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Lead exposure has been implicated in the aetiopathogenesis of male infertility via an oxidative stress-sensitive pathway. Conversely, acetate has been shown to confer cellular protection by improving the antioxidant defense mechanism. Yet, the effect of acetate on lead-induced testicular toxicity, viz., dysregulation of testicular steroidogenesis and spermatogenesis, has not been reported. The present study probed the influence of acetate on lead-induced dysregulation of testicular steroidogenesis and spermatogenesis. In our study, a reduction in body weight gain and testicular weight was identified in lead-exposed rats. While histopathological results established distortion of testicular histoarchitecture, reduced germ cell count, and suppressed spermatogenesis, biochemical studies confirmed that lead-deregulated testicular steroidogenesis was associated with reduced circulating gonadotropin-releasing hormone and gonadotropins, as well as down-regulated testicular 3β-HSD and 17β-HSD activities. These findings were accompanied by increased testicular malondialdehyde, TNF-α, IL-1β, and IL-6, and reduced glutathione, thiol and non-thiol protein levels, total antioxidant capacity, superoxide dismutase, and catalase activities. In addition, lead exposure increased NF k B and Bax levels, as well as caspase 3 activity, but reduced Bcl-2 levels. However, co-administration of acetate ameliorated lead-induced alterations. Collectively, acetate attenuated lead-induced dysregulation of testicular steroidogenesis and spermatogenesis by targeting oxidative stress, NF k B-mediated inflammation, and caspase 3-driven apoptosis., Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-024-00250-3., Competing Interests: Conflict of interestAll authors declare that they have no conflict of interest., (© The Author(s) under exclusive licence to Korean Society of Toxicology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Aims: The aim of this study was to investigate the potential antioxidant, anti-inflammatory, and sperm function-preserving properties of sodium acetate (ACE), a histone deacetylase (HDAC) inhibitor, in a rat model of testicular torsion/detorsion (T/D)., Main Methods: Littermate Wistar rats of identical weight were subjected to sham surgery or testicular T/D by rotating the left testis at 720° around its axis along the spermatic cord clockwise and fixing it in this position for two and a half hours. 1 h before detorsion, T/D + ACE-treated rats were treated with ACE (200 mg/kg/day, per os) while T/D rats were vehicle-treated by administering 0.5 mL of distilled water. After 72 h, animals were euthanized, and the left testes were harvested for bio-molecular and histological analysis., Key Findings: Acetate administration attenuated T/D-induced rises in serum and testicular HDAC and testicular xanthine oxidase, uric acid, MDA, GSSG, MPO, TNF-α, IL-1β, IL-6, NFkB, HIF-1α, and VCAM-1. In addition, acetate treatment alleviated T/D-induced decline in sperm quality (count, motility, viability, and normal morphology) and testicular 3β-HSD, 17β-HSD, testosterone, GSH, GSH/GSSG, SOD, catalase, GPx, GST, Nrf2, and HO-1. Furthermore, acetate prevented T/D-distorted testicular histoarchitecture and spermatogenic germ cell loss., Significance: Sodium acetate during the post-ischaemic phase of testicular T/D may be beneficial in preventing I/R injury and maintaining fertility., Competing Interests: Declaration of competing interest Authors have no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Arsenic is associated with male reproductive toxicity through histone deacetylation and oxido-inflammatory injury. Notwithstanding, short-chain fatty acids such as acetate exert anti-oxido-inflammatory activities and inhibit histone deacetylation. This study investigated the impact of acetate on arsenic-induced male reproductive toxicity. Forty eight adult male Wistar rats were allotted into any of these four groups (n = 12 rats per group): vehicle-treated, sodium acetate-treated, arsenic-exposed, and arsenic-exposed + sodium acetate-treated. The results revealed that arsenic exposure prolonged the latencies of mount, intromission, and ejaculation and reduced the frequencies of mount, intromission, and ejaculation, as well as mating and fertility indices, litter size and weight, anogenital distance, anogenital index, and survival rate in male F1 offspring at weaning. Also, arsenic reduced the circulating levels of gonadotropin-releasing hormone, luteinizing hormone, follicle-stimulating hormone, and testosterone and testicular 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase activities. In addition, arsenic reduced the daily and total spermatid production, sperm count, motility, and viability but increased the percentage of sperm cells with abnormal morphology. Furthermore, arsenic increased testicular xanthine oxidase activity, uric acid, and malondialdehyde levels, and reduced glutathione content, superoxide dismutase and catalase activities, total antioxidant capacity, and Nrf2 level. More so, arsenic exposure increased testicular iNOS activity and nitric oxide (NO), TNF-α, IL-1β, IL-6, and NFkB levels as well as Bax, caspase 9, and caspase 3 activities, and reduced Bcl-2. These findings were associated with arsenic-induced increase in testicular arsenic concentration, histone deacetylase activity, and reduced testicular weight. Histopathological examination revealed that arsenic also disrupted testicular histoarchitecture, which was accompanied by altered testicular planimetry and reduced spermatogenic cells. Notwithstanding, sodium acetate alleviated arsenic-induced sexual dysfunction as well as biochemical and histological alterations. These were accompanied acetate-driven downregulation of histone deacetylase (HDAC) activity. Succinctly, acetate attenuated arsenic-induced male reproductive toxicity by suppressing HDAC and uric acid-driven oxido-inflammatory NFkB/iNOS/NO response., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Oxidative stress has been linked with lead toxicity, including lead-induced sexual dysfunction. On the contrary, sodium acetate has been proven to exert antioxidant activity. However, the effect of sodium acetate on lead-induced sexual dysfunction has not been fully explored. This study investigated the effect of sodium acetate on lead-induced sexual dysfunction, exploring the involvement of testosterone, eNOS/NO/cGMP, and Nrf2/HO-1 signaling. Twenty male Wistar rats with similar weights were randomly assigned into four groups (n = 5 rats/group) after two weeks of acclimatization. Animals were vehicle-treated (0.5 ml/day of distilled water, per os), acetate-treated (200 mg/kg/day, per os), lead-treated (20 mg/kg/day, per os), or lead + acetate-treated. The results revealed that sodium acetate treatment attenuated lead-induced rise in penile lead, malondialdehyde and oxidized glutathione concentrations, and acetylcholinesterase activity. In addition, lead exposure prolonged mount, intromission, and ejaculation latency and reduced mount, intromission, and ejaculation frequency, as well as the motivation to mate and penile reflex, which were improved by acetate treatment. More so, acetate treatment ameliorated lead-induced reductions in absolute and relative penile weight, eNOS, NO, cGMP, luteinizing hormone, follicle-stimulating hormone, testosterone, dopamine, Nrf2, HO-1, and reduced glutathione concentrations, as well as glutathione reductase, glutathione peroxidase, glutathione-S-transferase, superoxide dismutase, and catalase activities. In conclusion, this study demonstrates that sodium acetate attenuated lead-induced sexual dysfunction by upregulating testosterone-dependent eNOS/NO/cGMP and Nrf2/HO-1 signaling. Despite the compelling data presented in this study, other possible associated mechanisms in the protective role of acetate should be explored., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: The present study evaluated the effect of lead exposure with and without zinc therapy on male sexual and erectile function., Methods: Twenty male Wistar rats were randomly assigned into four groups; the control, zinc-treated, lead-exposed, lead + zinc-treated groups. Administrations were per os daily for 28 days., Results: Zinc co-administration significantly improved absolute and relative penile weights and the latencies and frequencies of mount, intromission, and ejaculation in lead-exposed rats. Also, zinc ameliorated lead-induced reductions in motivation to mate and penile reflex/erection. These findings were accompanied by attenuation of lead-induced suppression of circulating nitric oxide (NO), penile cyclic guanosine monophosphate (cGMP), dopamine, serum luteinizing hormone, follicle-stimulating hormone, and testosterone. In addition, zinc alleviated lead-induced upregulation of penile activities of acetylcholinesterase and xanthine oxidase (XO), and uric acid (UA) and malondialdehyde (MDA) levels. Furthermore, zinc ameliorated the lead-induced decline in penile nuclear factor erythroid 2-related factor 2 (Nrf2) and reduced glutathione (GSH) levels, and catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) activities., Conclusion: This study revealed that co-administration of zinc improves lead-induced sexual and erectile dysfunction by suppressing XO/UA-driven oxidative stress and upregulating testosterone via Nrf2-mediated signaling.

Aim: This study evaluated the effect of lead, with or without zinc co-administration, on steroidogenic and xanthine oxidase (XO)/uric acid (UA)/caspase 3-mediated apoptotic signaling in the testis., Materials and Methods: Forty male Wistar rats were divided into four groups at random; vehicle-treated control, zinc-treated, lead-treated, and lead + zinc-treated groups., Results: Lead exposure significantly lowered overall weight gain, testicular, epididymal, seminal vesicle, and prostate weights. Also, lead decreased sperm count, viability and motility but increased the fraction of sperm with aberrant morphology. In addition, lead caused a marked rise in the level of UA and XO activity but a decrease in nuclear factor erythroid 2-related factor 2 (Nrf2), reduced glutathione (GSH) as well as total antioxidant capacity (TAC) levels, and superoxide dismutase (SOD) and catalase activities. Furthermore, lead increased the testicular levels of nuclear factor kappa B (NFkB), interleukin-1beta (IL-1β), and tumour necrotic factor-alpha (TNF-α), which were associated with an increase in testicular caspase 3 activity and DNA fragmentation as well as a decline in circulating gonadotropin releasing hormone (GnRH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and testicular 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase (17β-HSD). These were associated with lead-induced degenerative changes in testicular tissues evidenced by shrunken seminiferous tubules, degeneration and sloughing of germ cells. Co-administration of zinc prevented lead-induced testicular injury by ameliorating oxidative stress, apoptosis, and inflammation through downregulation of XO/UA/caspase 3 pathway and upregulation of testicular 3β-HSD/17β-HSD., Conclusion: This study demonstrated that zinc protected against lead-induced testicular toxicity via the downregulation of XO/UA/caspase 3 signaling.

Aim: Cyclophosphamide (CYP) chemotherapy induces bladder toxicity and hemorrhagic cystitis in cancer patients constituting a current clinical concern. Oxidative inflammatory cascades have been implicated as the mechanism contributing to CYP bladder urotoxicity. We thus assayed to explore whether zinc (Zn) supplementation could mitigate CYP-induced urotoxicity and evaluate the possible underlying mechanism in rats., Main Method: Rats were orally administered Zn (100 mg/kg b.w./day) for 10 days against urotoxicity induced by single injection of CYP (150 mg/kg b.w., ip) on day 7., Key Findings: CYP significantly depressed bladder activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH) levels, whereas malondialdehyde level was increased prominently. In addition, CYP induced marked increases in the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and nitric oxide (NO) confirmed by histological alterations. CYP prominently increased bladder inducible nitric oxide synthase (iNOS) activity, nuclear factor-kappa B (NF-ĸB) and expression of caspase-3 protein. Zinc supplementation considerably abrogated the bladder urotoxicity by restoring redox balance, proinflammatory and apoptotic cascades and alleviated histopathological changes., Significance: This is the first to reveal zinc potential to prevent CYP-induced urotoxic hemorrhagic cystitis via restoring redox balance and enhancing anti-inflammatory and antiapoptotic mechanisms in rat bladder., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Gentamicin is an effective antibiotic against severe infections; however, its major side effect is oxidative nephrotoxicity. We explored whether virgin coconut oil (VCO) could mitigate gentamicin-induced nephrotoxicity. Rats were fed with VCO-supplemented diet for 16 days against renal toxicity induced by gentamicin (100 mg/kg bw, ip) from Day 11 to 16. Gentamicin caused marked elevated serum urea, uric acid, and creatinine levels, followed by considerable depletion in renal antioxidant enzymes, glutathione (GSH), while the malondialdehyde (MDA) level increased significantly. It significantly increased renal cytokines and nitric oxide (NO) levels, confirmed by renal histopathology. The expression of inducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NF-ĸB), and caspase-3 was prominently increased. VCO-supplemented diet significantly modulated the levels of biochemical indices, downregulated the expression of NO, iNOS, NF-ĸB, caspase-3, cytokines, and alleviated histopathological lesions. VCO protects against gentamicin-induced nephrotoxicity; thus, it could be a promising dietary supplement for patients undergoing gentamicin treatment. PRACTICAL APPLICATIONS: Gentamicin is an efficacious clinical antibiotic used against severe infections; however, the robust body of evidence indicates that the nephrotoxic side effect constrained its use. Virgin coconut oil (VCO) is an edible oil with growing human consumption and pharmacological effects. Our study has reported herein, for the first time, that VCO diet prevented the nephrotoxicity of gentamicin. Dietary supplementation of this oil could be beneficial in alleviating the nephrotoxic side effect of gentamicin in patients., (© 2019 Wiley Periodicals, Inc.)

Objective: Vigna subterranea is widely consumed as a traditional staple food in Nigeria and some West African countries. The ethanolic seed extract of V. subterranea (EEVS) was investigated for its gastroprotective effects on aspirin plus pylorus ligation-induced gastric ulcerated rats using an in vivo assay., Methods: Gastric mucosal ulceration was induced experimentally in Groups 2 to 5 using aspirin plus pylorus ligation. Rats in Group 1 were orally pretreated with 3% Tween 80 only as normal control. Groups 2 to 5 were pretreated with 3% Tween 80 (ulcer group), 20 mg/kg of omeprazole (positive group), and 200 and 400 mg/kg of EEVS (experimental groups), respectively, once daily for 21 days before ulcer induction. Parameters including those for gastric secretions, ulcerated areas and gastric wall histology were assessed. Levels of superoxide dismutase (SOD), glutathione peroxidase (GP X ), and malondialdehyde (MDA) in the gastric tissue homogenate were also determined., Results: Pretreatment with EEVS significantly (P < 0.05) reduced the ulcer index, gastric volume and total acidity in rats with aspirin plus pylorus ligation-induced ulcer. The pH and mucus of gastric content increased significantly (P < 0.05) while the levels of SOD and GP X were observed to be elevated with a reduced amount of MDA. Significant severe gastric mucosal injury was exhibited in the ulcer group and EEVS or omeprazole offered significant (P < 0.05) protection against mucosal ulceration. Histologically, the gastric submucosal layer showed remarkable decrease in edema and leucocytes infiltration compared with ulcer group., Conclusion: The study suggests that EEVS offered a protective action against aspirin plus pylorus ligation-induced gastric ulcers in Wistar rats. The protective effect might be mediated via antisecretory, cytoprotective and antioxidative mechanisms., (Copyright © 2018 Shanghai Changhai Hospital. Published by Elsevier B.V. All rights reserved.)