Low testosterone (T) levels are a major cause of male infertility, as this hormone is crucial for several processes throughout the entire male reproductive tract. Leydig cells (LC) produce T through testicular steroidogenesis. Disrupted LC function can hinder steroid production and fertility. Among the factors that affect steroidogenesis, endocrine-disrupting chemicals (EDCs) raise concerns, as they disturb hormonal signaling. Chromium is classified as an EDC, and its main forms are hexavalent (Cr(VI)) and trivalent chromium (Cr(III)). While Cr(III) is controversially regarded as an essential metal, its compound Cr(III) picolinate (CrPic₃) is used as a nutritional supplement due to its antidiabetic and antioxidant properties. This review aims to identify the possible effects of CrPic₃ on testicular steroidogenesis and thus, on male fertility. The detriments caused by CrPic₃ in LC include the inhibition of enzymes involved in steroidogenesis, and, as in other cells, the induction of mutagenesis and apoptosis. Remarkably, CrPic₃ impacts male fertility through the alteration of reactive oxygen species (ROS), T levels, and sperm parameters (sperm motility and abnormal sperm count). However, gaps and inconsistencies exist in the literature concerning its effects on male fertility. Thus, further research is imperative to comprehend the underlying mechanisms of CrPic₃ in the physiological processes relevant to male fertility, ensuring the supplement’s safety for use by men.

Obesity results from a disproportionate accumulation of fat and has become a global health concern. The increase in adipose tissue is responsible for several systemic and testicular changes including hormone levels (leptin, adiponectin, testosterone, estrogen), inflammatory cytokines (increase in TNF-α and IL-6 and decrease in IL-10), and redox state (increase in reactive oxygen species and reduction in antioxidant enzymes). This results in poor sperm quality and compromised fertility in men with obesity. Lifestyle modifications, particularly diet transition to caloric restriction and physical exercise, are reported to reverse these negative effects. Nevertheless, precise mechanisms mediating these benefits, including how they modulate testicular oxidative stress, inflammation, and metabolism, remain to be fully elucidated. The main pathway described by which these lifestyle interventions reverse obesity-induced oxidative damage is the Nrf2-SIRT1 axis, which modulates the overexpression of antioxidant defenses. Of note, some of the detrimental effects of obesity on the testis are inherited by the descendants of individuals with obesity, and while caloric restriction reverses some of these effects, no significant work has been carried out regarding physical exercise. This review discusses the consequences of obesity-induced testicular oxidative stress on adult and pediatric populations, emphasizing the therapeutic potential of lifestyle to mitigate these detrimental effects.

Oxidative stress (OS), defined by an imbalance between reactive oxygen species (ROS) production and antioxidant defences, plays a bivalent and paradoxical role in the male reproductive system. At physiological levels, ROS are indispensable for sperm capacitation, hyperactivation and acrosome reaction, which are crucial for fertilization. However, excessive ROS – stemming from both endogenous sources (e.g. mitochondrial metabolism, enzyme‐mediated reactions, seminal leukocytes) and exogenous factors (e.g. environmental pollutants and lifestyle behaviours) – can trigger detrimental OS reactions, including lipid peroxidation, DNA damage and impaired sperm function, contributing to male infertility. This dualistic nature of OS complicates defining the distinction between its physiological and pathological concentrations of ROS. This review comprehensively examines the complex interplay between ROS and OS in male reproduction, delineating how lifestyle factors can contribute to this imbalance and what mechanisms are implicated. Furthermore, we discuss current and emerging non‐pharmacological strategies aimed at mitigating pathological OS, including antioxidant supplementation (e.g. resveratrol, vitamins C and E, coenzyme Q10), dietary interventions such as adherence to the Mediterranean diet and lifestyle modifications like regular moderate exercise and stress management techniques. By elucidating these multifaceted aspects, our analysis provides critical insights into maintaining redox homeostasis and advancing clinical interventions for improved male reproductive health. image

Leydig cells (LCs) play a pivotal role in male fertility, producing testosterone. Chromium (III) picolinate (CrPic₃), a contentious supplement with antidiabetic and antioxidant properties, raises concerns regarding male fertility. Using a rodent LC line, we investigated the cytotoxicity of increasing CrPic₃ doses. An insulin resistance (IR) model was established using palmitate (PA), and LCs were further exposed to CrPic₃ to assess its antioxidant/antidiabetic activities. An exometabolome analysis was performed using ¹H-NMR. Mitochondrial function and oxidative stress were evaluated via immunoblot. Steroidogenesis was assessed by quantifying androstenedione through ELISA. Our results uncover the toxic effects of CrPic₃ on LCs even at low doses under IR conditions. Furthermore, even under these IR conditions, CrPic₃ fails to enhance glucose consumption but restores the expression of mitochondrial complexes CII and CIII, alleviating oxidative stress in LCs. While baseline androgen production remained unaffected, CrPic₃ promoted androstenedione production in LCs in the presence of PA, suggesting that it promotes cholesterol conversion into androgenic intermediates in this context. This study highlights the need for caution with CrPic₃ even at lower doses. It provides valuable insights into the intricate factors influencing LCs metabolism and antioxidant defenses, shedding light on potential benefits and risks of CrPic₃, particularly in IR conditions.

Metabolic syndrome (MetS) represents a global health challenge mainly driven by chronic low-grade inflammation and persistent oxidative stress (OS). Current therapeutic and nutritional strategies often fail to resolve these interconnected core pathologies due to the multifactorial nature of MetS. Anthocyanins (ACNs), a class of potent dietary flavonoids, offer significant promise due to their established pleiotropic effects, including robust antioxidant activity through modulation of the Nrf2/ARE pathway, anti-inflammatory effects via NF-κB suppression, and overall support for glucose and lipid homeostasis. However, the therapeutic efficacy of ACNs is characterized by interindividual variability, which is intrinsically linked to their low systemic bioavailability. This heterogeneity in the response is due to the complex interplay between genetic polymorphisms affecting absorption, distribution, metabolism, and excretion (ADME), as well as the specific biotransformation capacity of the gut microbiome. This review proposes that achieving the full clinical potential of ACNs requires moving beyond conventional nutritional advice. We propose that precision nutrition, which integrates multi-omics data (e.g., genomics, metagenomics, and metabolomics), can determine the individual phenotype, predict functional metabolic response, and tailor safer and effective ACN-rich interventions. This integrated, multifactorial approach is essential for optimizing the antioxidant and metabolic benefits of ACNs for the prevention and management of MetS and its associated pathologies.

Male infertility affects 8–12% of couples worldwide and is solely responsible in up to 30% of cases. Assisted Reproductive Technologies (ARTs) provide potential solutions, particularly in conditions where spermatozoa display structural abnormalities or impaired motility, such as asthenozoospermia. Sperm metabolism demonstrates remarkable flexibility, shifting between glycolysis and oxidative phosphorylation to produce ATP required for motility. Glycerol kinase 2 (GK2) phosphorylates glycerol in the sperm midpiece, generating glycerol-3-phosphate, a key intermediate in glycolysis, lipid metabolism, and oxidative phosphorylation. The localization of GK2 suggests not only a regulatory role in sperm metabolism but also a possible association with VDAC proteins, contributing to ADP-ATP exchange between the cytosol and mitochondria. Elucidating the role of GK2 in spermatozoa is of particular relevance, as this enzyme not only contributes to key metabolic pathways but may also interact with VDAC proteins, influencing mitochondrial function and energy exchange. Such interactions could play a pivotal role in regulating sperm motility. A deeper understanding of these mechanisms could position GK2 as a valuable biomarker: in scenarios where GK2–VDAC interactions are confirmed, it may guide optimized sperm selection methods in ARTs, whereas the absence or impairment of such interactions could serve as a diagnostic indicator in asthenozoospermic men.