Pubertal Exposure To Bisphenol A Disrupts Adult Behaviors And ERα Expression In C57BL/6J Mice

In mammals, endogenous estrogens are crucial for the development and sexual differentiation of central nervous system structures controlling many neuroendocrine, behavioural and cognitive functions. The nervous system is progressively shaped over the life span by endogenous signals, exogenous or experimential factors, and interactions between the two factors. During sensitive or critical periods, the nervous system is especially susceptible to agents that organize neural circuits and determine responses to stimuli at later stages of development. In the perinatal period, extends from late prenatal life until the first 1-2 weeks after birth, estrogen irreversibly organizes male-type specific circuitries. However, the brain clearly retains a significant capacity for organizational modifications well beyond this early critical period, and puberty is another important window of development. In this period, sex hormones can still induce structural modifications of the central nervous system, with effects on the development of sexually differentiated behaviors. Alterations in the estrogenic milieu of the developing central nervous system (CNS) influence critical aspects of cellular differentiation, including neurite extension and branching, synapse formation, myelination, the expression of neurotransmitters and neuropeptides, and cell death and survival. So estrogenic chemicals such as estrogenic endocrine disrupters can thus interfere with the male-and female-typical development of brain areas that control the occurrence and pattern of a wide range of behaviours required for reproduction, such as sexual behaviours, as well as social and nonsocial behaviours in adult life. Bisphenol A (BPA) is a chemical component of polycarbonate plastic and epoxy resins. Over time, or with simple wear and heat and either acidic conditions accelerate hydrolysis of the ester bond linking BPA monomers, freeing monomers of BPA and the potential for human and envuronmental exposure. BPA has been demonstrated in both in vivo and in vitro experiments to act as an estrogenic endocrine disrupter. BPA has been shown to influence a number of physiology and behaviour during prenatal and/or neonatal periods, but less is known about how it might affect hormone dependent behaviors including locomotion, exploration, anxiety and sociality and estrogen receptor alpha (ERa) expression during pubertal period. Using C57BL/6J mice, we sought to determine how pubertal exposure to BPA affects locomotion, exploration, anxiety and sociality and ERa expression in adulthood. The animals were subcutaneously injected with either bisphenol A (BPA,50μg/kg),17β-estradiol (E2,10μg/kg) or the sesame oil (OIL, 0.05ml) from postnatal 23 to 30, and the behaviours of offspring in adulthood were observed in an open field, an elevated plus-maze, a nover cage and social interaction tests. After the behavioural tests, the expression of ERa was examed using immunocytochemistry method. The main results include the following points:1. E2-treated male mice show a significant decrease in their spontaneous locomotion activity when assessed in the elevated plus-maze (shorter total distance and lower number of total transitions) tests. BPA-treated male mice also show a decrease in this behavioral parameter, but no significant effect is observed.2. BPA and E2-treated female mouse showed a significant decrease in their spontaneous locomotion activity when assessed in the open-field (shorter total distance and lower number of total transitions between quadrants), elevated plus-maze (shorter total distance and lower number of total transitions), and female-female social interaction (shorter locomoted distance) tests.3. Pubertal BPA exposure produces significant anxiolytic effects in the open-field test and the social interaction test on males. E2 did not significantly affect the percentage of time spent in the open arms and the percentage of time spent in the centre of the OF in male mice, but these male mice tended to spend more time in the centre of the OF, and in the male-female social interaction test, mice display significantly more locomotion. These findings show that E2 has the same effects as BPA.4. Females pubertally treated with BPA and E2 produced significant anxiogenic effects in the open-field test and the elevated plus-maze test compared to the OIL controls.5. Pubertal BPA and E2 exposure did not affect exploratory behaviours on males in the novel cage test and social interaction test.6. The duration of exploratory behaviour in E2 females were also reduced showing decreased exploration from control females in the novel cage test. The effects found for BPA, which is weak but in the same direction of E2, indicate to be due to its estrogenic activity.7. Treatment with BPA and E2 did not affect sociability of male mice, with both BPA and E2-treated male mice showing no difference in affiliation behaviour compared to same-sex controls.8. Female mice pubertally exposed to BPA showed increased levels of affiliation behaviours to female stimulus mice and decreased levels of affiliation behaviours to male stimulus mice. At the same time, E2-treated females display decreased levels of affiliation behaviours to male stimulus mice.9. Pubertal BPA and E2 exposure did not affect expression of ERa in male mouse.10. The present result showed significantly higher ERa expressing in females in bed nucleus of the stria terminalis (BST), arcuate hypothalamic nucleus (Arc), ventromedial hypothalamic nucleus (VMH) and medial amygdaloid nucleus (MeA) induced by BPA exposure and in lateral septum (LS) induced by E2 exposure during puberty.The results from the present study suggest that femals pubertally treated with BPA decreased significantly spontaneous locomotion activity and exploration, and increased significantly anxiety. Treatment with BPA reduced anxiety in males. Femals pubertally treated with BPA showed the masculinization, but there was a non-significant effect for male affiliation behavior. The ERa expressing in males were not significantly affected by treated with BPA during puberty. However, the ERa expressing in females were increased by treatment in brain regions. In conclusion, treatment with BPA mainly affected female mice. The effects of pubertal BPA exposure similar to that of estrogen may produce masculinization effects on female mouse, and the obsered masculization of female behaviours such as exploration, anxiety and sociability following pubertal BPA administration is associated with ERa expressing neurons which increased in female brain regions.