Effects of combined exposure of adult male mice to di-(2-ethylexyl)phthalate and nonylphenol on behavioral and neuroendocrine responses

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The present study evaluates the effects of adult exposure to low doses of a mixture of di-(2-ethylexyl)phthalate (DEHP) and nonylphenol (NP) on reproductive neuroendocrine function and behavior. The neural circuitry that processes male sexual behavior is tightly regulated by testosterone and its neural metabolite estradiol. In previous studies, we showed that adult exposure of mice to low doses of each of these widespread environmental contaminants resulted in altered sexual behavior, without any effect on the regulation of the gonadotropic axis. Here, adult C57BL/6J male mice were exposed to DEHP/NP (0.5 or 5 μg/kg body weight/day) for 4 weeks before starting the analyses. Mice treated with DEHP/NP at 0.5 μg/kg/day show altered olfactory preference, and fewer of them emit ultrasonic vocalization compared to the other treatment groups. These mice also exhibit a lower number of mounts and thrusts, increased locomotor activity and unaffected anxiety-state level, along with unaltered testosterone levels and kisspeptin system, a key regulator of the gonadotropic axis. Analysis of the neural circuitry that underlies sexual behavior showed that the number of cells expressing androgen and estrogen receptors is comparable between control and DEHP/NP-exposed males. The comparison of these data with those obtained in males exposed to each molecule separately highlights synergistic effects at the lower dose of contaminants of 0.5 μg/kg/day. In contrast, the effects previously observed for each molecule at 5 μg/kg/day were not detected. A detailed comparison of the effects triggered by separate or combined exposure to DEHP and NP is discussed.