Abstract EN:

These last two decades, reproductive biologists have lifted the veil on two major phenomena affecting human reproduction: first, the fact that environmental contaminants may disturb the refined hormonal homeostasis of the body – referred to as endocrine disruption – and second, a secular alteration of the male reproductive system – which gave birth to the concept of Testicular Dysgenesis Syndrome. Taken together, these observations led the specialists to look for environmental pollutants that could exert disrupting effects on reproduction, trying to give part of the answers on the secular degradation of male reproductive function. Apart from epidemiological studies, the assessment of the reproductive effects of potential endocrine disruptors (EDs) encounters many obstacles. Indeed, if animal in vivo studies allow making considerable advances in the determination of the consequences of an exposure to EDs, strong species discrepancies make them hardly applicable to humans. Moreover, the accumulation of somewhat contradictory in vivo exposure data, depending on age, timing and dosage considerations, further puzzles the reprotoxicologists, stressing the need for direct proofs. Within this context, we developed models that would tackle the issue of direct effects of potential EDs on the human adult testicular function. We used the combination of two in vitro approaches: a human adult testis explants organotypic culture (named TEXAS out of Testis EXplants ASsay), and the human adrenocortical NCI-H295R cell line (named CELIAS out of CEll LIne Assay). We first applied our system to the exploration of the effects of di-(2-ehtylhexyl) phthalate (DEHP) and its primary metabolite mono-(2-ethylhexyl) phthalate (MEHP). These widely used plasticizers can leach from their innumerable supports (among which toys, food packaging, medical tubing and devices) to the environment, engendering extensive human exposure. Our experiments gave the first direct proof of concept that phthalate esters can alter human steroidogenesis. The active concentrations of phthalates which alter testosterone production appear to be within the range of concentrations found in men in recent epidemiological studies associating exposure to phthalates and impairment of androgenic status. This study also gave the first demonstration of the metabolic abilities of the human adult testis, which turned out to be able to biotransform both DEHP and MEHP. Our second project aimed at exploring the direct impact of mild analgesics on the adult testis physiology. Indeed, those highly consumed drugs have recently been shown to be a risk factor for the appearance of cryptorchidism in newborn boys. Furthermore, their ability to inhibit cyclooxygenases makes them specific inhibitors of the prostaglandin system, which has recently been shown to be a potential target of many putative endocrine disruptors. We therefore investigated the effects of paracetamol, aspirin and indomethacin on classic testicular functions markers - such as testosterone, insulin-like factor 3 (INSL3) or inhibin b – and on prostaglandins, to define their link with steroidogenesis in COX-disruptive conditions. Mild analgesics turned out to disrupt testicular hormonal balances and prostaglandin synthesis. The latter was disrupted unrelatedly to testosterone production.