Sex specific impact of perinatal bisphenol A (BPA) exposure over a range of orally administered doses on rat hypothalamic sexual differentiation

Abstract

Bisphenol A (BPA) is a high volume production chemical used in polycarbonate plastics, epoxy resins, thermal paper receipts, and other household products. The neural effects of early life BPA exposure, particularly to low doses administered orally, remain unclear. Thus, to better characterize the dose range over which BPA alters sex specific neuroanatomy, we examined the impact of perinatal BPA exposure on two sexually dimorphic regions in the anterior hypothalamus, the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the anterioventral periventricular (AVPV) nucleus. Both are sexually differentiated by estradiol and play a role in sex specific reproductive physiology and behavior. Long Evans rats were prenatally exposed to 10, 100, 1000, 10,000 mg/kg bw/day BPA through daily, noninvasive oral administration of dosed-cookies to the dams. Offspring were reared to adulthood. Their brains were collected and immunolabeled for tyrosine hydroxylase (TH) in the AVPV and calbindin (CALB) in the SDN-POA. We observed decreased TH-ir cell numbers in the female AVPV across all exposure groups, an effect indicative of masculinization. In males, AVPV TH-ir cell numbers were significantly reduced in only the BPA 10 and BPA 10,000 groups. SDN-POA endpoints were unaltered in females but in males SDN-POA volume was significantly lower in all BPA exposure groups. CALB-ir was significantly lower in all but the BPA 1000 group. These effects are consistent with demasculinization. Collectively these data demonstrate that early life oral exposure to BPA at levels well below the current No Observed Adverse Effect Level (NOAEL) of 50 mg/kg/day can alter sex specific hypothalamic morphology in the rat.

Sexual Behavior: From Hormonal Regulation to Endocrine Disruption

“…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]. These data strongly suggest that BPA does not trigger masculinization in the female neural circuitry during the highly sensitive perinatal period, despite its lack of binding to α-fetoprotein.…”

“…Indeed, increases in the number of tyrosine hydroxylase cells or AVPV volume have been described [47, 56, 57], suggesting demasculinization and/or feminization of this hypothalamic region. Opposite patterns have been observed, with either a decrease (resveratrol [47]; BPA [54]) or an increase in SDN volume or calbindin cell number (genistein or nonylphenol [55]; BPA or genistein [57]; BPA [53]). Overall, such neuroanatomical measures alone are probably not sufficient or enough sensitive to reflect EDC-induced effects on the expression of behavior.…”

“…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].…”

The Neuroendocrine and Neurodevelopmental Effects of Endocrine Disrupting Chemicals

“…Etkiler SDN-POA'da demaskülinizasyon ve AVPV'de defeminizasyon olmak üzere bölge ve cinsiyete spesifik olarak gerçekleşmektedir. 20 …”

Low-Dose Exposure to Bisphenol A in Early Life

“…However, recent studies describe the nonmonotonic dose response relationship of BPA. Perinatal exposure to lower dose of BPA than LOAEL has been reported the harmful effects on endocrine system including reproductive system [4][5][6][7], immune system [8][9][10], pituitary gland [11][12][13][14][15][16][17][18][19][20], and metabolic system [21][22][23][24]. Because, the fetus and neonates are extremely sensitive to perturbation by hormone like chemicals, early life exposure to low dose BPA probably is able to affect the epigenetic mechanism.…”