FRI373 Effect Of Neonatal R115866 Injection On Ovary Development In Mice

Abstract

Abstract Disclosure: M. Akroush: None. A. Urbanowski: None. A. Edwards: None. J. Kipp: None. The active metabolite of vitamin A, retinoic acid, is vital to several physiological functions and is most notably associated with vision and organ development. Its role in the male reproductive system is well understood, but studies on female reproduction are lacking. Recent studies show that Cyp26b1, a retinoic acid degrading enzyme, is expressed highly in the day 1-10 mouse ovary. This time point correlates with the establishment of the primordial follicle pool. In vitro studies show that both retinoic acid and R115866, a Cyp26b1 inhibitor that blocks retinoic acid metabolism, increase cell proliferation. Therefore, we hypothesize that retinoic acid plays a critical role in the early development of the ovary. To test this hypothesis, we injected neonatal mice with R115866 at either 0.5 or 1.0 mg/kg during the first 7 days after birth when the levels of Cyp26b1 expression are high. At day 19, week 7, and week 15, ovaries were harvested for morphological, immunohistochemical, and RT-PCR studies. Our results showed that animals injected with R115866 showed dose-dependent decreases in body weight in day 19 and week 7 mice, while week 15 mice appeared to recover. Neonatal R115866 injection increased the number of multi-nucleic oocytes at day 19 and bursa cysts at week 15. Cyp26b1 mRNA and protein levels were both increased by R115866 treatment in Day 19 ovaries, as confirmed by real-time RT PCR and immunohistochemical studies, consistent with the effect of these inhibitors in increasing RA levels which in turn induce Cyp26b1 expression. Neonatal R115866 injection also increased the expression of proliferative markers, including Ki67, Cyclin E1, and PCNA. Currently, we are completing studies on follicle classification and count. Overall, our results suggest that retinoic acid plays an important role in the development of the mouse ovary and that balanced retinoic acid levels in early development are needed for the health of ovaries. Presentation: Friday, June 16, 2023