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Abstract
In 2021, approximately 60 million people used opioids worldwide. Among them, nearly 40 million live with drug use disorders. Opioid use and overdose have increased in
recent years across several countries alongside its devastating impact on the United States. This opioid epidemic was initially attributed to the overabundance and overprescription of opioids for use in the management of chronic pain but has now shifted towards the abuse of highly potent opioids such as fentanyl appearing on the illicit drug market. Given the prevalence of male opioid users combined with both the addictive properties and the known detrimental health effects of these substances, there is a need to understand the potential consequences of opioid exposure on male reproductive health. Notably, global fertility rates have declined, and both semen parameters and sperm counts have been on a decline. Studies have highlighted the importance of environmental exposures as well as lifestyle choices in determining health outcomes over time. Emerging evidence suggests that exogenous opioid use in men reduce semen quality and induce DNA damage, hypogonadism, and DNA hypermethylation. While endogenous opioids are suggested to play a role in male reproductive function, there is little known on the direct effects these exogenous opioids on both the blood-testis barrier, a critical feature of this tightly regulated system, as well as the germ cells and their epigenome during development. To assess the effects of exogenous opioids on male reproductive health, we exposed critical male reproductive cells to pharmacologically relevant doses of Fentanyl using a novel in vitro human blood-testis barrier model alongside an in vitro human spermatogenesis model to investigate the consequences originating from opioid use.