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Cannabis and female fertility: an extensive in vitro and clinical investigation

ABSTRACT: Cannabis consumption and legalization is increasing globally, raising concerns about its impact on fertility. In humans, we previously demonstrated that tetrahydrocannabinol (THC) and its metabolites reach the ovarian follicle. An extensive body of literature describes THC’s impact on sperm, however no such studies have determined its effects on the oocyte. Herein, we investigate the impact of THC on human female fertility through both a clinical and in vitro analysis. We show that follicular fluid THC concentration is positively correlated with oocyte maturation and in vitro, we observe a similar but non-significant increase following THC exposure. In vitro, we report altered expression of key genes implicated in extracellular matrix remodeling, inflammation, and chromosome segregation. Furthermore, THC induces oocyte chromosome segregation errors and increases abnormal spindle morphology. Finally, THC-positive patients exhibit significantly lower embryo euploid rates than matched controls. This study highlights potential reproductive risks associated with cannabis use in females.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297757 | GEO | 2025/07/23

REPOSITORIES: GEO

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Project description:Background: Adolescent cannabis use leads to long-lasting behavioral changes involving cognitive and reward processes. However, the underlying molecular mechanisms are not well understood. To address this limitation, we performed gene network analyses using transcriptomic data from mice exposed during adolescence to Δ-9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis. Methods: We injected vehicle or THC in female and male mice during the entire adolescence period. Two weeks following the last exposure, we measured recognition memory, social interaction and anxiety-related behaviors. We generated 120 RNA-seq datasets from 5 brain regions for each mouse. We performed differential gene expression analysis and constructed co-expression networks to identify THC-induced transcriptional alterations at the level of individual genes, gene networks, biological pathways, and cellular specificity. Further, we integrated THC-correlated gene networks with human traits from genome-wide association studies and performed key driver analysis to identify potential regulators of disorder-associated networks. Results: THC impaired cognitive behaviors of mice, with memory being more impacted in females, which coincided with larger transcriptional alterations in the female brain. Gene network analyses identified brain region-, cell type- and sex- specific co-expressed genes (“modules”) dysregulated by THC. THC-induced memory deficits in females were correlated with disruption of gene networks involved in endocannabinoid signaling and inflammation. Additional THC-correlated modules in both sexes involved converging pathways related to dopamine signaling and addiction processes. Moreover, the connectivity map of THC-correlated modules uncovered intra- and inter-region molecular circuitries influenced by THC. Further, modules altered by THC treatment were enriched in genes relevant for human cognition and schizophrenia. Conclusions: These findings provide novel insights concerning the genes, cell types, and pathways underlying persistent behavioral deficits induced by adolescent exposure to THC in a sex-specific manner, and highlight the connection between adolescent cannabis use and neuropsychiatric disorders in humans.

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Cannabis and female fertility: an extensive in vitro and clinical investigation

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