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.
Bisphenol A promotes the proliferation of leiomyoma cells by GPR30‐EGFR signaling pathway, 2019
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.
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.
“Émission du Labo”, enregistrée en public au Lieu Unique, Nantes, le 14 mai 2019
Les sources d’exposition sont nombreuses et difficiles à maîtriser, tout comme leurs conséquences biologiques.
Historiquement, les perturbateurs endocriniens ont commencé à attirer l’attention des chercheur·euses dès les années 1950. Mais c’est l’affaire du distilbène qui, dans les années 1970, a fait exploser le sujet sur la scène scientifique et médiatique, alors même que le terme de “perturbateur endocrinien” n’était pas encore utilisé.
Aujourd’hui, c’est un enjeu majeur de santé publique, pour nous qui sommes vivants, mais aussi pour les générations futures, celles qui n’ont pas encore vu le jour. Référence.
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.
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.
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 Newsreports. 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.
Multigenerational effects of bisphenol A or ethinyl estradiol exposure on F2 California mice (Peromyscus californicus) pup vocalizations
California mice is used as a special model for parental behaviors with high relevance to humans, because they are monogamous, with both parents caring for neonates. In this study, Johnson and colleagues found changes in the vocalization patterns of the mice pups whose parents were exposed to BPA prenatally (i.e., through exposure of grandparents). These changes in communication abilities could have impacts on the amount of parental care they receive.
2018 Study Abstract
Rodent pups use vocalizations to communicate with one or both parents in biparental species, such as California mice (Peromyscus californicus). Previous studies have shown California mice developmentally exposed to endocrine disrupting chemicals, bisphenol A (BPA) or ethinyl estradiol (EE), demonstrate later compromised parental behaviors. Reductions in F1 parental behaviors might also be due to decreased emissions of F2 pup vocalizations. Thus, vocalizations of F2 male and female California mice pups born to F1 parents developmentally exposed to BPA, EE, or controls were examined. Postnatal days (PND) 2–4 were considered early postnatal period, PND 7 and 14 were defined as mid-postnatal period, and PND 21 and 28 were classified as late postnatal period. EE pups showed increased latency to emit the first syllable compared to controls. BPA female pups had decreased syllable duration compared to control and EE female pups during the early postnatal period but enhanced responses compared to controls at late postnatal period; whereas, male BPA and EE pups showed greater syllable duration compared to controls during early postnatal period. In mid-postnatal period, F2 BPA and EE pups emitted greater number of phrases than F2 control pups. Results indicate aspects of vocalizations were disrupted in F2 pups born to F1 parents developmentally exposed to BPA or EE, but their responses were not always identical, suggesting BPA might not activate estrogen receptors to the same extent as EE. Changes in vocalization patterns by F2 pups may be due to multigenerational exposure to BPA or EE and/or reduced parental care received.
Effects of maternal or paternal bisphenol A exposure on offspring behavior
2018 Study Highlights
No significant behavioral effects of preconception paternal BPA exposure.
Increased anxiety-like behavior in juvenile offspring maternally exposed to BPA.
Increased duration and median frequency of ultrasonic vocalizations in BPA pups.
Females outperform males in an operant reversal learning task.
BPA females earn fewer rewards than control females during operant training.
Bisphenol A (BPA) is an endocrine disrupting chemical used in the production of polycarbonate plastics and resins. Exposure to BPA during gestation has been proposed as a risk factor for the development of neurobehavioral disorders, such as autism spectrum disorder. To address the behavioral impact of developmental exposure to BPA, we tested offspring of mice exposed to a daily low dose of BPA during pregnancy. We also asked if preconception exposure of the sire affected behaviors in offspring.
Sires that consumed BPA for 50 days prior to mating weighed less than controls, but no effects on any reproductive measures were noted. Juvenile offspring exposed to BPA maternally, but not paternally, spent less time in the open arms of the elevated plus maze than controls, indicating increased anxiety-like behavior. However, neither parental exposure group differed significantly from controls in the social recognition task.
We also assessed the behaviors of maternally exposed offspring in two novel tasks: ultrasonic vocalizations (USVs) in pups and operant reversal learning in adults.
Maternal BPA exposure increased the duration and median frequency of USVs emitted by pups during maternal separation. In the reversal learning task, females responded more accurately and earned more rewards than males. Additionally, control females received more rewards than BPA females during the acquisition phase of the task.
These are among the first studies conducted to ask if BPA exposure via the sire affects offspring behavior and the first study to report effects of gestational BPA exposure on pup USVs and adult operant responding.
A plurality of molecular targets: The receptor ecosystem for bisphenol-A (BPA)
2018 Study Highlights
Bisphenol-A exerts a range of non-estrogenic effects.
Care should be taken in selecting positive controls, given BPA’s range of activity.
Non-estrogenic effects can account for many phenotypes produced by BPA exposure.
Bisphenol-A (BPA) is a well-known endocrine disrupting compound (EDC), capable of affecting the normal function and development of the reproductive system, brain, adipose tissue, and more. In spite of these diverse and well characterized effects, there is often comparatively little known about the molecular mechanisms which bring them about. BPA has traditionally been regarded as a primarily estrogenic EDC, and this perspective is often what guides research into the effects of BPA. However, emerging data from in-vitro and in-silico models show that BPA binds with a significant number of hormone receptors, including a number of nuclear and membrane-bound estrogen receptors, androgen receptors, as well as the thyroid hormone receptor, glucocorticoid receptor, and PPARγ. With this increased diversity of receptor targets, it may be possible to explain some of the more puzzling aspects of BPA pharmacology, including its non-monotonic dose-response curve, as well as experimental results which disagree with estrogenic positive controls.
This paper reviews the receptors for which BPA has a known interaction, and discusses the implications of taking these receptors into account when studying the disruptive effects of BPA on growth and development.