# Depletion of Fkbp5 Protects Against the Rapid Decline in Ovarian Reserve Induced by Prenatal Stress in Female Offspring of Wild-Type Mice

## TL;DR

Prenatal stress harms ovarian development in female mice, but removing a stress-related protein called FKBP51 prevents this damage.

## Contribution

The study identifies FKBP51 as a key mediator of ovarian dysfunction caused by prenatal stress in mice.

## Key findings

- Prenatal stress increased follicle atresia and reduced total follicle counts in wild-type mice offspring.
- FKBP51 levels were elevated in granulosa cells of follicles in mice exposed to prenatal stress.
- Fkbp5−/− mice were protected from the negative effects of prenatal stress on ovarian reserve.

## Abstract

Prenatal stress (PNS) impairs offspring ovarian development by exerting negative long-term effects on postnatal ovarian function and folliculogenesis. FKBP51 is a stress-responsive protein that inhibits glucocorticoid and progesterone receptors. We hypothesize that FKBP51 contributes to impaired ovarian development and folliculogenesis induced by PNS. Timed-pregnant Fkbp5+/+ (wild-type) and Fkbp5−/− (knockout) mice were randomly assigned to either the undisturbed (nonstress) or PNS group, with exposure to maternal restraint stress from embryonic days 8 to 18. Ovaries from the offspring were harvested and stained, and follicles were counted according to their stages. Ovarian expressions of FKBP51 were evaluated by immunohistochemistry and Fkbp5 and steroidogenic enzymes were evaluated by qPCR. Compared to controls, Fkbp5+/+ PNS offspring had increased peripubertal primordial follicle atresia and fewer total follicles in the adult and middle-aged groups. In adult Fkbp5+/+ offspring, PNS elevated FKBP51 levels in granulosa cells of primary to tertiary follicles. Our results suggest that PNS administration increased FKBP51 levels, depleted the ovarian reserve, and dysregulated ovarian steroid synthesis. However, these PNS effects were tolerated in Fkbp5−/− mice, supporting the conclusion that FKBP51 contributes to reduced ovarian reserve induced by PNS.