have been reported to interact with various receptors and enzyme systems, and their potential endocrine-disrupting properties have been recently reviewed.⁸² The results from a prospective cohort of children across the United States conducted by the National Children’s Study did not establish a relationship between placental PCB levels and methylation in the placenta.⁸³ A study conducted by Li and colleagues, however, did suggest a positive association between specific PCB congeners and miR-1537 expression.⁴⁶ Walker and colleagues have reported that methylation of the enzyme DNMT in the brain was altered by early-life exposure to PCBs.^10,84 It has also been shown that the DNA methylation status is affected differently by non-dioxin-like and dioxin-like PCBs: the former favoring hypomethylation, the latter resulting in more methylation.⁸⁵ Studies in rats have suggested that miRNAs may be influenced by perinatal exposure to PCBs.⁸⁶ The totality of the evidence points toward an epigenetic mechanism underlying the ED properties of the PCBs.

Risk Assessment Considerations

Making use of data on epigenetic changes in risk assessment was suggested in 2014, although at the time, the information concerned toxic metals traditionally researched in toxicology, such as arsenic, cadmium, chromium, lead, and mercury.⁸⁷ In 2017, a group of authors further developed this idea, considering EDCs, BPA and di (2-ethylhexyl)phthalate (DEHP), concepts like adverse outcome pathways (AOPs), evidence of causality, and potential application of information in hazard identification, dose-response assessment, and risk characterization.⁸⁸ EFSA published a summary report on epigenetics and risk assessment the same year, aiming to identify the role of epigenetics in food safety assessment. The report stated that more work was needed to translate limited experimental data that is available into action relevant to public health. Evaluating data in the context of modes of action (MOAs) and AOPs was identified as the critical step to linking epigenetic modifications to actual alterations in gene expression. Also, the possible hereditary nature of epigenetic changes was identified as highly relevant.⁸⁹ To support research on causality, studies examining content of toxic substances in tissues have been conducted recently, focusing on EDCs such as cadmium or epigenetic mechanisms such as DNA methylation or those modulated by miRNAs.^90–92 Before epigenetic data is used in risk assessment, another key point to consider is that epigenetic mechanisms can overlap and intertwine and that the totality of epigenetic-related effects could differ from the sum of individual modifications should be considered.^88,93 Although the present knowledge on epigenetics and EDCs is limited, thus preventing its use in risk assessment at the moment, recent advancements have paved the way for future experimental studies that could result in information needed to apply this knowledge in real-world risk assessment.

Conclusion

The adverse effects of toxic metals as endocrine disruptors appear to involve their interaction with the epigenome. Defining the precise mechanism by which Pb and the heavy metals act on the epigenome leading to harmful effects, will require more research in the clinic and at the bench. Although there has been undeniable advancement in understanding BPA, phthalates, and BCBs, many aspects of exposure, especially tissue- and organ-specific effects, mechanistic data, and the translation of the conclusions from animal to human remain largely unexplored. A clearer interpretation of the diverse and at times conflicting results surrounding EDCs is warranted and further research is needed to ensure better risk assessments, EDC management, and regulation for legacy EDCs with a rational approach to the introduction of new replacement chemicals that are not endocrine disruptors.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the The work of AB and DM was supported by the Science Fund of the Republic of Serbia, PROMIS, DecodExpo (6066532), The work of AAT was supported by the Russian Ministry of Science and Higher Education (0856-2020-0008).

ORCID iDs

Djurdjica Maric

A. Wallace Hayes

References

Bergman

Heindel

Jobling

, et al. State-of-the-science of endocrine disrupting chemicals, 2012. Toxicol Lett 2012; 211: S3.

Organization

Programme

UNE

. State of the Science of Endocrine Disrupting Chemicals. UNEP - UN Environment Programme.

Goumenou

Djordjevic Buha

Vassilopoulou

, et al. Endocrine disruption and human health risk assessment in the light of real-life risk simulation. In: Toxicological Risk Assessment and Multi-System Health Impacts from Exposure, 2021, pp. 147–162.

Wild

. Complementing the genome with an ‘exposome’: the outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol Biomarkers Prev 2005; 14: 1847–1850.

Biswas

Ghosh

Das

, et al. Female reproduction: at the crossroads of endocrine disruptors and epigenetics. Proc Zool Soc 2021; 74: 532–545.

Nettore

Franchini

Palatucci

, et al. Epigenetic mechanisms of endocrine-disrupting chemicals in obesity. Biomedicines 2021; 9: 1–15.

Jacobs

Colacci

Corvi

, et al. Chemical carcinogen safety testing: OECD expert group international consensus on the development of an integrated approach for the testing and assessment of chemical non-genotoxic carcinogens. Arch Toxicol 2020; 94: 2899–2923.

Bommarito

Martin

Fry

, et al. Effects of prenatal exposure to endocrine disruptors and toxic metals on the fetal epigenome. Epigenomics 2017; 9: 333–350.

Plunk

Richards

. Epigenetic modifications due to environment, ageing, nutrition, and endocrine disrupting chemicals and their effects on the endocrine system. Int J Endocrinol. 2020. 1, 11, Epub ahead of print 2020. DOI: 10.1155/2020/9251980.

10.

Walker

Gore

. Epigenetic impacts of endocrine disruptors in the brain. Front Neuroendocrinol 2017; 44: 1–26.

11.

Rattan

Flaws

. The epigenetic impacts of endocrine disruptors on female reproduction across generations. Biol Reprod 2019; 101: 635–644.

12.

Hamm

Costa

. Epigenomes as therapeutic targets. Pharmacol Ther 2015; 151: 72–86.

13.

Zhang

. Epigenetics meets endocrinology. J Mol Endocrinol 2011; 46: R11–R32.

14.

Agency for Toxic Substances and Disease Registry (ATSDR) . Toxicol Profile for Cadmium. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, 2012.

15.

EFSA 2009. EFSA sets lower tolerable intake level for cadmium in food, https://www.efsa.europa.eu/en/news/efsa-sets-lower-tolerable-intake-level-cadmium-food

16.

Sarkar

Ravindran

Krishnamurthy

. A brief review on the effect of cadmium toxicity: from cellular to organ level. Int J Bio-Technology Res 2013; 3: 2249–6858.

17.

Silva

Peiris-John

Wickremasinghe

, et al.

Cadmium a metalloestrogen: Are we convinced?

J Appl Toxicol 2012; 32: 318–332.

18.

Satarug

Moore

. Emerging roles of cadmium and heme oxygenase in type-2 diabetes and cancer susceptibility. Tohoku J Exp Med 2012; 228: 267–288.

19.

Buha

Antonijević

Bulat

, et al. The impact of prolonged cadmium exposure and co-exposure with polychlorinated biphenyls on thyroid function in rats. Vesna Milovanovi C 2013; 221: 83–90.

20.

Cupertino

Novaes

Santos

, et al. Differential susceptibility of germ and leydig cells to cadmium-mediated toxicity: impact on testis structure, adiponectin levels, and steroidogenesis. Oxid Med Cell Longev 2017. Epub ahead of print 2017. DOI: 10.1155/2017/3405089.

21.

Wang

Shao

, et al. Cadmium and its epigenetic effects. Curr Med Chem 2012; 19: 2611–2620.

22.

IARC . IARC monographs on the evaluation of carcinogenic risks to humans, volume 100c: cadmium and cadmium compounds. IARC Monogr 2012; 1993: 121–145.

23.

Buha

Wallace

Matovic

, et al. Cadmium exposure as a putative risk factor for the development of pancreatic cancer: three different lines of evidence. Biomed Res Int 2017: 1–8. Epub ahead of print 2017. DOI: 10.1155/2017/1981837.

24.

Buha

Matovic

Antonijevic

, et al. Overview of cadmium thyroid disrupting effects and mechanisms. Int J Mol Sci; 19: 1501. Epub ahead of print March 2018. DOI: 10.3390/IJMS19051501.

25.

Liang

Zhu

, et al. Differential epigenetic and transcriptional profile in MCF-7 breast cancer cells exposed to cadmium. Chemosphere 2020; 261: 128148.

26.

Everson

Punshon

Jackson

, et al. Cadmium-associated differential methylation throughout the placental genome: Epigenome-wide association study of two U.S. birth cohorts. Environ Health Perspect 2018; 126: 1–13.

27.

Saintilnord

Tenlep

SYN

Preston

, et al. Chronic exposure to cadmium induces differential methylation in mice spermatozoa. Toxicol Sci 2021; 180: 262–276.

28.

EC . Commission regulation (EU) 2015/1006. Off J Eur Union 2015; L 161/14: 14–16.

29.

Maiti

Smarajit

Chattopadhyay

Sandip

Deb

Bimal

, et al. Antioxidant and metabolic impairment result in DNA damage in arsenic-exposed individuals with severe dermatological manifestations in Eastern India. Environ Toxicol 2010; 27: 342–350.

30.

Huang

H Bin

Chen

Wang

, et al. Exposure to heavy metals and polycyclic aromatic hydrocarbons and DNA damage in Taiwanese traffic conductors. Cancer Epidemiol Biomarkers Prev 2013; 22: 102–108.

31.

Hei

Liu

SUX

Waldren

, et al. Mutagenicity of arsenic in mammalian cells: Role of reactive oxygen species. Proc Natl Acad Sci U S A 1998; 95: 8103–8107.

32.

Ozturk

Metin

Altay

, et al. Arsenic and human health: genotoxicity, epigenomic effects, and cancer signaling. Biol Trace Elem Res 2022; 200: 988–1001. Epub ahead of print 2021. DOI: 10.1007/s12011-021-02719-w.

33.

Cardoso

A.P.F.

Al-Eryani

States

. Arsenic-induced carcinogenesis. The Impact of miRNA Dysregulation 2018; 165: 284–290.

34.

Fang

Sun

, et al. miRNA-182-5p, via HIF2α, contributes to arsenic carcinogenesis: evidence from human renal epithelial cells. Metallomics 2018; 10: 1607–1617.

35.

Mandal

. Molecular insight of arsenic-induced carcinogenesis and its prevention. Naunyn Schmiedebergs Arch Pharmacol 2017; 390: 443–455.

36.

Zhou

. A Review on Arsenic Carcinogenesis: Epidemiology, Metabolism, Genotoxicity and Epigenetic Changes. Elsevier. Epub ahead of print 2018. DOI: 10.1016/j.yrtph.2018.09.010.

37.

Chen

Sinogeeva

, et al. Arsenic trioxide promotes histone H3 phosphoacetylation at the chromatin of CASPASE-10 in acute promyelocytic leukemia cells. J Biol Chem 2002; 277: 49504–49510.

38.

Green

Karagas

Punshon

, et al. Epigenome-wide assessment of DNA methylation in the placenta and arsenic exposure in the new hampshire birth cohort study (USA). Environ Health Perspect 2016; 124: 1253–1260.

39.

Wallace

Taalab

Heinze

, et al. Toxic-metal-induced alteration in miRNA expression profile as a proposed mechanism for disease development. Cells; 9: 901. Epub ahead of print 2020. DOI: 10.3390/cells9040901.

40.

Castro

Haimila

Sareneva

, et al. Association of HLA-DRB1, interleukin-6 and cyclin D1 polymorphisms with cervical cancer in the Swedish population - A candidate gene approach. Int J Cancer 2009; 125: 1851–1858.

41.

Longatto-Filho

Pinheiro

Martinho

, et al. Molecular characterization of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinoma. BMC Cancer 2009; 9: 1–8.

42.

IARC Working Group on the Evaluation of Carcinogenic Risks to Humans . Inorganic and organic lead compounds. IARC Monogr Eval Carcinog Risks Hum 2006; 87: 1–471.

43.

FDA 2018. FDA monitoring and testing of lead in food, including dietary supplements and foodwares: interim reference level, https://www.fda.gov/Food/FoodborneIllnessContaminants/Metals/ucm2006791.htm.

44.

Masoud

Bihaqi

Machan

, et al. Early-life exposure to lead (Pb) alters the expression of microrna that target proteins associated with Alzheimer’s disease. J Alzheimer’s Dis 2016; 51: 1257–1264.

45.

Kong

APS

Xiao

Choi

, et al. Associations between microRNA (miR-21, 126, 155 and 221), albuminuria and heavy metals in Hong Kong Chinese adolescents. Clin Chim Acta 2012; 413: 1053–1057.

46.

Kappil

, et al. Exploring the associations between microRNA expression profiles and environmental pollutants in human placenta from the National Children’s Study (NCS). Epigenetics 2015; 10: 793–802.

47.

Dodds

Lawson

. Synthetic oestrogenic agents without the phenanthrene nucleus. Nature 1936; 137: 996.

48.

vom Saal

Welshons

W V

. Evidence that bisphenol A (BPA) can be accurately measured without contamination in human serum and urine, and that BPA causes numerous hazards from multiple routes of exposure. Mol Cell Endocrinol 2014; 398: 101–113.

49.

Gore

Chappell

Fenton

, et al. EDC-2: the endocrine society’s second scientific statement on endocrine-disrupting chemicals. Endocr Rev 2015; 36: E1–E150.

50.

Onuzulu

Rotimi

, et al. Epigenetic modifications associated with in utero exposure to endocrine disrupting chemicals BPA, DDT and Pb. Rev Environ Health 2019; 34: 309–325.

51.

Choi

Knudsen

Mizrak

, et al. Identification of exposure to environmental chemicals in children and older adults using human biomonitoring data sorted by age: Results from a literature review. Int J Hyg Environ Health 2017; 220: 282–298.

52.

Choi

Y-J

Lee

Hong

Y-C

, et al. Effect of prenatal bisphenol A exposure on early childhood body mass indexthrough epigenetic influence on the insulin-like growth factor 2 receptor(IGF2R) gene. Environ Int 2020; 143: 105929.

53.

Song

Zhou

Yang

, et al. Association between prenatal bisphenol a exposure and promoter hypermethylation of CAPS2, TNFRSF25, and HKR1 genes in cord blood. Environ Res 2020; 190: 109996.

54.

Miura

Araki

Minatoya

, et al. An epigenome-wide analysis of cord blood DNA methylation reveals sex-specific effect of exposure to bisphenol A. Sci Rep 2019; 9: 12369.

55.

Strakovsky

Wang

Engeseth

, et al. Developmental bisphenol A (BPA) exposure leads to sex-specific modification of hepatic gene expression and epigenome at birth that may exacerbate high-fat diet-induced hepatic steatosis. Toxicol Appl Pharmacol 2015; 284: 101–112.

56.

Junge

Leppert

Jahreis

, et al. MEST mediates the impact of prenatal bisphenol A exposure on long-term body weight development. Clin Epigenet 2018; 10: 58.

57.

Salian

Doshi

Vanage

, et al. Impairment in protein expression profile of testicular steroid receptor coregulators in male rat offspring perinatally exposed to Bisphenol A. Life Sci 2009; 85: 11–18.

58.

Salian

Doshi

Vanage

, et al. Perinatal exposure of rats to Bisphenol A affects the fertility of male offspring. Life Sci 2009; 85: 742–752.

59.

Walker

Gore

. Transgenerational neuroendocrine disruption of reproduction. Nat Rev Endocrinol 2011; 7: 197–207.

60.

S-M

Tang

W-Y

de Frausto

, et al. Developmental exposure to estradiol and bisphenol a increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer Res 2006; 66: 5624–5632.

61.

Dolinoy

Huang

Jirtle

, et al. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A 2007; 104: 13056–13061.

62.

Bowman

Choudhury

. Phthalates in neonatal health: friend or foe? J Dev Orig Health Dis 2016; 7: 652–664.

63.

EFSA 2019. FAQ: phthalates in plastic food contact materials, https://www.efsa.europa.eu/en/news/faq-phthalates-plastic-food-contact-materials.

64.

Lee

Martinez-Arguelles

Campioli

, et al. Fetal exposure to low levels of the plasticizer DEHP predisposes the adult male adrenal gland to endocrine disruption. Endocrinology 2017; 158: 304–318.

65.

Franszczyk

van der Meer

, et al. An epigenome-wide association study identifies multiple DNA methylation markers of exposure to endocrine disruptors. Environ Int 2020; 144: 106016.

66.

Quaye

Owiredu

WKBA

Amidu

, et al. Comparative abilities of body mass index, waist circumference, abdominal volume index, body adiposity index, and conicity index as predictive screening tools for metabolic syndrome among apparently healthy Ghanaian adults. J Obes 2019: 1–10. Epub ahead of print 2019. DOI: 10.1155/2019/8143179.

67.

Pereira

Faria

FR De

Faria

ER De

, et al. Anthropometric indices to identify metabolic syndrome and hypertriglyceridemic waist phenotype: A comparison between the three stages of adolescence. Rev Paul Pediatr 2015; 33: 194–203.

68.

Perona

Schmidt-RioValle

Fernández-Aparicio

, et al. Waist circumference and abdominal volume index can predict metabolic syndrome in adolescents, but only when the criteria of the international diabetes federation are employed for the diagnosis. Nutrients, 11. Epub ahead of print 2019. DOI: 10.3390/nu11061370.

69.

Agredo-Zúñiga

Aguilar-De Plata

Suárez-Ortegón

, et al. Waist: height ratio, waist circumference and metabolic syndrome abnormalities in Colombian schooled adolescents: a multivariate analysis considering located adiposity. Br J Nutr 2015; 114: 700–705.

70.

McCarthy

. Body fat measurements in children as predictors for the metabolic syndrome: focus on waist circumference. Proc Nutr Soc 2006; 65: 385–392.

71.

Liang

Hou

Zhao

, et al. Childhood obesity affects adult metabolic syndrome and diabetes. Endocrine 2015; 50: 87–92.

72.

Tindula

Murphy

Grenier

, et al. DNA methylation of imprinted genes in Mexican-American newborn children with prenatal phthalate exposure. Epigenomics 2018; 10: 1011–1026.

73.

Rolfo

Nuzzo

Amicis

R De

, et al. Fetal-Maternal Exposure to Endocrine Disruptors: Correlation with Diet Intake and Pregnancy Outcomes. Nutrients 2020; 12: 1744.

74.

Almstrup

Frederiksen

Andersson

A-M

, et al. Levels of endocrine-disrupting chemicals are associated with changes in the peri-pubertal epigenome. Endocr Connect 2020; 9: 845–857.

75.

Wei

Hao

Chen

, et al. Epigenetic repression of miR-17 contributed to di(2-ethylhexyl) phthalate-triggered insulin resistance by targeting Keap1-Nrf2/miR-200a axis in skeletal muscle. Theranostics 2020; 10: 9230–9248.

76.

Zota

Geller

VanNoy

, et al. Phthalate exposures and microRNA expression in uterine fibroids: the FORGE study. Epigenetics Insights 2020; 13: 2516865720904057.

77.

Zhou

Goodrich

Strakovsky

, et al. Mitochondrial epigenetics and environmental health: making a case for endocrine disrupting chemicals. Toxicol Sci 2020; 178: 16–25, kfaa129.

78.

Wen

Rattan

Flaws

, et al. Multi and transgenerational epigenetic effects of di-(2-ethylhexyl) phthalate (DEHP) in liver. Toxicol Appl Pharmacol 2020; 402: 115123.

79.

Knutsen

Alexander

Barregård

, et al. Risk for animal and human health related to the presence of dioxins and dioxin-like PCBs in feed and food. EFSA J 2018; 16: e05333. Epub ahead of print 2018. DOI: 10.2903/j.efsa.2018.5333.

80.

Vizcaino

Grimalt

Fernández-Somoano

, et al. Transport of persistent organic pollutants across the human placenta. Environ Int 2014; 65: 107–115.

81.

Wang

Zhang

Zeng

, et al. Association of traffic-related air pollution with children’s neurobehavioral functions in Quanzhou, China. Environ Health Perspect 2009; 117: 1612–1618.

82.

Djordjevic

Antonijevic

Curcic

, et al. Endocrine-disrupting mechanisms of polychlorinated biphenyls. Curr Opin Toxicol 2020; 19: 42–49.

83.

Kappil

, et al. utero exposures to environmental organic pollutants disrupt epigenetic marks linked to fetoplacental development. Environ Epigenet 2. Epub ahead of print March 2016. DOI: 10.1093/EEP/DVV013.

84.

Walker

Goetz

Gore

, et al. Dynamic postnatal developmental and sex-specific neuroendocrine effects of prenatal polychlorinated biphenyls in rats. Mol Endocrinol 2014; 28: 99–115.

85.

Alatsathianos

. International Journal Of Chemotherapy Research And Practice. Int J Chemother Res Pract; 1 https://www.clinmedjournals.org/articles/ijsrp/international-journal-of-surgery-research-and-practice-ijsrp-8-126.php?jid=ijsrp (2018.

86.

Topper

Walker

Gore

, et al. Sexually dimorphic effects of gestational endocrine-disrupting chemicals on microRNA expression in the developing rat hypothalamus. Mol Cell Endocrinol 2015; 414: 42–52.

87.

Ray

Yosim

Fry

, et al. Incorporating epigenetic data into the risk assessment process for the toxic metals arsenic, cadmium, chromium, lead, and mercury: strategies and challenges. Front Genet 2014; 5: 1–26.

88.

Cote

McCullough

Hines

, et al. Application of epigenetic data in human health risk assessment. Curr Opin Toxicol 2017; 6: 71–78.

89.

Efsa Scientific Colloquium. 2013.

90.

Wong

Southey

Terry

, et al. Integrating DNA methylation measures to improve clinical risk assessment: are we there yet? The case of BRCA1 methylation marks to improve clinical risk assessment of breast cancer. Br J Cancer 2020; 122: 1133–1140.

91.

Anđelković

Djordjevic

Miljaković

, et al. Cadmium tissue level in women diagnosed with breast cancer – A case control study. Environ Res 2021; 199: 111300.

92.

Mortoglou

Manić

Buha Djordjevic

, et al. Nickel’s role in pancreatic ductal adenocarcinoma: potential involvement of microRNAs. Toxics 2022; 10: 148.

93.

Manić

Wallace

Onganer

, et al. Epigenetic mechanisms of metal carcinogenicity. Toxicol Rep 2022; 9: 778–787.

The effects of endocrine-disrupting chemicals (EDCs) on the epigenome-A short overview

Abstract

Keywords

Introduction

Cadmium

Arsenic

Lead

Bisphenol A

Phthalates

Polychlorinated biphenyls

Risk Assessment Considerations

Conclusion

Footnotes

Declaration of conflicting interests

Funding

ORCID iDs

References