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.

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 1 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 1, 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 1 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.)

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