Transgenerational BPA exposure may contribute to autism

Transgenerational Bisphenol A Causes Deficits in Social Recognition and Alters Postsynaptic Density Genes in Mice, 2019

According to a recent mouse study, BPA exposure has transgenerational effects on gene linked to autism – social recognition test used for first time in mice showed behavioral deficit – the Endocrine Society reports.

2019 Study Abstract

Bisphenol A (BPA) is a ubiquitous endocrine-disrupting chemical. Developmental exposure produces changes in behavior and gene expression in the brain. Here, we examined social recognition behaviors in mice from the third familial generation (F3) after exposure to gestational BPA. Second-generation mice were bred in one of four mating combinations to reveal whether characteristics in F3 were acquired via maternal or paternal exposures. After repeated habituation to the same mouse, offspring of dams from the BPA lineage failed to display increased investigation of a novel mouse. Genes involved in excitatory postsynaptic densities (PSDs) were examined in F3 brains using quantitative PCR. Differential expression of genes important for function and stability of PSDs were assessed at three developmental ages. Several related PSD genes―SH3 and multiple ankyrin repeat domains 1 (Shank1), Homer scaffolding protein 1c (Homer1c), DLG associated protein 1 (Gkap), and discs large MAGUK scaffold protein 4 (PSD95)―were differentially expressed in control- vs BPA-lineage brains. Using a second strain of F3 inbred mice exposed to BPA, we noted the same differences in Shank1 and PSD95 expression in C57BL/6J mice. In sum, transgenerational BPA exposure disrupted social interactions in mice and dysregulated normal expression of PSD genes during neural development. The fact that the same genetic effects were found in two different mouse strains and in several brain regions increased potential for translation. The genetic and functional relationship between PSD and abnormal neurobehavioral disorders is well established, and our data suggest that BPA may contribute in a transgenerational manner to neurodevelopmental diseases.

DES and the GENES

Endocrine disruptors alter female reproduction throughout multiple generations

OR23-1 Transgenerational Effects of Endocrine Disrupting Chemicals on Pubertal Timing through Epigenetic Reprogramming of the Hypothalamus

According to a recent animal study, endocrine disruptors, hormone-altering chemicals that are widespread in our environment, can shape the brain through four generations, altering offspring’s maternal behavior, sexual development and reproduction, The Endocrine Society reports.

Abstract

Endocrine disrupting chemicals (EDCs) are a rising concern for public health due to their ubiquitous presence as complex mixtures affecting development throughout generations. Our goal was to study the effect of a mixture of EDCs on female sexual development during 3 generations. Female rats (F0 generation) were orally exposed to a mixture of 14 anti-androgenic and estrogenic EDCs or corn oil for 2 weeks before and throughout gestation and until weaning. The mixture was composed of plasticizers (BPA, DBP, DEHP), fungicides/pesticides (Vinclozolin, Procymidon, Prochloraz, Epoxynazole, Linurone, p-p’-DDT), UV filters (4-MBC, OMC), Butyl Paraben and the analgesic Acetaminophen. The doses were in the micrograms/kg range in order to represent human exposure. Sexual development (vaginal opening, GnRH interpulse interval and estrous cyclicity) as well as maternal behavior were studied from F1 to F3 generations. At PND21 the mediobasal hypothalamus of the F1 and F3 were removed for gene expression analysis by RNAseq and RT-qPCR as well as for Chromatin Immunoprecipitation of histone modifications at regulatory regions of target genes. While F2 and F3 females showed delayed vaginal opening, decreased percentage of regular estrous cycles and decreased GnRH interpulse interval, no such changes were detected in F1 animals. These reproductive phenotypes were associated with alterations in both transcriptional and histone posttranslational modifications of hypothalamic genes involved in reproductive competence and behavior like kisspeptin (Kiss1), oxytocin (Oxt), estrogen (Esr1), glutamate (Grin2d), dopamine signaling (Th and Drd1) as well as glucocorticoid activity (Nr3c1 and Crh). Concomitant with a decrease in transcriptional activity, we have observed either a decrease of active histone marks (H3K4me3, H3K9ac) for Esr1 and Oxt promoter regions, an increase of repressive histone modifications (H3K27me3, H3K9me3) for Grin2D, Th and Nr3c1 promoter regions or both for the Kiss1 promoter. Up-regulated genes (Pomc, and CRH) showed decreased H3K9me3 and increased H3K9ac at their 5’regulatory regions. F1 females that were exposed in utero to the EDC mixture, showed a reduction in Th mRNA expression and decreased grooming/licking behavior while spending more time resting alone. These alterations on maternal behavior are known to cause transgenerational alterations of the development of the corticotropic and gonadotropic axis. Overall, our data shows that gestational and lactational exposure to an environmentally relevant EDC mixture transgenerationally affects sexual development throughout epigenetic reprogramming of the hypothalamus. Such effects could be mediated by alterations of maternal behavior caused by exposure of the first generation to the EDC mixture.

About DES and the GENES

Bisphenol-A can promote fibroids growth, study says

Bisphenol A promotes the proliferation of leiomyoma cells by GPR30‐EGFR signaling pathway, 2019

Abstract

Aim
To study the molecular mechanism of G protein‐coupled receptor 30‐epidermal growth factor receptor (GPR30‐EGFR) signaling pathway on the proliferation of leiomyoma cells exposed with bisphenol A.

Methods
Primary cultures and subcultures of human uterine leiomyoma (UL) cells. The expressions of messenger RNA and proteins of GPR30 and EGFR in 15 leiomyoma tissue specimens and all groups were detected by real‐time quantitative polymerase chain reaction assay and Western blot assay. The protein of mitogen‐activated protein kinases (MAPK)/extracellular signal–regulated kinases (ERK)/c‐fos signaling pathway members was detected by Western blot assay.

Results
Bisphenol A promoted the growth of UL cells and the expressions of GPR30, EGFR, c‐fos and p‐ERK1/2.

Conclusion
Bisphenol A was found to be a promoter specifically to proliferate the human UL cells by activating the transcription and translation of GPR30‐EGFR and MAPK/ERK/c‐fos signaling pathway members.

BPF and BPS linked to obesity in children and teens

Urinary bisphenols and obesity prevalence among US children and adolescents, 2019

Bisphenol S (BPS) and bisphenol F (BPF), used as substitutes for bisphenol A (BPA), may contribute to childhood weight gain and obesity, according to a new study published today in the Journal of the Endocrine Society, the Environmental Health News reports.
Image credit Drouin Secondary College.

“Replacing BPA with similar chemicals does nothing to mitigate the harms chemical exposure has on our health.
It will continue to be an issue given that human exposure to these compounds is likely to continue to increase in the future.”

2019 Study Abstract

Bisphenol A (BPA) has been recognized as an endocrine disrupting chemical and identified as an obesogen. Although once ubiquitous, human exposure to BPA is declining due to its substitution with other bisphenols. Two structurally similar substitutes, bisphenol S (BPS) and bisphenol F (BPF), have raised similar concerns, although fewer studies have been conducted on these newer derivatives. We used data from the US National Health and Nutrition Examination Surveys from the years 2013-2016 to evaluate associations between BPA, BPS, and BPF and body mass outcomes among children and adolescents aged 6 to 19 years. Concentrations of BPA, BPS, and BPF were measured in spot urine samples using high performance liquid chromatography with tandem mass spectrometry. General obesity was defined as ≥95th percentile of age- and sex-standardized body mass index (BMI) z-scores according to 2000 US norms. Abdominal obesity was defined as ratios of waist circumference to height ≥0.5. BPA, BPS, and BPF were detected in 97.5%, 87.8% and 55.2% of urine samples, respectively. Log-transformed urinary BPS concentrations were associated with an increased prevalence of general obesity (OR=1.16, 95% CI: 1.02, 1.32) and abdominal obesity (OR=1.13, 95% CI: 1.02, 1.27). BPF detection (vs. not detected) was associated with an increased prevalence of abdominal obesity (OR=1.29, 95% CI: 1.01, 1.64) and continuous BMI z-score (β=0.10, 95% CI: 0.01, 0.20). BPA and total bisphenols were not statistically significantly associated with general obesity, abdominal obesity, or any body mass outcome. This study suggests that BPA substitute chemicals are correlated with obesity in contemporary children.

Current uses of BPA are safe – Not

Getting a Clear View : Lessons From The CLARITY-BPA Study, 2019

Listen to Dr. Laura Vandenberg, Associate Professor and Graduate Program Director in the Department of Environmental Health Sciences in the University of Massachusetts Amherst School of Public Health and Health Sciences, analyses The CLARITY-BPA study. Reference.

Bisphenol A (BPA) is produced in high volume and is still in use in a variety of products globally. Many independent, academic studies have demonstrated an association between exposure to BPA and multiple adverse health outcomes including endocrine-disrupting end-points. However, studies included in regulatory risk assessments have been cited as evidence that current uses of BPA are safe.

The U.S. National Institute of Environmental Health Sciences (NIEHS), the National Toxicology Program (NTP), and the Food and Drug Administration (FDA) sought to address these disparities in scientific findings and put together the Consortium Linking Academic and Regulatory Insights on BPA Toxicity, otherwise known as CLARITY-BPA.

60 MiNueTs Toxic

UCSF Program on Reproductive Health and the Environment, 2017

Video published on 18 Apr 2019 by the UCSF Program on Reproductive Health and the Environment.

The University of California San Francisco (UCSF) Program on Reproductive Health and the Environment (PRHE)’s mission is to create a healthier environment for human reproduction and development through advancing scientific inquiry, clinical care and health policies that prevent exposures to harmful chemicals in our environment.

More Information

Endocrine disruptors have an impact on reproduction for several generations

Endocrine disruptors transgenerationally alters pubertal timing through epigenetic reprogramming of the hypothalamus

2019 Study Abstract

Endocrine disruptors are a rising concern for public health due to their ubiquitous presence affecting reproductive development throughout generations.

We aim at studying the transgenerational effect of an EDC mixture on female sexual development and reproduction.

Female rats (F0 generation) were orally exposed to a mixture of 14 anti-androgenic and estrogenic EDCs or corn oil for 2 weeks before and throughout gestation and until weaning. The mixture was composed of plasticizers (BPA, DBP, DEHP), fungicides/pesticides (Vinclozolin, Procymidon, Prochloraz, Epoxynazole, Linurone, p-p’-DDT), UV filters (4-MBC, OMC), Butylparaben and the analgesic Acetaminophen. Doses were in the human exposure range (μg/kg).

Sexual development and reproductive parameters (vaginal opening, GnRH secretion, estrous cyclicity and folliculogenesis) were studied from F1 to F3 generations. Maternal behavior was measured from F0 to F2 generations. At PND21, mediobasal hypothalamus of the F1 and F3 were removed for gene expression analysis (RNAseq, RT-PCR) as well as for Chromatin Immunoprecipitation of histone modifications at regulatory regions of target genes.

The results show multiple multi- and transgenerational effects after ancestral EDC exposure. While F2 and F3 females showed delayed vaginal opening, decreased percentage of regular estrous cycles, decreased GnRH interpulse interval and altered folliculogenesis, no such changes were detected in F1 animals. These alterations were accompanied with transcriptional and histone posttranslational modifications of key hypothalamic genes involved in puberty and reproduction. We observed a downregulation of estrogen signaling (Esr1), genes involved in the GnRH network (Kisspeptin, Grin2d, Tac3R), maternal behavior (Th, Oxt, Avp, Drd1, Drd2) and stress responsiveness (Nr3c1). Upregulated gens involved glucocorticoid activity (Crh) and metabolism (Pomc, Cart). Concomitantly with transcriptional levels, while downregulated genes present higher levels of repressive histone marks (H3K9me3, H3K27me3) and decreased levels of activational histone marks (H3K4me3, H3K9ac), upregulated genes present the opposite pattern. Such histone marks related to changes in the polycomb/thritorax group of protein balance, involved in the control of female puberty. F1 and F2 females displayed decreased licking while spending more time resting alone. F1 RNAseq showed a reduction in Th, Drd1 and Drd2 mRNA expression. These alterations on maternal behavior are known to cause transgenerational alterations of the development of the corticotropic and gonadotropic axis.

In conclusion, exposure to an environmentally relevant EDC mixture transgenerationally affects sexual development and reproduction throughout epigenetic reprogramming of the hypothalamus. While not yet clear, such effects could be mediated by alterations of maternal behavior caused by exposure to the first generation.

ReferenceImage.

DES and the GENES

Effect of environmental and pharmaceutical exposures on fetal testis development and function

A systematic review of human experimental data, 2019

Abstract

BACKGROUND
Overall, the incidence of male reproductive disorders has increased in recent decades. Testicular development during fetal life is crucial for subsequent male reproductive function. Non-genomic factors such as environmental chemicals, pharmaceuticals and lifestyle have been proposed to impact on human fetal testicular development resulting in subsequent effects on male reproductive health. Whilst experimental studies using animal models have provided support for this hypothesis, more recently a number of experimental studies using human tissues and cells have begun to translate these findings to determine direct human relevance.

OBJECTIVE AND RATIONALE
The objective of this systematic review was to provide a comprehensive description of the evidence for effects of prenatal exposure(s) on human fetal testis development and function. We present the effects of environmental, pharmaceutical and lifestyle factors in experimental systems involving exposure of human fetal testis tissues and cells. Comparison is made with existing epidemiological data primarily derived from a recent meta-analysis.

SEARCH METHODS
For identification of experimental studies, PubMed and EMBASE were searched for articles published in English between 01/01/1966 and 13/07/2018 using search terms including ‘endocrine disruptor’, ‘human’, ‘fetal’, ‘testis’, ‘germ cells’, ‘testosterone’ and related search terms. Abstracts were screened for selection of full-text articles for further interrogation. Epidemiological studies involving exposure to the same agents were extracted from a recent systematic review and meta-analysis. Additional studies were identified through screening of bibliographies of full-texts of articles identified through the initial searches.

OUTCOMES
A total of 25 experimental studies and 44 epidemiological studies were included. Consistent effects of analgesic and phthalate exposure on human fetal germ cell development are demonstrated in experimental models, correlating with evidence from epidemiological studies and animal models. Furthermore, analgesic-induced reduction in fetal testosterone production, which predisposes to the development of male reproductive disorders, has been reported in studies involving human tissues, which also supports data from animal and epidemiological studies. However, whilst reduced testosterone production has been demonstrated in animal studies following exposure(s) to a variety of environmental chemicals including phthalates and bisphenol A, these effects are not reproduced in experimental approaches using human fetal testis tissues. Image credit academic.oup.

WIDER IMPLICATIONS
Direct experimental evidence for effects of prenatal exposure(s) on human fetal testis development and function exists. However, for many exposures the data is limited. The increasing use of human-relevant models systems in which to determine the effects of environmental exposure(s) (including mixed exposures) on development and function of human tissues should form an important part of the process for assessment of such exposures by regulatory bodies to take account of animal-human differences in susceptibility.

Components of plastic : experimental studies in animals and relevance for human health

You are what you eat, and drink

Abstract

Components used in plastics, such as phthalates, bisphenol A (BPA), polybrominated diphenyl ethers (PBDE) and tetrabromobisphenol A (TBBPA), are detected in humans. In addition to their utility in plastics, an inadvertent characteristic of these chemicals is the ability to alter the endocrine system. Phthalates function as anti-androgens while the main action attributed to BPA is oestrogen-like activity. PBDE and TBBPA have been shown to disrupt thyroid hormone homeostasis while PBDEs also exhibit anti-androgen action. Experimental investigations in animals indicate a wide variety of effects associated with exposure to these compounds, causing concern regarding potential risk to human health. For example, the spectrum of effects following perinatal exposure of male rats to phthalates has remarkable similarities to the testicular dysgenesis syndrome in humans. Concentrations of BPA in the foetal mouse within the range of unconjugated BPA levels observed in human foetal blood have produced effects in animal experiments. Finally, thyroid hormones are essential for normal neurological development and reproductive function. Human body burdens of these chemicals are detected with high prevalence, and concentrations in young children, a group particularly sensitive to exogenous insults, are typically higher, indicating the need to decrease exposure to these compounds.

General Conclusions

Exposure of humans to pharmaceuticals is deliberate, with the intention of achieving a desired effect. Development and testing of medications involves a series of evaluations culminating in human clinical trials before marketing is approved. This is quite different from the situation with chemicals, whose presence in biota and humans is inadvertent. In the field of toxicology, information regarding potential human health effects is mainly derived from experimental studies and, when available, from epidemiological studies. Difficulties are not only encountered with extrapolation from animal models to humans, but epidemiological studies are also thwarted by drawbacks such as controlling for confounding factors. In particular, subjects are exposed to an assortment of chemicals on a daily basis and, often, lack of data regarding the extent of exposure at what may have been the critical time frame. One of the goals of toxicology is to identify effects in animal models with the aim to lower the risks of negatively impacting human health. Implicit in this task is that toxicological data, derived from animal studies indicating a potential for adverse effects, serve as a basis to limit exposure before effects appear or are confirmed in humans. The evidence from animal studies on single exposures to the chemicals discussed here suggests the potential for risk to human health. Moreover, data derived from co-exposure studies support the contention that the assortment of chemicals to which we are exposed on a daily basis increases the likelihood of health effects. The high prevalence of body burdens of these chemicals and simultaneous exposure to a number of substances, in conjunction with the fact that the highest concentrations have been demonstrated in the developing young, a sensitive subpopulation of society, indicate the need to decrease the exposure to these compounds.

Read the full study (free access) on NCBI PubMed, 2009 Jul 27.

BPA link to precursor of type 2 diabetes

Experimental BPA Exposure and Glucose-Stimulated Insulin Response in Adult Men and Women

A first-of-its-kind study of a small group of people exposed to a very small amount of bisphenol-A (BPA) is raising questions about the federal government’s stance that low doses of the common chemical are safe — as well as the ethics of conducting such an experiment on humans. The controversial study suggests that BPA exposure deemed safe by the feds could alter the amount of insulin released and elevate people’s type 2 diabetes risk, Environmental Health News reports.
Featured image credit Simon Zhu.

2018 Study Abstract

Aims
Human cross-sectional and animal studies have shown an association of the chemical bisphenol A (BPA) with insulin resistance, type 2 diabetes and other metabolic diseases, but no human experimental study has investigated whether BPA alters insulin/C-peptide secretion.

Methods
Men and post-menopausal women (non-diabetic) were orally administered either the vehicle or a BPA dose of 50-µg/kg body weight, which has been predicted by U.S. regulators (FDA, EPA) to be the maximum safe daily oral BPA dose over the lifetime. Insulin response was assessed in two cross-over experiments using an oral glucose tolerance test (OGTT; experiment 1) and a hyperglycemic clamp (HG clamp; experiment 2). Main outcomes were the percent change of BPA session measures relative to those of the control session.

Results
Serum bioactive BPA after experimental exposure was at levels detected in human biomonitoring studies. In the OGTT, a strong positive correlation was found between HbA1c and the percent change in the insulinogenic index (Spearman=0.92), an indicator of early phase insulin response, and the equivalent C-peptide index (Pearson = 0.97). In the HG clamp study, focusing on the later phase insulin response to a stable level of glucose, several measures of insulin and C-peptide appeared suppressed during the BPA session relative to the control session; the change in insulin Cmax (maximum concentration) was negatively correlated with HbA1c and the Cmax of bioactive serum BPA.

Conclusions
This exploratory study suggests that BPA exposure to a dose considered safe by U.S. regulators may alter glucose-stimulated insulin response in humans.