Role of the endocannabinoid system in gonadal development: Implications for endocrine disruption and reproductive toxicity.

The endocannabinoid system (ECS) plays a pivotal role in reproductive physiology, including gonadal development, though its influence on testis and ovary development has only recently gained attention. The ECS comprises lipid-derived ligands such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), along with cannabinoid receptors CB1 and CB2, which are expressed in various gonadal cells. Emerging research indicates that ECS signaling is critical for testosterone synthesis and gonadal cell proliferation and differentiation. This review explores the expression and function of ECS components in developing gonads, highlighting the differential roles of CB1 and CB2 receptors in species-specific contexts. Furthermore, the ECS has been suggested to be involved in the adverse effects of endocrine-disrupting chemicals (EDCs) on reproductive development. EDCs, such as phthalates, may interfere with ECS signaling, potentially leading to reproductive abnormalities that resemble the human Testicular Dysgenesis Syndrome (TDS). Understanding the molecular interactions between EDCs and the ECS could reveal novel mechanisms underlying reproductive toxicities. Future research should focus on the detailed localization and temporal expression of ECS components in fetal gonads, the mechanisms of cannabinoid-mediated testosterone inhibition, and the potential direct interaction of EDCs with the ECS. This knowledge could be crucial for developing strategies to mitigate reproductive health risks associated with EDC exposure.