Graduation Year

2025

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medicine

Major Professor

Ozlem Guzeloglu-Kayisli, M.Sc, Ph.D.

Co-Major Professor

Michael Teng, Ph.D.

Committee Member

Laura J. Blair, Ph.D.

Committee Member

Patricia Kruk, Ph.D.

Committee Member

Thomas McDonald, M.D.

Keywords

FK506 binding protein 51, Maternal stress, Ovarian reserve, Reproduction

Abstract

FK506-binding protein 51 (FKBP51) is an immunophilin that acts as a co-chaperone with heat shock protein 90 that negatively regulates transcriptional activity of glucocorticoid receptor (GR) and progesterone receptor (PR), and FKBP51 levels are increased by stress conditions. Our previous studies demonstrate that Fkbp5 gene depletion was protective against maternal re-strained stress-induced preterm birth (PTB), fetal growth restriction (FGR), and maternal stress-induced age-related decline in live births. We hypothesize that FKBP51 contributes to impaired ovarian development and folliculogenesis induced by prenatal stress (PNS). Timed-pregnant Fkbp5+/+ (wild-type) and Fkbp5−/− (knockout) mice were randomly assigned to either the undis-turbed (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 ac-cording to their stages. Ovarian expressions of FKBP51 were evaluated by immunohistochemis-try 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, and Fkbp5+/+ offspring spent more time in estrus compared to Fkbp−/− mice. Our results suggest that PNS administration in-creased FKBP51 levels, depleted the ovarian reserve, and dysregulated ovarian steroid synthe-sis. However, these PNS effects were tolerated in Fkbp5−/− mice, supporting the conclusion that FKBP51 contributes to reduced ovarian reserve induced by PNS.

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