The anti-androgenic fungicide vinclozolin disrupts sexual differentiation of the external genitalia

Meeting Abstract


22-3  Friday, Jan. 4 10:45 – 11:00  The anti-androgenic fungicide vinclozolin disrupts sexual differentiation of the external genitalia LEWIS, AK*; COHN, MJ; University of Florida; University of Florida

In recent decades, there has been a rise of endocrine-related diseases and disorders, including genital malformations, low semen quality, adverse pregnancy outcomes, neurobehavioral conditions, cancers of reproductive organs, earlier onset of breast development, obesity, and type 2 diabetes (UNEP and WHO, 2013). For example, congenital penile anomalies (CPA) now affect 1 in 120, or 0.83%, of male newborns (Nelson et al., 2005). The most commonly reported CPA is hypospadias, which is characterized by mislocalization of the urethral opening along the penile shaft, within the scrotum, or in the perineum, with the most severe cases resulting in ambiguous genitalia. Our lab previously demonstrated that conditional deletion of the androgen receptor (AR) gene from mesenchymal cells of the mouse genital tubercle – the embryonic precursor to the penis and clitoris – induces penile anomalies that mimic human CPAs (Zheng et al., 2015). Moreover, the timing of AR disruption, whether by genetic or pharmacologic mechanisms, determines the type of CPA that arises, reflecting a critical window of susceptibility. Here we report that male mouse embryos exposed to vinclozolin, an environmental endocrine disruptor, during the same temporal window also develop external genital defects that mimic human CPAs. Dissection of the cellular and molecular mechanisms that mediate vinclozolin-induced hypospadias revealed disruption of fetal sex steroid levels and the distribution of their respective receptors. Furthermore, we find that the sexually dimorphic patterns of cell death and proliferation that occur during normal genital development are disrupted in treated mice. Taken together, these results suggest that transitory exposure to vinclozolin during the critical period of susceptibility causes genital malformations by abolishing male- and female-specific endocrine profiles and morphogenetic processes.

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