Exploring the potential impact of nutritionally actionable genetic polymorphisms on idiopathic male infertility: a review of current evidence.

Infertility affects about 15% of the world's population. In 40%-50% of infertile couples, a male factor underlies the problem, but in about 50% of these cases, the etiology of male infertility remains unexplained. Some clinical data show that lifestyle interventions may contribute to male reproductive health. Cessation of unhealthy habits is suggested for preserving male fertility; there is growing evidence that most preexisting comorbidities, such as obesity and metabolic syndrome, are highly likely to have an impact on male fertility. The analysis of genetic polymorphisms implicated in metabolic activity represents one of the most exciting areas in the study of genetic causes of male infertility. Although these polymorphisms are not directly connected with male infertility, they may have a role in specific conditions associated with it, that is, metabolic disorders and oxidative stress pathway genes that are potentially associated with an increased risk of male infertility due to DNA and cell membrane damage. Some studies have examined the impact of individual genetic differences and gene-diet interactions on male infertility, but their results have not been synthesized. We review the current research to identify genetic variants that could be tested to improve the chances of conceiving spontaneously through personalized diet and/or oral vitamin and mineral supplementation, by examining the science of genetic modifiers of dietary factors that affect nutritional status and male fertility.

Activation of antioxidant defences of human mammary epithelial cells under leptin depend on neoplastic state.

BACKGROUND: Obesity is associated with oxidative stress, a major factor in carcinogenesis, and with high leptin concentration. The aim of this study was to determine the effects of leptin on the antioxidant response in three human mammary epithelial cells each presenting a different neoplastic status: healthy human mammary epithelial cells (HMEC), oestrogen-receptor positive MCF-7 cells and triple-negative MDA-MB-231 cells. METHODS: This in vitro kinetic study characterized the cell antioxidant response after 1, 6 and 24 h in the presence of leptin (10 or 100 ng/ml).The antioxidant response was defined in terms of cell glutathione content, gene expression and catalytic activity of antioxidant enzymes (i.e. glutathione peroxidase 1 (Gpx1), glutathione reductase (GR), glutathione S transferase (GST), heme-oxygenase 1 (HO-1) and cyclooxygenase-2 (COX-2)). Oxidative stress occurrence was assessed by lipid hydro peroxide (HPLIP) and isoprostane concentrations in culture media at 24 h. RESULTS: At both concentrations used, leptin induced ROS production in all cell models, contributing to various antioxidant responses linked to neoplastic cell status. HMEC developed a highly inducible antioxidant response based on antioxidant enzyme activation and an increase in cell GSH content at 10 ng/ml of leptin. However, at 100 ng/ml of leptin, activation of antioxidant response was lower. Conversely, in tumour cells, MCF-7 and MDA-MB-231, leptin did not induce an efficient antioxidant response, at either concentration, resulting in an increase of lipid peroxidation products. CONCLUSIONS: Leptin can modulate the oxidative status of mammary epithelial cells differently according to their neoplastic state. These novel results shed light on oxidative status changes in mammary cells in the presence of leptin.

Leptin induces ROS via NOX5 in healthy and neoplastic mammary epithelial cells.

NADPH oxidase (NOX) complexes (a family of seven isoforms) drive cellular ROS production in patho-logical processes such as cancer. NOX-driven ROS production is involved in cell mechanisms from signalling to oxidative stress. Leptin, an adipokine overexpressed in obese patients, has been investigated in studies on breast carcinogenesis, but its effects on oxidative stress remain largely unexplored, especially in breast cancer. The study used three human mammary epithelial cell models presenting different neoplastic status (healthy primary HMECs, neoplastic MCF-7 cells and neoplastic MDA-MB-231 cells) to determine the effects of leptin on short-term ROS production and to characterize the enzymes involved. All three cell models significantly expressed NADPH oxidase isoform 5 (NOX5) in our culture conditions. All models showed induced ROS production regardless of leptin concentration (10 ng/ml mimicking good health, 100 ng/ml mimicking obesity). Cell treatment with either siRNA against NOX5, NOX inhibitor DPI or a calcium channel blocker (verapamil) confirmed the putative involvement of the NOX5 isoenzyme in ROS production. Moreover, cell treatments suppressed ROS production under leptin at both concentrations. Neoplastic cells appeared unable to downregulate NOX5 mRNA expression under leptin. Leptin emerged as a potential activator of ROS production in human epithelial mammary cells, where the ROS production was apparently linked to NOX5 activation. This novel finding could shed light on the potential role of obesity-associated hyperleptinemia in mammary cells via the activation of NOX enzymes.