Testosterone (T) profoundly influences central sexual differentiation and functions. In the brain, T signals either directly through androgen receptor (AR) or indirectly through estrogen receptor (ER) following aromatization into E2 (17-␤-estradiol).As T, through AR, also controls peripheral male sexual differentiation, the relative contribution of central AR in T-mediated regulation of behavioral and neuroendocrine responses still remains unclear. To address this question, we generated, by using Cre-loxP technology, mice selectively lacking AR expression in the nervous system. The mutant male urogenital tract was normally developed, and mice were able to produce offspring. Nonetheless, sexual motivation and performance as well as aggressive behaviors were affected. Only a low percentage of males displayed a complete sexual behavior and offensive attacks. The latency to show masculine behaviors was increased and copulation length prolonged. Erectile activity during mating was also altered. These alterations occurred despite increased levels of T and its metabolites, and an unaffected number of ER␣-immunoreactive cells. Olfactory preference and neuronal activation, mapped by Fos immunoreactivity, following exposure to estrus female-soiled bedding were also normal. At comparable T levels, greater differences in masculine behaviors were observed between gonadectomized control and mutant males. AR invalidation in the nervous system also disrupted the somatotropic axis since mutant males exhibited growth retardation and decreased serum levels of insulin-like growth factor I. Our findings show that central AR is required in T-induced regulation of male-typical behaviors and gonadotrope and somatotropic axes. This genetic model offers a unique opportunity in the understanding of AR's role in cerebral functions of T.

There are human reproduction concerns associated with extensive use of bisphenol A (BPA)-containing plastic and, in particular, the leaching of BPA into food and beverages. In this context, it remains unclear whether and how exposure to BPA interferes with the developmental organization and adult activation of male sexual behavior by testosterone. We evaluated the developmental and adult exposure to oral BPA at doses equivalent to the no-observed-adverse-effect-level (5 mg/kg body weight per day) and tolerable daily intake (TDI) (50 μg/kg body weight per day) on mouse sexual behavior and the potential mechanisms underlying BPA effects. Adult exposure to BPA reduced sexual motivation and performance at TDI dose only. Exposed males took longer to initiate mating and reach ejaculation despite normal olfactory chemoinvestigation. This deficiency was not restored by sexual experience and was associated with unchanged circulating levels of testosterone. By contrast, developmental exposure to BPA at TDI or no-observed-adverse-effect-level dose did not reduce sexual behavior or alter the neuroanatomical organization of the preoptic area. Disrupting the neural androgen receptor resulted in behavioral and neuroanatomical effects similar to those induced by adult exposure to TDI dose. Moreover, adult exposure of mutant males to BPA at TDI dose did not trigger additional alteration of sexual behavior, suggesting that BPA and neural androgen receptor mutation share a common mechanism of action. This shows, for the first time, that the neural circuitry underlying male sexual behavior is vulnerable to chronic adult exposure to low dose of BPA and suggests that BPA could act in vivo as an antiandrogenic compound.

Motoneurons in the spinal nucleus of the bulbocavernosus (SNB) and their target bulbocavernosus (BC) and levator ani (LA) muscles play a role in male copulation and fertility. Testosterone (T) induces sexual differentiation of this SNB neuromuscular system during development and maintains its activation in adulthood. In the rat, T-induced effects mostly involve the androgen receptor (AR). However, the role of central AR in T-induced effects remains to be studied with pertinent genetic models. We addressed this question by using specific motoneuron immunolabeling and retrograde tracing in mice selectively disrupted for AR in the nervous system. This work reveals that nervous system AR is not required either for T-induced development of BC-LA muscles and perinatal sparing of SNB motoneurons from atrophy or for adult sensitivity of BC-LA muscles to T. By contrast, loss of AR expression in the nervous system resulted in SNB motoneurons having smaller somata and shorter dendrites than controls. We studied the effects of adult castration and T supplementation on SNB cell morphology in control and mutant males; these experiments showed that central AR is involved in the developmental regulation of soma size and dendritic length and in the adult maintenance of soma size of SNB motoneurons. T seemed to act indirectly through BC-LA muscles to maintain dendritic length in adulthood. Our results also suggest that central AR functions may contribute to normal activity of SNB motoneurons and perineal muscles because mutant mice displayed diminished copulatory behavior and fertility.