BPA and altered behavior

It is not surprising that BPA, as it was synthesized as a synthetic estrogen, affects behavior. In zebrafish, the binding of BPA to the estrogen receptor activates the genes producing aromatase, the enzyme that converts testosterone into estrogen. Male fish exposed to synthetic estrogens become intersexual and cannot reproduce (Kidd et al. 2007). Indeed, estrogen activates certain brain neurons and directs sex-specific behaviors. Aromatase is thought to be one of the enzymes that is important in mediating these behaviors. Chung and colleagues (2011) showed that BPA activated aromatase gene expression in the same set of neurons as estrogen (Figure 1).

Figure 1 BPA induces aromatase gene expression in the same regions of the zebrafish brain as estradiol (estrogen). Embryos were treated either with control solvent (A; DMSO), Estrogen (B), or BPA (C). In situ hybridization showed that BPA and estrogen induced aromatase expression in the mediobasal hypothalamus (MBH), preoptic area (POA), and telencephalon (Tel.) (After Chung et al. 2011.)

Yet BPA also seems to regulate influence brain development and behavior outside that of reproduction (Wolstenholme et al. 2011; Kundakovic and Champagne 2011). For example, exposure of rodents to BPA around the time of birth (while the brain is developing) modifies sex differences in the brain (Patisaul et al. 2006; Rubin et al. 2006). In mice, such exposure to BPA is associated with increased anxiety, aggression, impaired cognition, and decreased desire to explore novel situations (Miyagawa et al. 2007; Tian et al. 2010; Xu et al. 2010) Moreover, the effects of this exposure may be inherited from one generation to another by alteration of the methylation pattern of DNA (see Sidelights and Speculations in the textbook, p. 557.). In the offspring of monkeys exposed in utero or perinatally to BPA, males displayed fewer social behaviors (Nakagami et al. 2009). In humans, BPA exposure in the uterus has been associated with hyperactivity and aggression in 2-year-old children (Braun et al. 2009) and with anxiety and depression in older children (Braun et al. 2011).

Recently, Wolstenholme and colleagues (2012) gave pregnant mice food containing BPA and measured levels of BPA in their blood that was within the range of that found in humans. The offspring were significantly less social than control mice (using metrics used to assess some aspects of autism in children) Figure 2 shows that two measures of behavior, side-by-side sitting (A) and exploratory sniffing (B) were markedly affected by prenatal. BPA appeared to have these effects by interfering with the way that the transcription of oxytocin and vasopressin occurs in the brain (Figure 2, C and D). These two hormones are involved in mediating social behaviors, especially trust and intimacy. Moreover, the effects of exposure on behaviors and gene expression in the brain could be seen three generations later.

Figure 2 Effects of gestational BPA exposure on behaviors and neurohormone gene expression in mice. Pregnant mice were fed food containing BPA such that the serum BPA concentrations approximated those found in adult humans. Gene expression was measured at the last day of gestation (to prevent effects from nursing) and behaviors were measured in juveniles. (A, B) Juvenile mice born with prenatal exposure to BPA had greater side-by-side sitting behaviors (A), but less exploratory sniffing (B), than their control counterparts. (C, D) BPA caused decrease in vasopressin (C) and oxytocin (D) mRNAs. (After Wolstenholme et al 2012.) (Click image to enlarge.)

Literature Cited

Braun, J. M., Yolton, K., Dietrich, K. N., Hornung, R., Ye X., Calafat, A. M., and Lanphear, B. P. 2009. Prenatal bisphenol A exposure and early childhood behavior. Environ Health Perspect 117:1945–1952.

Braun, J. M., Kalkbrenner, A. E., Calafat, A. M., Yolton, K., Ye, X., Dietrich, K. N., and Lanphear, B. P. 2011. Impact of early-life bisphenolA exposure on behavior and executive function in children. Pediatrics 128:873–882.

Chung, E., Genco, M. C., Megrelis, L., and Ruderman, J. V. 2011. Effects of bisphenol A and triclocarban on brain-specific expression of aromatase in early zebrafish embryos. Proc Natl Acad Sci U S A. 108: 17732–17737.

Kidd, K. A., Blanchfield, P. J., Mills, K. H., Palace, V. P., Evans, R. E., Lazorchak, J. M., and Flick, R. W. 2007. Collapse of a fish population after exposure to a synthetic estrogen. Proc Natl Acad Sci U S A. 104: 8897–8901.

Kundakovic, M., and Champagne, F. A. 2011 Epigenetic perspective on the developmental effects of bisphenol A. Brain Behav Immun 25: 1084–1093.

Miyagawa, K., Narita, M., Narita, M., Akama, H., Suzuki, T. 2007. Memory impairment associated with a dysfunction of the hippocampal cholinergic system induced by prenatal and neonatal exposures to bisphenol-A. Neurosci Lett 418: 236–241.

Nakagami, A., Negishi, T., Kawasaki, K., Imai, N., Nishida, Y., Ihara, T., Kuroda, Y., Yoshikawa, Y., and Koyama, T. 2009. Alterations in male infant behaviors towards its mother by prenatal exposure to bisphenol A in cynomolgus monkeys (Macaca fascicularis) during early suckling period. Psychoneuroendocrinology 34:1189–1197.

Patisaul, H. B., Fortino A. E., and Polston E. K. 2006 Neonatal genistein or bisphenol-A exposure alters sexual differentiation of the AVPV. Neurotoxicol Teratol 28: 111–118.

Rubin, B. S., Lenkowski, J. R., Schaeberle, C. M., Vandenberg, L. N., Ronsheim, P. M., and Soto, A. M. 2006 Evidence of altered brain sexual differentiation in mice exposed perinatally to low, environmentally relevant levels of bisphenol A. Endocrinology 147: 3681–3691.

Tian, Y. H., Baek, J. H., Lee, S. Y., and Jang, C. G. 2010 Prenatal and postnatal exposure to bisphenol a induces anxiolytic behaviors and cognitive deficits in mice. Synapse 64: 432–439.

Xu, X. H., Zhang, J., Wang, Y. M., Ye, Y. P., Luo, Q. Q. 2010. Perinatal exposure to bisphenol-A impairs learning-memory by concomitant down-regulation of N-methyl-D-aspartate receptors of hippocampus in male offspring mice. Horm Behav 58: 326–333.

Wolstenholme, J. T., Rissman, E. F., and Connelly, J. J. 2011 The role of Bisphenol A in shaping the brain, epigenome and behavior. Horm. Behav. 59: 296–305.

Wolstenholme J. T., Edwards M, Shetty S. R., Gatewood J. D., Taylor J. A., Rissman E. F., and Connelly J. J. 2012. Gestational exposure to bisphenol A produces transgenerational changes in behaviors and gene expression. Endocrinology. Aug;153(8):3828–38. doi: 10.1210/en.2012-1195. Epub 2012 Jun 15.

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