FP38-6 PRENATAL BISPHENOL A TREATMENT REDUCES KISSPEPTIN CELL NUMBER IN THE POA AND CAUSES AN IMBALANCE OF KNDY PEPTIDES IN THE ARC DURING ADULT LIFE IN SHEEP

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP38-Physiological Impacts of Endocrine Disrupting Chemicals
Basic/Translational
Monday, June 17, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 11:10 AM
Room 256 (Moscone Center)

Poster Board MON-342
Chrysanthi Fergani*1, Lique M Coolen2, Michael N Lehman3 and Vasantha Padmanabhan4
1University of Mississippi Medical Center, Jackson, MS, 2University of Mississippi Medical Center, MS, 3University of Mississippi Medica, Jackson, MS, 4Univ of Michigan, Ann Arbor, MI
Recent studies have found that prenatal exposure to Bisphenol A (BPA), an endocrine-disrupting chemical (EDC), with estrogenic and anti-androgenic effects, disrupts the estrous cycle during adult life, and this is characterized by severely dampened or even absent pre-ovulatory LH surges [1]. We tested the hypothesis that this disruption may involve altered kisspeptin expression in the preoptic area (POA) and/or an imbalance in KNDy (kisspeptin, neurokinin B/dynorphin) peptide expression in the arcuate nucleus (ARC).  Both these neuronal populations play a key role in transducing steroid feedback signals to GnRH neurons and initiating the LH surge in sheep [2,3]. Pregnant Suffolk ewes were given daily s.c. injections of cottonseed oil (controls), or three different doses of BPA: a low (BPALOW; 0.05 mg/kd/day), medium (BPAMED; 0.5 mg/kd/day), or high dose (BPAHIGH; 5 mg/kd/day) from day 30 to 90 of gestation (term 147 d). The doses used were chosen to produce maternal blood levels of BPA approaching the lowest, twice the mean and twice the highest level of BPA found in maternal circulation of U.S. women, respectively [4]. Female offspring from these animals (n=7-12/group) were euthanized as adults, during the late follicular phase following synchronization of estrus with prostaglandinF2α, just before the expected onset of pre-ovulatory LH surge. Hypothalamic sections were processed for dual-label immunocytochemistry for Estrogen Receptor α (ERα)/Kisspeptin and Progesterone Receptor (PR)/Dynorphin and numbers of single and dual labeled cells were counted. In the POA, prenatal BPAMED and BPAHIGH treatment significantly reduced the number of kisspeptin-positive cells compared to control or BPALOW treatment. In the ARC, there was no change in kisspeptin cell number among the groups; however, the number of dynorphin-positive cells was significantly reduced in the BPALOW and BPAHIGH groups compared to controls. The percentage of POA and ARC kisspeptin cells co-localizing ERα and ARC dynorphin cells co-localizing PR did not differ between BPA–treated and control females. These data are consistent with the hypothesis that the dampened or absent LH surges observed after prenatal BPA exposure is due to a reduction in kisspeptin in the POA. Furthermore, the decreased dynorphin expression in KNDy cells in BPA-treated ewes may indicate reduced sensitivity to progesterone negative feedback, since dynorphin in the ARC is important for conveying the inhibitory influence of progesterone on GnRH pulses [5]. This hypothesis remains to be tested. Overall, these data suggest that BPA exposure during fetal life impairs neuroendocrine pathways mediating steroid feedback control of GnRH, and thereby has adverse effects on fertility in adult life.

[1]Savabieasfahani et al., Endocrinology, 147: 5956–5966, 2006. [2]Lehman et al., Brain Research, 1364: 90–102, 2010. [3]Merkley et al., Endocrinology, 153:5406-14, 2012. [4]Padmanabhan et al., Journal of Periantology, 28:258-63, 2008. [5]Goodman et al., Endocrinology, 145: 2959–2967, 2004.

Nothing to Disclose: CF, LMC, MNL, VP

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Supported by NIH R01 ES16541 (VP) and P01 HD44232 (VP, MNL).
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