Neuroendocrine and behavioral effects of maternal exposure to oral bisphenol A in female mice

Abstract

Bisphenol A (BPA) is a widespread estrogenic compound. We investigated the effects of maternal exposure to BPA at reference doses on sexual behavior and neuroendocrine functions of female offspring in C57BL/6J mice. The dams were orally exposed to vehicle alone or vehicle-containing BPA at doses equivalent to the no observed adverse effect level (5 mg/kg body weight per day) and tolerable daily intake (TDI, 0.05 mg/kg body weight per day) level from gestational day 15 until weaning. Developmental exposure to BPA increased the lordosis quotient in naive females exposed to BPA at the TDI dose only. BPA exposure had no effect on olfactory preference, ability to express masculine behaviors or number of calbindin-positive cells, a sexually dimorphic population of the preoptic area. BPA at both doses selectively increased kisspeptin cell number in the preoptic periventricular nucleus of the rostral periventricular area of the third ventricle in adult females. It did not affect the number of GNRH-positive cells or percentage of kisspeptin appositions on GNRH neurons in the preoptic area. These changes were associated with higher levels of estradiol (E 2 ) at the TDI dose while levels of LH, estrus cyclicity, ovarian and uterine weights, and fertility remained unaffected. Delay in the time of vaginal opening was observed during the postnatal period at TDI dose, without any alteration in body growth. This shows that developmental exposure to BPA at reference doses did not masculinize and defeminize the neural circuitry underlying sexual behavior in female mice. The TDI dose specifically exacerbated responses normally induced by ovarian E 2 , through estrogen receptor a, during the postnatal/prepubertal period.

Sexual Behavior: From Hormonal Regulation to Endocrine Disruption

“…However, pre- or postnatal exposure to BPA decreased proceptive behavior in one study [75] and increased the frequency of lordosis in another [44]. In one study on mice, exposure to BPA at a dose of 50 µg/kg/day resulted in a significant increase in lordosis quotient in naïve but not sexually experienced females, whereas a dose 100 times higher had no effect [76]. Olfactory preferences were unchanged, as BPA-exposed females displayed normal levels of interest in chemoinvestigating males relative to females [76].…”

“…In one study on mice, exposure to BPA at a dose of 50 µg/kg/day resulted in a significant increase in lordosis quotient in naïve but not sexually experienced females, whereas a dose 100 times higher had no effect [76]. Olfactory preferences were unchanged, as BPA-exposed females displayed normal levels of interest in chemoinvestigating males relative to females [76]. Following ovariectomy and testosterone treatment, females displayed no masculinization of their behavior, with no difference in mounting or thrusting behaviors relative to the vehicle-treated group.…”

“…Following ovariectomy and testosterone treatment, females displayed no masculinization of their behavior, with no difference in mounting or thrusting behaviors relative to the vehicle-treated group. Most neuroanatomical studies have reported no effects on the SDN, corresponding calbindin cells [42, 53, 54, 59, 73, 76], and TH neurons [56]. By contrast, an increase in the number of kisspeptin neurons in the AVPV was observed in the study reporting an increase in lordosis behavior following BPA exposure in mice [76].…”

“…Most neuroanatomical studies have reported no effects on the SDN, corresponding calbindin cells [42, 53, 54, 59, 73, 76], and TH neurons [56]. By contrast, an increase in the number of kisspeptin neurons in the AVPV was observed in the study reporting an increase in lordosis behavior following BPA exposure in mice [76]. Changes in the number of tyrosine hydroxylase neurons have also been reported in rats [54, 56].…”

“…It is not possible to draw any firm conclusions from the small number of studies assessing hormone levels in intact females. An absence of effect [42, 105, 108] or increases in hormone levels have been reported following exposure to BPA [76]. Lower levels of estradiol and LH were observed in rats exposed to methoxychlor [109] or BPA [110], whereas phthalates had no effect [94].…”