Environmental Epigenomics and Susceptibility for Developmental Disorders: Findings from the Keystone Symposium
By Guest Blogger, Jennifer T. Wolstenholme, PhD, Postdoctoral Fellow at the University of Virginia, Charlottesville, VA, working with two Autism Speaks-funded researchers, Emile Rissman, Ph.D. and Jennifer Connelly, Ph.D.
In recent work in our lab, we have established a mouse model for gestational exposure to an endocrine disrupting compound, bisphenol A (BPA), at human physiological levels. We asked if a low BPA dose ingested during pregnancy (20 ug BPA/kg body weight/day) would affect the social behaviors of the juvenile offspring mice. In addition, we continued to breed the mice from these litters to ask if these effects could be transmitted to future generations that were not directly exposed to dietary BPA. We also examined a handful of genes known to be affected by BPA or involved in social behaviors to determine if BPA also changed the expression of these genes in the brain during embryogenesis. The take home message is this: we do not know if exposure to endocrine disrupting chemicals causes any neurobiological disorders, including autism spectrum disorders (ASD). However, the data are interesting enough to cause us and others to continue to test the hypothesis that exposure to BPA during gestation may result in modified social behaviors in juvenile mice.
Bisphenol A (BPA) is a man-made compound used to make polycarbonate plastics (i.e. food and water containers), epoxy resins (i.e. canned food linings) and thermal register receipts. Human exposure to this chemical is wide spread and nearly unavoidable as it has been detected in urine in 90% of all humans sampled [1, 2]. Public health concerns have been fueled by findings that BPA exposure can reduce sex differences both behaviorally and in the brain. In rats and mice, perinatal exposure to BPA is associated with aggressive behavior, cognitive impairments, increased novelty seeking and impulsivity [3-5]. BPA can also influence social interactions and anxiety in rodents [6-10]. This list of associations have suggested to some that BPA may be somehow related to human neurological disorders, such as ASD. However, such a conclusion at this time is premature.
Many laboratories have suggested that BPA exposure disrupts normal brain development and behaviors through its actions on the steroid receptors [18, 19]. BPA acts as an analog of steroid hormones. Steroid hormones organize the brain during neonatal development [11-13]. BPA has steroid-like properties and binds estrogen receptors, (ERa, ERb ), as well as androgen and thyroid receptors [15-17].
In addition to steroid-related effects, BPA may have even more global actions as it can alter DNA methylation . Dysregulation of DNA methylation during critical developmental windows could disrupt the normal progression of brain and endocrine system development causing robust changes in the developing embryo that can persist into adulthood or even beyond if effects extend to germ cells that later serve reproduction as sperm or egg cells. Embryonic development is a particularly sensitive period, specifically when the body’s germ line cells undergo epigenetic programming and experience a wave of DNA de-methylation and re-methylation.
Skinner et al. have shown trans-generational effects for several endocrine disrupting compounds, but at much higher doses than humans are typically exposed [21, 22]. Specifically, endocrine disruptors found in plastics, pesticides, hydrocarbons and herbicides can affect embryonic testes development and lead to deficits in sperm production in adulthood. These effects are trans-generational in rodents directly exposed to these chemicals during gestation (F1 generation) and through to the great, great grandchildren (F2, F3 and F4 generations).
We use a paradigm in which inbred female mice are placed on control diet free of any phytoestrogens, or control diet with BPA (5mg BPA per kg diet). This diet produced BPA blood levels equivalent to those reported in humans. A week after the start of the diet females were mated. At birth, pups were fostered to control dams to limit BPA’s effect only to gestation. Three generations of offspring were tested for social behaviors at 21 days after birth.
BPA exposure had effects on several social and non-social behaviors and some of these differences between mice on control and BPA-containing diets persisted over generations. The great, great grandchildren of the BPA lineage (the F4 generation) were never directly exposed to dietary sources of BPA, yet social interactions resembled those of mice exposed during gestation. Some of these behavioral effects are correlated with different levels of gene expression in the brains of mice directly exposed to BPA compared to mice that were never exposed to dietary BPA. More work needs to be done to discover if the relationships between the affected genes and the behavioral changes are causal. Since exposure to BPA appears to alter social interactions in young mice, this compound may contribute to the risk of developing neurological disorders such as autism spectrum disorders, but further studies, especially in humans are needed to show a causal relationship.
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2. vom Saal, F.S., et al., Chapel Hill bisphenol A expert panel consensus statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. Reprod Toxicol, 2007. 24(2): p. 131-8.
3. Kawai, K., et al., Aggressive behavior and serum testosterone concentration during the maturation process of male mice: the effects of fetal exposure to bisphenol A. Environ Health Perspect, 2003. 111(2): p. 175-8.
4. Miyagawa, K., et al., Memory impairment associated with a dysfunction of the hippocampal cholinergic system induced by prenatal and neonatal exposures to bisphenol-A. Neurosci Lett, 2007. 418(3): p. 236-41.
5. Tian, Y.H., et al., Prenatal and postnatal exposure to bisphenol a induces anxiolytic behaviors and cognitive deficits in mice. Synapse, 2010. 64(6): p. 432-9.
6. Dessi-Fulgheri, F., S. Porrini, and F. Farabollini, Effects of perinatal exposure to bisphenol A on play behavior of female and male juvenile rats. Environ Health Perspect, 2002. 110 Suppl 3: p. 403-7.
7. Negishi, T., et al., Behavioral alterations in response to fear-provoking stimuli and tranylcypromine induced by perinatal exposure to bisphenol A and nonylphenol in male rats. Environ Health Perspect, 2004. 112(11): p. 1159-64.
8. Ryan, B.C. and J.G. Vandenbergh, Developmental exposure to environmental estrogens alters anxiety and spatial memory in female mice. Horm Behav, 2006. 50(1): p. 85-93.
9. Cox, K., et al., Gestational exposure to bisphenol A and cross-fostering affect behaviors in juvenile mice. Horm Behav, 2010. 58(5): p. 754-61.
10. Porrini, S., et al., Early exposure to a low dose of bisphenol A affects socio-sexual behavior of juvenile female rats. Brain Res Bull, 2005. 65(3): p. 261-6.
11. McEwen, B.S. and S.E. Alves, Estrogen actions in the central nervous system. Endocr Rev, 1999. 20(3): p. 279-307.
12. Phoenix, C.H., et al., Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology, 1959. 65: p. 369-82.
13. Negri-Cesi, P., et al., Sexual differentiation of the brain: role of testosterone and its active metabolites. J Endocrinol Invest, 2004. 27(6 Suppl): p. 120-7.
14. Kuiper, G.G., et al., Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology, 1998. 139(10): p. 4252-63.
15. Sohoni, P. and J.P. Sumpter, Several environmental oestrogens are also anti-androgens. J Endocrinol, 1998. 158(3): p. 327-39.
16. Xu, L.C., et al., Evaluation of androgen receptor transcriptional activities of bisphenol A, octylphenol and nonylphenol in vitro. Toxicology, 2005. 216(2-3): p. 197-203.
17. Bonefeld-Jorgensen, E.C., et al., Endocrine-disrupting potential of bisphenol A, bisphenol A dimethacrylate, 4-n-nonylphenol, and 4-n-octylphenol in vitro: new data and a brief review. Environ Health Perspect, 2007. 115 Suppl 1: p. 69-76.
18. Fujimoto, T., K. Kubo, and S. Aou, Prenatal exposure to bisphenol A impairs sexual differentiation of exploratory behavior and increases depression-like behavior in rats. Brain Res, 2006. 1068(1): p. 49-55.
19. Rubin, B.S., et al., Evidence of altered brain sexual differentiation in mice exposed perinatally to low, environmentally relevant levels of bisphenol A. Endocrinology, 2006. 147(8): p. 3681-91.
20. Dolinoy, D.C., D. Huang, and R.L. Jirtle, Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A, 2007. 104(32): p. 13056-61.
21. Anway, M.D., et al., Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science, 2005. 308(5727): p. 1466-9.
22. Chang, H.S., et al., Transgenerational epigenetic imprinting of the male germline by endocrine disruptor exposure during gonadal sex determination. Endocrinology, 2006. 147(12): p. 5524-41.
23. Patisaul, H.B. and H.L. Bateman, Neonatal exposure to endocrine active compounds or an ERbeta agonist increases adult anxiety and aggression in gonadally intact male rats. Horm Behav, 2008. 53(4): p. 580-8.
24. Farabollini, F., et al., Effects of perinatal exposure to bisphenol A on sociosexual behavior of female and male rats. Environ Health Perspect, 2002. 110 Suppl 3: p. 409-14.
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