Over the past five decades, semen parameters, including sperm counts, have rapidly declined in men worldwide. Although this decline remains largely unexplained, exposure to lifestyle factors, such as medication usage, could provide a possible explanation.Reproductive-aged men are using more medications than in previous years. Additionally, men are waiting longer to father children than previously, which has been associated with greater medication use. Together, these factors have increased the number of over-the-counter medications men take in their reproductive years.

Some scientific evidence suggests that medications, even the common nonsteroidal anti-inflammatory drugs (NSAIDs), can negatively impact male reproductive health. Even though NSAIDs account for more than half of all analgesic usage worldwide, the mechanisms by which these drugs impact male fertility remain largely uncharacterized. Animal studies provide valuable information; however, applications to humans are sometimes limited by the differences in drug metabolism and pharmacokinetics, warranting more human-like models to further our understanding. Using an established stem cell-based model of human spermatogenesis, we evaluated two NSAIDs, naproxen and ibuprofen, under long-term conditions at physiologically relevant concentrations. Here, we demonstrate that long-term naproxen and ibuprofen exposure have marginal effects in vitro. Expanding upon this study to include the somatic niche, we assessed the impact of both NSAIDs on non-human primate (NHP) primary Sertoli cells and the functionality of the blood-testis barrier (BTB), a specialized structure formed from junctions between adjacent Sertoli cells that regulates the entry of nutritional substances,vital molecules (e.g., hormones), and toxicants (e.g., drugs, environmental toxicants) into the adluminal compartment where spermiogenesis takes place. Our study revealed that serum levels of naproxen and ibuprofen exposure compromises the function of the BTB by perturbing the Sertoli cell tight junctions. Together, these models provide a unique opportunity to experimentally study drug toxicity on the seminiferous tubule epithelium while also providing the ability to assess mechanisms in a cost-effective manner. The results of these studies highlight the potential for these common medications to affect male fertility in vitro and potentially associate NSAID usage as a contributing factor in the decline of sperm counts.