Defining Critical Developmental Windows of Exposure to Bisphenol a in Pituitary Development and Elucidating Sex Differences

Presentation Number: FRI 117
Date of Presentation: April 1st, 2016

Kirsten Eckstrum*1, Karen Weis2 and Lori T Raetzman3
1UIUC, Urbana, IL, 2University of Illinois Urbana-Champaign, 3University of Illinois at Urbana-Champaign, Urbana, IL

Abstract

Exposures to endocrine disrupting chemicals (EDCs) are linked to deficits in estrogen sensitive endocrine systems leading to reproductive dysfunction and obesity. EDC exposures are often more detrimental during critical periods of development and can have persistent effects into adulthood. One EDC that is ubiquitous in the environment is Bisphenol A (BPA), a compound found in polycarbonate plastics, epoxy resins, and thermal paper. Exposure to BPA during mouse embryonic development has previously been shown to influence pituitary progenitor cells to become luteinizing hormone (LH) and follicle stimulating hormone (FSH) producing gonadotrope cells. Interestingly, this effect was seen only in females. However, the neonatal period, a time at which the hypothalamic-pituitary-gonadal axis has begun to function, has not been examined. Our goal was to determine if this second period was sensitive to BPA exposure and to determine if the response would be similar to 17β-estradiol (E2). To address this question, we dosed neonatal mice from postnatal day (PND)0 (day of birth) to PND7 with E2 or three doses of BPA: 50μg/kg/day, which is the oral reference dose for BPA, and 0.5 and 0.05μg/kg/day, both of which are within the range of human exposure. We examined the effects of these postnatal exposures on pituitary cell fate choices by looking at expression of lineage specific genes. Nr5a1 mRNA, specific to the gonadotrope lineage, exhibits an almost significant sex difference with males having more than females (p=0.053) and treatment with E2 increases the female levels to match the males. Similarly, the sex difference in Lhb mRNA levels is lessened with E2 exposure as females have more Lhb mRNA than males, but E2 decreases the levels in both males and females, making females no longer different than control males. No effect was seen with any dose of BPA for Nr5a1 or Lhb mRNA, unlike during embryonic exposure. Next, we examined Pit1 mRNA, which is specifically expressed in the somatotrope, thyrotrope, and lactotrope lineages. Surprisingly, we found that BPA exposures at 0.5μg/kg/day and 0.05μg/kg/day decrease the transcript levels of Pit1 mRNA, in males, but not females. No significant effect with 50μg/kg/day BPA or E2 is observed in either sex. Analysis of hormone mRNA levels of the PIT1 lineage (Prl, Gh, or Tshb) shows that there are no changes correlated with BPA exposure. E2 did increase Prl mRNA in both sexes, as expected. The changes in Pit1 mRNA did not persist to PND30. Overall, these data demonstrate that the neonatal period of pituitary development is less sensitive to BPA exposure than prenatal development.  Additionally, at both time windows, BPA and E2 exposure can have sex-specific effects. Thus, BPA can subtly alter neonatal pituitary development however, its ability to compensate and recover from such insults demonstrate the profound plasticity of the pituitary during neonatal development.

 

Nothing to Disclose: KE, KW, LTR