The Footprints of Oxidative Stress and Mitochondrial Impairment in Arsenic Trioxide-Induced Testosterone Release Suppression in Pubertal and Mature F1-Male Balb/c Mice via the Downregulation of 3ß-HSD, 17ß-HSD, and CYP11a Expression.

Exposure to arsenic (AS) causes abnormalities in the reproductive system; however, the precise cellular pathway of AS toxicity on steroidogenesis in developing F1-male mice has not been clearly defined. In this study, paternal mice were treated with arsenic trioxide (As2O3; 0, 0.2, 2, and 20 ppm in drinking water) from 5 weeks before mating until weaning and continued for male offspring from weaning until maturity (in vivo). Additionally, Leydig cells (LCs) were isolated from the testes of sacrificed F1-intact mature male mice and incubated with As2O3 (0, 1, 10, and 100 µM) for 48 h (in vitro). Biomarkers of mitochondrial impairment, oxidative stress, and several steroidogenic genes, including the steroidogenic acute regulatory (StAR) protein, cytochrome P450 side-chain cleaving enzyme (P450scc; Cyp11a), 3ß-hydroxysteroid dehydrogenase (3ß-HSD), and 17ß-hydroxysteroid dehydrogenase (17ß-HSD), were evaluated. High doses of As2O3 interrupted testosterone (T) biosynthesis and T-related gene expression in these experimental models. Altogether, overconsumption of As2O3 can cause testicular and LC toxicity through mitochondrial-related pathways and oxidative stress indices as well as downregulation of androgenic-related genes in mice and isolated LCs. These results could lead to the development of preventive/therapeutic procedures against As2O3-induced reproductive toxicity. Graphical Abstract Mohammad Mehdi Ommati and Reza Heidari contributed equally to this study.

Carnosine and Histidine Supplementation Blunt Lead-Induced Reproductive Toxicity through Antioxidative and Mitochondria-Dependent Mechanisms.

Lead (Pb)-induced reproductive toxicity is a well-characterized adverse effect associated with this heavy metal. It has been found that Pb exposure is associated with altered spermatogenesis, increased testicular degeneration, and pathological sperm alterations. On the other hand, it has been reported that Pb-induced reproductive toxicity is associated with increased reactive oxygen species (ROS) formation and diminished antioxidant capacity in the reproductive system. Hence, administration of antioxidants as protective agents might be of value against Pb-induced reproductive toxicity. This study was designed to investigate whether carnosine (CAR) and histidine (HIS) supplementation would mitigate the Pb-induced reproductive toxicity in male rats. Animals received Pb (20 mg/kg/day, oral, 14 consecutive days) alone or in combination with CAR (250 and 500 mg/kg/day, oral, 14 consecutive days) or HIS (250 and 500 mg/kg/day, oral, 14 consecutive days). Pb toxicity was evident in the reproductive system by a significant increase in tissue markers of oxidative stress along with severe histopathological changes, seminal tubule damage, tubular desquamation, low spermatogenesis index, poor sperm parameters, and impaired sperm mitochondrial function. It was found that CAR and HIS supplementation blunted the Pb-induced oxidative stress and mitochondrial dysfunction in the rat reproductive system. Thereby, antioxidative and mitochondria-protective properties serve as primary mechanisms for CAR and HIS against Pb-induced reproductive toxicity.

Dual effects of sulfasalazine on rat sperm characteristics, spermatogenesis, and steroidogenesis in two experimental models.

There are reports of sulfasalazine (Salazosulfapyridine; SASP)-induced reproductive toxicity, but there it is not known whether the SASP molecule or its intestinal metabolites are responsible for this effect. Rats received SASP (150, 300, and 600mg/kg) for 60 consecutive days (in vivo). Additionally, epididymal sperm was isolated and incubated with SASP (10µM-1600µM) (in vitro). Markers of oxidative stress, mitochondrial function, and sperm functionality, along with testis histopathology as well as several steroidogenic genes and proteins, including steroidogenic acute regulatory (StAR) protein, cytochrome P450 side chain cleavage enzyme (P450scc; Cyp11a), 3ß-hydroxysteroid dehydrogenase (3ß-HSD), 17ß-hydroxysteroid dehydrogenase (17ß-HSD) were measured. SASP toxicity was evident as shown by severe testicular histopathological alterations, along with poor sperm parameters and increased markers of oxidative stress. Plasma testosterone level and steroidogenesis-related gene and protein (StAR, 3-beta-HSD, 17-beta-HSD) expressions, as well as mitochondrial membrane potential, were significantly decreased at high doses of SASP (in vivo). Interestingly, in vitro treatment of sperm with SASP not only caused no significant detrimental effect on rat sperm but also increased parameters of sperm functionality and decreased markers of oxidative stress. SASP had paradoxical actions on the rat sperm in these experimental models. The findings might be useful in understanding the mechanism(s) of SASP-induced reproductive toxicity. The present findings have opened a new molecular window into the relationship between disrupted steroidogenesis and mammalian reproduction indices and also are vital regarding clinical administration of SASP and human reproductive health.