Low dose effects of bisphenol A on sexual differentiation of the brain and behavior in rats

Kubo, Keishi; Arai, Okio; Omura, Masaaki; Watanabe, Rumi; Ogata, Ryo; Aou, Shuji

doi:10.1016/s0168-0102(02)00251-1

Cited by 293 publications

(194 citation statements)

References 46 publications

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“…Our results are consistent with previous studies showing that perinatal or prenatal BPA exposure abolished sex differences in open-field (29,31) and play behavior (28). Similar to our findings, previous studies have shown that some aspects of social behavior are affected by BPA in a sexspecific way (46) whereas other domains are affected similarly in both sexes (47).…”

Section: Discussionsupporting

confidence: 93%

“…One of the most striking neurobiological effects of BPA is the loss of sexual dimorphism in brain structure and behavior illustrated by animal studies (4,(28)(29)(30)(31), findings concordant with human epidemiological studies (5-7). The molecular mechanisms underlying BPA-induced disruption of sexually dimorphic phenotypes are not understood.…”

Section: Discussionsupporting

confidence: 60%

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Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure

Kundaković

Gudsnuk

Franks

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

438

390

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Bisphenol A (BPA) is an estrogenic endocrine disruptor widely used in the production of plastics. Increasing evidence indicates that in utero BPA exposure affects sexual differentiation and behavior; however, the mechanisms underlying these effects are unknown. We hypothesized that BPA may disrupt epigenetic programming of gene expression in the brain. Here, we provide evidence that maternal exposure during pregnancy to environmentally relevant doses of BPA (2, 20, and 200 μg/kg/d) in mice induces sex-specific, dose-dependent (linear and curvilinear), and brain region-specific changes in expression of genes encoding estrogen receptors (ERs; ERα and ERβ) and estrogen-related receptor-γ in juvenile offspring. Concomitantly, BPA altered mRNA levels of epigenetic regulators DNA methyltransferase (DNMT) 1 and DNMT3A in the juvenile cortex and hypothalamus, paralleling changes in estrogen-related receptors. Importantly, changes in ERα and DNMT expression in the cortex (males) and hypothalamus (females) were associated with DNA methylation changes in the ERα gene. BPA exposure induced persistent, largely sex-specific effects on social and anxiety-like behavior, leading to disruption of sexually dimorphic behaviors. Although postnatal maternal care was altered in mothers treated with BPA during pregnancy, the effects of in utero BPA were not found to be mediated by maternal care. However, our data suggest that increased maternal care may partially attenuate the effects of in utero BPA on DNA methylation. Overall, we demonstrate that low-dose prenatal BPA exposure induces lasting epigenetic disruption in the brain that possibly underlie enduring effects of BPA on brain function and behavior, especially regarding sexually dimorphic phenotypes.environmental | fetal origin of adult disease

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 60%

Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure

Kundaković

Gudsnuk

Franks

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

438

390

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show abstract

“…Again, not all studies confirm effects of prenatal xenoestrogens on SDN-POA sexual differentiation. Kubo et al [86] did not find effects of resveratrol, DES or bisphenol A on SDN-POA volume, although they reported effects in a different brain region, the locus coeruleus. Again, differences among studies are likely to be due to differential timing in the exposures to, or doses of, the EDCs.…”

Section: Effects Of Perinatal Edcs On the Avpv And Sdn-poa Morphologymentioning

confidence: 94%

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

Gore¹

2008

Frontiers in Neuroendocrinology

230

122

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The ability of a species to reproduce successfully requires the careful orchestration of developmental processes during critical time points, particularly the late embryonic and early postnatal periods. This article begins with a brief presentation of the evidence for how gonadal steroid hormones exert these imprinting effects upon the morphology of sexually differentiated hypothalamic brain regions, the mechanisms underlying these effects, and their implications in adulthood. Then, I review the evidence that aberrant exposure to hormonally-active substances such as exogenous endocrine-disrupting chemicals (EDCs), may result in improper hypothalamic programming, thereby decreasing reproductive success in adulthood. The field of endocrine disruption has shed new light on the discipline of basic reproductive neuroendocrinology through studies on how early life exposures to EDCs may alter gene expression via non-genomic, epigenetic mechanisms, including DNA methylation and histone acetylation. Importantly, these effects may be transmitted to future generations if the germline is affected via transgenerational, epigenetic actions. By understanding the mechanisms by which natural hormones and xenobiotics affect reproductive neuroendocrine systems, we will gain a better understanding of normal developmental processes, as well as to develop the potential ability to intervene when development is disrupted.

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“…Animal studies have provided evidence that fetal exposure to low levels of BPA can influence development, growth and reproduction. 3,[38][39][40][41] To what extent do these studies relate to any threat posed in humans is a contentious topic. 3,42,43 We recently found reduced birth weight and adult reproductive deficits in sheep following sustained maternal exposure to BPA 26 (at twice the levels found in human maternal circulation [27][28][29] (also this study)).…”

mentioning

confidence: 99%

Maternal bisphenol-A levels at delivery: a looming problem?

et al. 2008

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Objective: The objective was to determine whether bisphenol-A (BPA) is found in maternal circulation of pregnant women in the US population and is related to gestational length and birth weight.Method: Circulating levels of BPA were quantified by high performance liquid chromatography-tandem mass spectrometry at delivery in 40 southeastern Michigan mothers and correlated with gestational length and birth weight of offspring.Result: Maternal levels of unconjugated BPA ranged between 0.5 and 22.3 ng ml À1 in southeastern Michigan mothers. There was no correlation between BPA concentrations and gestational length or birth weight of offspring.Conclusion: This is the first study to document measurable levels of BPA in maternal blood of the US population. Long-term follow-up studies of offspring are needed to validate or refute concerns over human fetal exposure to synthetic exogenous steroids.

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Low dose effects of bisphenol A on sexual differentiation of the brain and behavior in rats

Cited by 293 publications

References 46 publications

Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure

Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

Maternal bisphenol-A levels at delivery: a looming problem?

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