Neonatal exposure to genistein adversely impacts the ontogeny of hypothalamic kisspeptin signaling pathways and ovarian development in the peripubertal female rat.
Neonatal exposure to estrogenic endocrine disrupting compounds (EDCs) can advance pubertal onset and induce premature anestrous in female rats. It was recently discovered that hypothalamic kisspeptin (KISS) signaling pathways are sexually dimorphic and regulate both the timing of pubertal onset and estrous cyclicity. Thus we hypothesized that disrupted sex specific ontogeny of KISS signaling pathways might be a mechanism underlying these EDC effects. We first established the sex specific development of KISS gene expression, cell number and neural fiber density across peripuberty in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC), hypothesizing that the sexually dimorphic aspects of KISS signaling would be most vulnerable to EDCs. We next exposed female rats to the phytoestrogen genistein (GEN, 1 or 10 mg/kg bw), estradiol benzoate (EB, 10 μg), or vehicle from post natal day (P) 0-3 via subcutaneous (sc) injection. Animals were sacrificed on either P21, 24, 28, or 33 (n=5-14 per group at each age). Vaginal opening was significantly advanced by EB and the higher dose of GEN compared to control animals and was accompanied by lower numbers of KISS immunoreactive fibers in the AVPV and ARC. Ovarian morphology was also assessed in all age groups for the presence of multiple oocyte follicles (MOFs). The number of MOFs decreased over time in each group, and none were observed in control animals by P24. MOFs were still present, however, in the EB and 10 mg/kg GEN groups beyond P24 indicating a disruption in the timing of ovarian development.
North Carolina State University, Department of Biology, Raleigh, NC 27695, United States.
Sandra M
SM
Losa
Karina L
KL
Todd
Alana W
AW
Sullivan
Jinyan
J
Cao
Jillian A
JA
Mickens
Heather B
HB
Patisaul
D000818:Animals; D000831:Animals, Newborn; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D019833:Genistein / Q000633:toxicity*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D059648:Kisspeptins; D020644:Midline Thalamic Nuclei / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000187:drug effects* / Q000254:growth & development; D048789:Phytoestrogens / Q000633:toxicity*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D012737:Sex Factors; D012741:Sexual Maturation / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
C491406:Kiss1 protein, rat; D059648:Kisspeptins; D048789:Phytoestrogens; D011506:Proteins; D012333:RNA, Messenger; D019833:Genistein