Parental Exposure to Bisphenol A During Pregnancy and the Anogenital Distance of Male Offspring

Abstract Accumulating evidence has suggested that a suboptimal early life environment produces multigenerational developmental defects. A proposed mechanism is stable inheritance of DNA methylation. Here we show that maternal bisphenol A (BPA) exposure in C57BL/6 mice produces multigenerational metabolic phenotypes in their offspring. Using various methods including dual-energy X-ray absorptiometry analyses, glucose tolerance tests, and perifusion islet studies, we showed that exposure to 10 μg/kg/d and 10 mg/kg/d BPA in pregnant F0 mice was associated with higher body fat and perturbed glucose homeostasis in F1 and F2 male offspring but not female offspring. To provide insight into the mechanism of the multigenerational metabolic abnormalities, we investigated the maternal metabolic milieu and inheritance of DNA methylation across generations. We showed that maternal glucose homeostasis during pregnancy was altered in the F0 but not F1 female mice. The results suggested that a compromised maternal metabolic milieu may play a role in the health of the F1 offspring but cannot account for all of the observed multigenerational phenotypes. We further demonstrated that the metabolic phenotypes in the F1 and F2 BPA male offspring were linked to fetal overexpression of the imprinted Igf2 gene and increased DNA methylation at the Igf2 differentially methylated region 1. Studies in H19Δ3.8/+ mouse mutants supported the role of fetal Igf2 overexpression in altered adult glucose homeostasis. We conclude that early life BPA exposure at representative human exposure levels can perturb metabolic health across multiple generations in the mouse through stable inheritance of DNA methylation changes at the Igf2 locus.

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Maternal exposure to low doses of bisphenol A affects learning and memory in male rat offspring with abnormal N-methyl-d-aspartate receptors in the hippocampus

Toxicology and Industrial Health ◽

10.1177/0748233720984624 ◽

2021 ◽

pp. 074823372098462

Author(s):

Chong Wang ◽

Yao Shu ◽

Li Xu ◽

Qiling Liu ◽

Bei Zhang ◽

...

Keyword(s):

Bisphenol A ◽

Learning And Memory ◽

Maternal Exposure ◽

Male Offspring ◽

Male Rat ◽

Control Group ◽

Sprague Dawley ◽

Expression Levels ◽

Rat Offspring ◽

Sprague Dawley Rats

Bisphenol A (BPA), a component of polycarbonate and epoxy resins, has been reported to induce learning and memory deficits. However, the mechanisms have not been fully elucidated. Growing evidence has suggested that N-methyl-d-aspartate receptors (NMDARs) are involved in cognitive impairments. In this study, BPA was administered to female Sprague–Dawley rats (six per dose group) at concentrations of 0 (control), 4, 40, and 400 μg/kg·body weight/day from gestation day 1 through lactation day 21. Spatial learning was evaluated using the Morris water maze on postnatal day 22. Expression levels of NMDARs were determined using real-time polymerase chain reaction and Western blot. The results showed that male offspring exposed to BPA exhibited increased latency in reaching the platform and reduced time in the target quadrant, and the number of crossing the platform was less, as compared with the control group. The mRNA and protein expression levels of NMDARs in the hippocampus were significantly downregulated when compared with the control group of male offspring. The data showed that maternal exposure to BPA at low dosage can cause cognitive deficits in male rat offspring, probably due to a decrease in NMDARs in the hippocampus.

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Paternal Inheritance of Bisphenol A Cardiotoxic Effects: The Implications of Sperm Epigenome

International Journal of Molecular Sciences ◽

10.3390/ijms22042125 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2125

Author(s):

Marta Lombó ◽

María Paz Herráez

Keyword(s):

Gene Expression ◽

Bisphenol A ◽

Histone Acetyltransferase ◽

Epigallocatechin Gallate ◽

Histone Acetyltransferases ◽

Paternal Inheritance ◽

Congenital Diseases ◽

Parental Exposure ◽

Expression Of Genes ◽

Histone Hyperacetylation

Parental exposure to bisphenol A (BPA) has been linked to a greater incidence of congenital diseases. We have demonstrated that BPA induces in zebrafish males an increase in the acetylation of sperm histones that is transmitted to the blastomeres of the unexposed progeny. This work is aimed to determine whether histone hyperacetylation promoted by paternal exposure to BPA is the molecular mechanism underlying the cardiogenesis impairment in the descendants. Zebrafish males were exposed to 100 and 2000 µg/L BPA during early spermatogenesis and mated with non-exposed females. We analyzed in the progeny the expression of genes involved in cardiogenesis and the epigenetic profile. Once the histone hyperacetylation was confirmed, treatment with epigallocatechin gallate (EGCG), an inhibitor of histone acetyltransferases, was assayed on F1 embryos. Embryos from males exposed to 2000 µg/L BPA overexpressed the transcription factor hand2 and the receptor esr2b, showing their own promoters—as well as that of kat6a—an enrichment in H3K9ac. In embryos treated with EGCG, both gene expression and histone acetylation (global and specific) returned to basal levels, and the phenotype was recovered. As shown by the results, the histone hyperacetylated landscape promoted by BPA in the sperm alters the chromatin structure of the progeny, leading to the overexpression of the histone acetyltransferase and genes involved in cardiogenesis.

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Evaluation of the Toxicity of Bisphenol A in Reproduction and Its Effect on Fertility and Embryonic Development in the Zebrafish (Danio rerio)

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph19020962 ◽

2022 ◽

Vol 19 (2) ◽

pp. 962

Author(s):

Lilian de Paula Gonçalves Reis ◽

Antonio Jesús Lora-Benítez ◽

Ana Mª Molina-López ◽

Rafael Mora-Medina ◽

Nahúm Ayala-Soldado ◽

...

Keyword(s):

Embryonic Development ◽

Bisphenol A ◽

Danio Rerio ◽

Chemical Substance ◽

Toxic Effects ◽

Control Group ◽

Histopathological Study ◽

Parental Exposure ◽

Electron Microscopes ◽

Histopathological Studies

Bisphenol A (BPA) is a chemical substance commonly used in the manufacture of plastic products. Its inhalation or ingestion from particles in suspension, water, and/or polluted foods can trigger toxic effects related to endocrine disruption, resulting in hormonal, reproduction, and immunological alterations in humans and animals. The zebrafish (Danio rerio) is an ideal experimental model frequently used in toxicity studies. In order to assess the toxic effects of BPA on reproduction and embryonic development in one generation after parental exposure to it, a total of 80 zebrafish, males and females, divided into four groups in duplicate (n = 20) were exposed to BPA concentrations of 500, 50, and 5 µg L−1, along with a control group. The fish were kept in reproduction aquariums for 21 days. The embryos obtained in the crosses were incubated in a BPA-free medium and observed for signs of embryotoxicity. A histopathological study (under optical and electron microscopes) was performed of adult fish gonads. The embryos of reproducers exposed to BPA were those most frequently presenting signs of embryotoxicity, such as mortality and cardiac and musculoskeletal malformations. In the histopathological studies of adult individuals, alterations were found in ovocyte maturation and in spermatazoid formation in the groups exposed to the chemical. Those alterations were directly related to BPA action, affecting fertility in both sexes, as well as the viability of their offspring, proportionally to the BPA levels to which they were exposed, so that our results provide more information by associating toxic effects on the offspring and on the next generation.

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EPIGENOMIC EFFECTS OF EXPOSURE OF PREGNANT RATS TO LOW DOSE OF BISPHENOL A REGARDING THE NEUROENDOCRINE SYSTEM OF THE MALE F1 GENERATION (short communication)

JOURNAL OF THE NATIONAL ACADEMY OF MEDICAL SCIENCES OF UKRAINE ◽

10.37621/jnamsu-2020-1-2-3 ◽

2021 ◽

pp. 23-28

Author(s):

Alexander Reznikov ◽

Olha Sachynska ◽

Аnna Lymareva ◽

Lyubov Polyakova

Keyword(s):

Sexual Behavior ◽

Bisphenol A ◽

Low Dose ◽

Male Offspring ◽

Male Rats ◽

Normal Male ◽

Potential Hazard ◽

Preoptic Nucleus ◽

Female Behavior ◽

Medial Preoptic Nucleus

Aim: To study the long-term effects of exposure of pregnant Wistar rats to low dose of bisphenol A (BPA) by measuring to the level of steroid hormones and sexual behavior of adult male offspring of the first generation. Material and research methods: BPA as part of the Dorfman gel was gavaged during the last week of pregnancy, when androgen-dependent sexual brain differentiation occurs, in a daily dose of 25 mcg/kg b.w. (threshold teratogenic dose). Male sexual behavior was evaluated by proceptive reactions, the duration of latent and refractory periods, the number of mounts, intromissions and ejaculations in the presence of a receptive female. Female sexual behavior was assessed by lordosis reactions of orchidectomized and activated by the introduction of estradiol and progesterone males in the presence of a normal male. A neuromorphological analysis of the sex-dimorphic area of the brain, the medial preoptic nucleus of the hypothalamus, was performed by histological examination and karyometry of neurons. Results: Prenatally administered BPA caused a very slight increase in the anogenital distance in newborn animals and did not affect the terms of puberty. The levels of testosterone and corticosterone in the blood plasma of males of 6 months of age did not differ from the control indices. At 10 months of age, all experimental males showed sharply weakened sexual motivation for mating with females, and in 4 from 5 animals, copulative components of sexual behavior were absent. There was no ejaculations in the 5th male as well, while numbers of the mounts without intromissions and ones with intromissions significantly reduced. In the BPA group, all descendants showed active female behavior in the presence of a normal male, which manifested in lordosis reactions and a high lordosis index. According to the histological study of medial preoptic nucleus, the activity of neurocytes in the male offspring of BPA-exposed females was significantly reduced, and their nuclei volume distribution was some different from the control. Conclusions: The data obtained indicate epigenetic disorders of the sexual brain differentiation program due to the prenatal exposure to BPA in dose that does not cause significant teratogenic effects. This should be taken into account when evaluating the potential hazard of BPA for reproductive health. Key words: bisphenol A, prenatal effect, male rats, sexual behavior, corticosterone, testosterone.

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Parental Exposure to Bisphenol A During Pregnancy and the Anogenital Distance of Male Offspring

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Bisphenol A Exposure Disrupts Metabolic Health Across Multiple Generations in the Mouse

Maternal exposure to low doses of bisphenol A affects learning and memory in male rat offspring with abnormal N-methyl-d-aspartate receptors in the hippocampus

Paternal Inheritance of Bisphenol A Cardiotoxic Effects: The Implications of Sperm Epigenome

Evaluation of the Toxicity of Bisphenol A in Reproduction and Its Effect on Fertility and Embryonic Development in the Zebrafish (Danio rerio)

EPIGENOMIC EFFECTS OF EXPOSURE OF PREGNANT RATS TO LOW DOSE OF BISPHENOL A REGARDING THE NEUROENDOCRINE SYSTEM OF THE MALE F1 GENERATION (short communication)

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