Dietary Cholesterol-Induced Post-Testicular Infertility

This work shows that an overload of dietary cholesterol causes complete infertility in dyslipidemic male mice (the Liver X Receptor-deficient mouse model). Infertility resulted from post-testicular defects affecting the fertilizing potential of spermatozoa. Spermatozoa of cholesterol-fed lxr−/− animals were found to be dramatically less viable and motile, and highly susceptible to undergo a premature acrosome reaction. We also provide evidence, that this lipid-induced infertility is associated with the accelerated appearance of a highly regionalized epididymal phenotype in segments 1 and 2 of the caput epididymidis that was otherwise only observed in aged LXR-deficient males. The epididymal epithelial phenotype is characterized by peritubular accumulation of cholesteryl ester lipid droplets in smooth muscle cells lining the epididymal duct, leading to their transdifferentiation into foam cells that eventually migrate through the duct wall, a situation that resembles the inflammatory atherosclerotic process. These findings establish the high level of susceptibility of epididymal sperm maturation to dietary cholesterol overload and could partly explain reproductive failures encountered by young dyslipidemic men as well as ageing males wishing to reproduce

Liver X receptors, lipids and their reproductive secrets in the male

International audienceLiver X receptor (LXR) a and LXRb belong to the nuclear receptor superfamily. For many years they have been called orphan receptors, as no natural ligand was identified. In the last decade the LXR natural ligands have been shown to be oxysterols, molecules derived from cholesterol. While these nuclear receptors have been abundantly studied for their roles in the regulation of lipid metabolism, it appears that they also present crucial activities in reproductive organs such as testis and epididymis, as well as prostate. Phenotypic analyses of mice lacking LXRs (−/−) pointed out their physiological activies in the various cells and organs regulating reproductive functions. This review summarizes the impact of LXR-deficiency in male reproduction, highlighting the novel information coming from the phenotypic analyses of −/−, −/− and −/− mice

Epididymis Response Partly Compensates for Spermatozoa Oxidative Defects in snGPx4 and GPx5 Double Mutant Mice

We report here that spermatozoa of mice lacking both the sperm nucleaus glutathione peroxidase 4 (snGPx4) and the epididymal glutathione peroxidase 5 (GPx5) activities display sperm nucleus structural abnormalities including delayed and defective nuclear compaction, nuclear instability and DNA damage. We show that to counteract the GPx activity losses, the epididymis of the double KO animals mounted an antioxydant response resulting in a strong increase in the global H2O2-scavenger activity especially in the cauda epididymis. Quantitative RT-PCR data show that together with the up-regulation of epididymal scavengers (of the thioredoxin/peroxiredoxin system as well as glutathione-S-transferases) the epididymis of double mutant animals increased the expression of several disulfide isomerases in an attempt to recover normal disulfide-bridging activity. Despite these compensatory mechanisms cauda-stored spermatozoa of double mutant animals show high levels of DNA oxidation, increased fragmentation and greater susceptibility to nuclear decondensation. Nevertheless, the enzymatic epididymal salvage response is sufficient to maintain full fertility of double KO males whatever their age, crossed with young WT female mice

Effects of environmental Bisphenol A exposures on germ cell development and Leydig cell function in the human fetal testis

<div><p>Background</p><p>Using an organotypic culture system termed human Fetal Testis Assay (hFeTA) we previously showed that 0.01 μM BPA decreases basal, but not LH-stimulated, testosterone secreted by the first trimester human fetal testis. The present study was conducted to determine the potential for a long-term antiandrogenic effect of BPA using a xenograft model, and also to study the effect of BPA on germ cell development using both the hFETA and xenograft models.</p><p>Methods</p><p>Using the hFeTA system, first trimester testes were cultured for 3 days with 0.01 to 10 μM BPA. For xenografts, adult castrate male nude mice were injected with hCG and grafted with first trimester testes. Host mice received 10 μM BPA (~ 500 μg/kg/day) in their drinking water for 5 weeks. Plasma levels of total and unconjugated BPA were 0.10 μM and 0.038 μM respectively. Mice grafted with second trimester testes received 0.5 and 50 μg/kg/day BPA by oral gavage for 5 weeks.</p><p>Results</p><p>With first trimester human testes, using the hFeTA model, 10 μM BPA increased germ cell apoptosis. In xenografts, germ cell density was also reduced by BPA exposure. Importantly, BPA exposure significantly decreased the percentage of germ cells expressing the pluripotency marker AP-2γ, whilst the percentage of those expressing the pre-spermatogonial marker MAGE-A4 significantly increased. BPA exposure did not affect hCG-stimulated androgen production in first and second trimester xenografts as evaluated by both plasma testosterone level and seminal vesicle weight in host mice.</p><p>Conclusions</p><p>Exposure to BPA at environmentally relevant concentrations impairs germ cell development in first trimester human fetal testis, whilst gonadotrophin-stimulated testosterone production was unaffected in both first and second trimester testis. Studies using first trimester human fetal testis demonstrate the complementarity of the FeTA and xenograft models for determining the respective short-term and long term effects of environmental exposures.</p></div

Epididymal approaches to male contraception

Résumé Aujourd’hui, un vaste arsenal de méthodes contraceptives interférant à différents niveaux de l’axe reproductif féminin est. disponible. Ce n’est. pas le cas des hommes pour qui, jusqu’à présent, il n’existe pas de méthode masculine réversible fiable et pour qui la vasectomie, le préservatif et le retrait sont les seules options à disposition. Malgré cette offre limitée, plus d’un tiers de toutes les méthodes contraceptives utilisées dans le monde entier reposent sur la coopération du partenaire masculin. A côté du développement d’approches hormonales pour arrêter la production de sperme, il peut y avoir des approches attrayantes qui interféreront avec les fonctions du sperme plutôt qu’avec la production. Les fonctions des spermatozoïdes sont principalement établies pendant la maturation post-testiculaire, l’épididyme assurant la plus grande part. Le but de cette revue est. de présenter certaines des pistes prometteuses ou/et déjà abandonnées qui ressortent des efforts de recherche ciblant l’épididyme et ses activités comme moyens potentiels de parvenir à une contraception post-méiotique masculine

Protection post-testiculaire des gamètes mâles contre les dommages radicalaires

Lorsqu’ils quittent le testicule, les spermatozoïdes sont fonctionnellement immatures et disposent de moyens de défense intrinsèques limités. Ils deviendront mobiles et fécondants après leur descente et leur maturation progressive dans le tubule épididymaire. L’épididyme assure aussi la survie et la protection des gamètes mâles pendant cette phase de maturation post-testiculaire et pendant la période de stockage entre deux éjaculations. Parmi les agressions communes auxquelles les spermatozoïdes sont soumis, le stress oxydant occupe une place particulière et ambiguë. Les événements de la maturation épididymaire requièrent un certain niveau d’oxydation alors que le gamète mâle y est, par ailleurs, particulièrement sensible. Un équilibre très fin entre oxydation ménagée bénéfique et stress oxydant délétère est ainsi maintenu dans l’environnement épididymaire. Les enzymes antioxydantes de la famille des peroxydases à glutathion à activité thiol peroxydase jouent un rôle clé dans le contrôle de cet équilibre

Male Infertility and Oxidative Stress: A Focus on the Underlying Mechanisms

Reactive oxygen species (ROS) play a critical role in defining the functional competence of human spermatozoa. When generated in moderate amounts, ROS promote sperm capacitation by facilitating cholesterol efflux from the plasma membrane, enhancing cAMP generation, inducing cytoplasmic alkalinization, increasing intracellular calcium levels, and stimulating the protein phosphorylation events that drive the attainment of a capacitated state. However, when ROS generation is excessive and/or the antioxidant defences of the reproductive system are compromised, a state of oxidative stress may be induced that disrupts the fertilizing capacity of the spermatozoa and the structural integrity of their DNA. This article focusses on the sources of ROS within this system and examines the circumstances under which the adequacy of antioxidant protection might become a limiting factor. Seminal leukocyte contamination can contribute to oxidative stress in the ejaculate while, in the germ line, the dysregulation of electron transport in the sperm mitochondria, elevated NADPH oxidase activity, or the excessive stimulation of amino acid oxidase action are all potential contributors to oxidative stress. A knowledge of the mechanisms responsible for creating such stress within the human ejaculate is essential in order to develop better antioxidant strategies that avoid the unintentional creation of its reductive counterpart