In the last decades, several studies evidenced a decrease in male fertility in developed countries. Although the aetiology of this trend in male reproductive health remains a matter of debate, environmental compounds that predispose to weight gain, namely obesogens, are appointed as contributors because of their action as endocrine disruptors. Obesogens favour adipogenesis by an imbalance of metabolic processes and can be found virtually everywhere. These compounds easily accumulate in tissues with high lipid content. Obesogens change the functioning of male reproductive axis, and, consequently, the testicular physiology and metabolism that are pivotal for spermatogenesis. The disruption of these tightly regulated metabolic pathways leads to adverse reproductive outcomes. Notably, adverse effects of obesogens may also promote disturbances in the metabolic performance of the following generations, through epigenetic modifications passed by male gametes. Thus, unveiling the molecular pathways by which obesogens induce toxicity that may end up in epigenetic modifications is imperative. Otherwise, a transgenerational susceptibility to metabolic diseases may be favoured. We present an up-to-date overview of the impact of obesogens on testicular physiology, with a particular focus on testicular metabolism. We also address the effects of obesogens on male reproductive parameters and the subsequent consequences for male fertility.

Human exposure to environmental contaminants is widespread. Some of these contaminants have the ability to interfere with adipogenesis, being thus considered as obesogens. Recently, obesogens have been singled out as a cause of male infertility. Sertoli cells (SCs) are essential for male fertility and their metabolic performance, especially glucose metabolism, is under a tight endocrine control, being essential for the success of spermatogenesis. Herein, we studied the impact of the model obesogen tributyltin in the metabolic profile of SCs. For that, ex vivo-cultured rat SCs were exposed to increasing doses of tributyltin. SCs proliferation was evaluated by the sulforhodamine B assay and the maturation state of the cells was assessed by the expression of specific markers (inhibin B and the androgen receptor) by quantitative polymerase chain reaction. The metabolic profile of SCs was established by studying metabolites consumption/production by nuclear magnetic resonance spectroscopy and by analyzing the expression of key transporters and enzymes involved in glycolysis by Western blot. The proliferation of SCs was only affected in the cells exposed to the highest dose (1000 nM) of tributyltin. Notably, SCs exposed to 10 nM tributyltin decreased the consumption of glucose and pyruvate, as well as the production of lactate. The decreased lactate production hampers the development of germ cells. Intriguingly, the lowest levels of tributyltin were more prone to modulate the expression of key players of the glycolytic pathway. This is the first study showing that tributyltin reprograms glucose metabolism of SCs under ex vivo conditions, suggesting new targets and mechanisms through which obesogens modulate the metabolism of SCs and thus male (in)fertility.

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anti-androgen drugs are the standard pharmacological therapies for treatment of non-metastatic prostate cancer (Pca). However, the response of Pca cells may depend on the anti-androgen used and often patients become resistant to treatment. Thus, studying how the anti-androgen drugs affect oncogenes expression and action and the identification of the best strategy for combined therapies are essential to improve the efficacy of treatments. The Six Transmembrane epithelial antigen of the Prostate 1 (STeaP1) is an oncogene associated with Pca progression and aggressiveness, although its relationship with the androgen receptor signaling remains to be elucidated. The present study aimed to evaluate the effect of anti-androgens in regulating STeaP1 expression and investigate whether silencing STeaP1 can make Pca cells more sensitive to anti-androgen drugs. For this purpose, wild-type and STeaP1 knockdown lncaP cells were exposed to bicalutamide, enzalutamide and apalutamide. Bicalutamide decreased the expression of STeaP1, but enzalutamide and apalutamide increased its expression. However, decreased cell proliferation and increased apoptosis was observed in response to all drugs. overall, the cellular and molecular effects were similar between lncaP wild-type and lncaP-STeaP1 knockdown cells, except for c-myc expression levels, where a cumulative effect between anti-androgen treatment and STeaP1 knockdown was observed. The effect of STeaP1 knockdown alone or combined with anti-androgens in c-myc levels is required to be addressed in future studies.

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