EFFECTS OF CANNABIS CONSTITUENTS ON OVARIAN HEALTH AND FUNCTION: A FOCUS ON PRENATAL EXPOSURE

Abstract

As cannabis use increases, it is important to understand its impact on human health. Particularly, the effect of cannabis constituents on female reproductive health and the long-term effects on the offspring, when used during pregnancy, are not fully understood. The goal of this thesis was to address this knowledge gap by evaluating the impact of delta-9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, on ovarian health and function, focusing on the long-term effects of prenatal exposure and the underlying mechanisms. Gestational THC exposure resulted in altered follicle dynamics, decreased vascularization and increased follicular apoptosis in the adult rat ovary. These alterations were associated with changes in ovarian miRNA and mRNA expression, as well as altered protein levels of important regulating factors. Specifically, prenatal THC exposure increased the expression of miR-122-5p and decreased the expression of its target gene insulin-like growth factor 1 receptor (IGF-1R), involved in the regulation of folliculogenesis, angiogenesis, and granulosa cell proliferation and apoptosis. Reduced vascularization in THC-exposed ovaries was also associated with decreased expression of the angiogenic factor vascular endothelial growth factor (VEGF) and its receptor (VEGFR-2), as well as increased expression of the antiangiogenic factor thrombospondin 1 (TSP-1). The differential expression of these important factors, along with the decreased vascularization and increased follicular apoptosis may partially explain the follicle dynamics observed in prenatally THC-exposed rats at 6 months of age, as they had accelerated folliculogenesis with follicular development arrest, which could lead to premature reproductive senescence. The direct impact of THC on rat ovarian explants and granulosa cells was also evaluated, revealing similarities and differences between the in utero, ex vivo and in vitro models. Taken together, our results indicate that cannabis constituents have the ability to alter key pathways in the developing ovary that may lead to detrimental effects on female reproductive health and fertility.