The neural circuitry processing male sexual behavior is tightly regulated by testosterone and its neural metabolite estradiol. The present study evaluated the effects of adult exposure to low doses of nonylphenol (NP), a widespread environmental contaminant, on the neuroendocrine regulation of testosterone and expression of sexual behavior. Oral exposure of C57BL/6J males to NP (0.5, 5 or 50 μg/kg/day) for 4 weeks did not affect circulating levels of testosterone or the kisspeptin system, a key regulator of the gonadotropic axis. In contrast, mice exposed to NP at 5 μg/kg/day emitted an increased number and duration of ultrasonic vocalizations, took longer to reach ejaculation and showed increased number of mounts, intromissions and thrusts. This was associated with normal olfactory preference and locomotor activity, and increased anxiety level. Analysis of the neural circuitry that underlies sexual behavior showed changes in the number of cells expressing androgen and estrogen receptors in males exposed to NP at 5 μg/kg/day. The neural circuitry underlying sexual behavior is thus highly sensitive to adult exposure to NP. Furthermore, almost all the observed effects were induced at 5 μg/kg/day of NP, indicating that this endocrine disrupter triggers a non-monotonic response in the adult male mouse brain.
Nonylphenol (NP) is an organic compound used in the manufacture of NP ethoxylate surfactants, but derives also from alkylphenol degradation that occurs during sewing water treatment or in the environment. Alkylphenols are nonionic surfactants that have been used since 1950 in a wide variety of industrial, agricultural and domestic applications such as soap, cosmetics, paints, herbicides and pesticides, or plastic fabrication. This results in major environmental contamination by NP of ecosystems including sewing water and rivers. NP was classified by the EU in 2000 as a priority substance “presenting a significant risk to or via the aquatic environment” in the Water Framework Directive 2000/60/EC, which was updated in 2008 and 20131. Due to its widely-reported estrogenic activity, NP may affect male reproductive capacities as was highlighted in a recent systematic review2.
Male reproduction is controlled by finely regulated cross-talk between neural and peripheral structures. Synthesis and liberation of testosterone by the testes are under the control of hypothalamic gonadotropin-releasing hormone (GnRH) and pituitary luteinizing hormone (LH). In turn, testosterone acts on the male brain through androgen (AR) and estrogen (ER) receptor-dependent signaling pathways to regulate GnRH release, thereby controlling gonadotropin secretion and circulating testosterone levels. One key neuronal system that mediates the negative feedback exerted by testosterone and its neural metabolite estradiol on GnRH release is kisspeptin neurons of the arcuate nucleus3. The sexually dimorphic anteroventral periventricular area (AVPV) and periventricular (PeN) of the preoptic area contain much fewer kisspeptin neurons in males4,5. AR and ER signaling in kisspeptin neurons regulate transcription of the Kiss1 gene, which encodes the potent GnRH secretagogue kisspeptin. The kisspeptin system has recently emerged as a key central target of endocrine disruptors that affect sex steroid signaling and reproductive function [see6,7 for a review].
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