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Benzo[a]pyrene (BaP) is a contaminant that is generated in the environment through processes such as smoke, incomplete combustion of fossil fuels, vehicle exhaust emissions, entry into the body is through inhalation, and consumption of contaminated food. It is an omnipresent environmental pollutant with unavoidable exposure. BaP metabolites are observed in the male reproductive system, especially in the testes and epididymis of animals, and are responsible for reduced testicular and epididymal function. The protective effect of atorvastatin (ATV) on testicular damage was investigated previously. The aim of the present study was to investigate the protective effect of ATV on testicular toxicity induced by benzo[a]pyrene (BaP) during pregnancy in Wistar rats. This experimental laboratory study involved 40 adult rats, divided into seven groups and maintained under standard environmental conditions. The groups received different diets [control, corn oil, ATV (10 mg/kg), BaP (10 and 20 mg/kg), and ATV + BaP (10 and 20 mg/kg)] at gestation Days 7-16, orally. Male offspring were examined 10 weeks after birth. Testis and serum samples were collected, and testosterone level, malondialdehyde (MDA), and glutathione (GSH) were measured. Histological and immunohistochemical assays were performed under a light microscope. Statistical analysis was conducted using SPSS, with analysis of variance and Tukey tests to assess significant differences between groups. ATV significantly reduced MDA, a marker of lipid peroxidation and oxidative stress in rat testes following BaP administration. Treatment with ATV at doses of 10 mg/kg increased GSH levels, correcting disruptions in the antioxidant system caused by BaP. Testosterone concentration in rats treated with ATV and BaP substantially prevented the decrease induced by BaP. Histomorphometry revealed that ATV significantly prevented the detrimental effects of BaP on the thickness of spermatogenic epithelium and the diameter of seminiferous tubules. Under ATV treatment, testicular tissue histopathology improved, and spermatogenesis returned to a almost back to normal state. Caspase-3 expression decreased, and apoptosis activity in testicular tissue improved under ATV treatment, indicating a positive effect of ATV in reducing apoptotic damage caused by BaP. In conclusion, exposure to BaP can induce oxidative stress-related damage to testicular tissue, as evidenced by an increase in MDA levels, which ATV treatment can mitigate. Additionally, ATV enhances intracellular antioxidant GSH and protects the testes against BaP-induced damage while increasing testosterone levels, which are reduced due to exposure to BaP., (© 2024 Wiley Periodicals LLC.)

Although cyclophosphamide (CP) has been approved as an anticancer drug, its toxic effect on most organs, especially the testis, has been established. Piperine (PIP) is an alkaloid that has antioxidant, antiapoptotic, and anti-inflammatory activities. This study was investigated the protective effects of PIP on CP-induced testicular toxicity in the mice. In this experimental study, 48 adult male BALB/c mice (30-35 g) were divided into six groups (n = 8), receiving normal saline (C), 5 mg/kg of PIP (PIP5), 10 mg/kg of PIP (PIP10), 200 mg/kg of CP, 200 mg/kg of CP + PIP5, and 200 mg/kg of CP + PIP10. On the eighth day of the study, blood and testis samples were prepared for serum testosterone hormone quantification, sperm analysis, histological, and immunohistochemical assays. The results of this study showed that CP induced testicular toxicity with the decrease of sperm count, motility, and viability. Also, CP treatment caused histological structure alterations in the testis, including exfoliation, degeneration, vacuolation of spermatogenic cells, and reducing the thickness of the epithelium and the diameter of the seminiferous tubule. In addition, CP decreased glutathione (GSH) levels, increased malondialdehyde (MDA) levels, Caspase-3, and NF-κB. At the same time, PIP treatment reduced testicular histopathological abnormalities, oxidative stress, and apoptosis that were induced by CP. These results showed that PIP improved CP-induced testicular toxicity in mice, which can be related to its antioxidant, antiapoptotic, and anti-inflammatory activities., (© 2024 Wiley Periodicals LLC.)

Antimicrobial agent resistance has become a growing health issue across the world. Colistin (COL) is one of the drugs used in the treatment of multidrug-resistant bacteria resulting in toxic effects. Naringin (NRG), a natural flavonoid, has come to the fore as its antioxidant, anti-inflammatory, and antiapoptotic activities. The aim of the present study was to determine whether NRG has protective effects on COL-induced toxicity in testicular tissue. Thirty-five male Spraque rats were randomly divided into five groups (n = 7 per group): Control, COL, NRG, COL + NRG 50, COL + NRG 100. COL (15 mg/kg b.w., i.p., once per/day), and NRG (50 or 100 mg/kg, oral, b.w./once per/day) were administered for 7 days. The parameters of oxidative stress, inflammation, apoptosis, and autophagic damage were evaluated by using biochemical, molecular, western blot, and histological methods in testicular issues. NRG treatment reversed the increased malondialdehyde level and reduced antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione) levels due to COL administration (p < 0.001), and oxidative stress damage was mitigated. Nuclear factor erythroid 2-related factor-2 pathway, one of the antioxidant defence systems, was stimulated by NRG (p < 0.001). NRG treatment reduced the levels of markers for the pathways of apoptotic (p < 0.001) and autophagic (p < 0.001) damages induced by COL. Sperm viability and the live/dead ratio were reduced by COL but enhanced by NRG treatment. Testicular tissue integrity was damaged by COL but showed a tendency to improve by NRG. In conclusion, COL exhibited toxic effect on testicular tissue by elevating the levels of oxidative stress, apoptosis, autophagy, inflammation, and tissue damage. NRG demonstrated a protective effect by alleviating toxic damage., (© 2024 Wiley Periodicals LLC.)

Exposure to Lead -causes testicular dysfunction through oxidative stress, inflammation, and apoptosis; however, naringenin (NGN) therapeutic impact against lead-evoked testicular dysfunction remains elusive. Herein, the point of the study was to examine the defensive impact of NGN on testicular dysfunction initiated by lead. Seventy-Two male Wistar rats were allotted into nine groups; control group, drug control groups, lead acetate group, as well as NGN treated groups (10, 25, and 50 mg/kg) respectively, given 5 days before lead acetate treatment. The result showed clearly the impact of lead on reduced sperm count, sperm motility as well as serum testosterone and LH levels. Additionally, it caused a significant rise in testicular inflammatory markers TNF-α, IL-1β, and TGFβ, effects that were accompanied by a reduction of AKT and mTOR levels. Lead acetate also caused degenerative changes in the testis, atrophy, and loss of spermatogenic series. Our findings revealed that NGN in a dose-dependent manner improved spermiotoxicity induced by lead acetate via restoration of the testicular function, preservation of spermatogenesis, halting inflammatory cytokines along with the enhancement of germ cell survival using upregulation of AKT/mTOR expressions. The present study discloses that NGN suppresses lead acetate toxicity that is involved in the antioxidant effect in a dose-dependent manner, besides its anti-inflammatory property., (© 2023 Wiley Periodicals LLC.)

Lead (Pb) is one of the most common toxic heavy metals. It is a well-known testicular toxicant. Selenium nanoparticles (SeNPs) are a more effective form of elemental selenium that reduces drug-induced toxicities. This study aimed to study the possible ameliorating effect of SeNPs on the toxicological and morphological changes in testes of lead acetate intoxicated rats. The study was conducted on 40 adult male albino rats divided into four groups; control, SeNPs-treated, lead acetate-treated, lead acetate and SeNPS treated groups. The concurrent treatment of lead acetate-exposed rats with SeNPs (0.1 mg/kg/day) for 12 weeks significantly lowered the blood and testicular lead levels, increased serum testosterone, and decreased luteinizing hormone and follicle-stimulating hormone to approach control values. In addition, it improved the histopathological, and ultrastructural alterations of the testes and improved the immunohistochemical expression of the c-kit. This was accompanied by maintenance of the testicular oxidant/antioxidant balance and reversing the lead-induced disrupted calmodulin-related genes expression in testicular tissue in the form of downregulation of CAMMK2 and MAP2K6 and upregulation of CXCR4 genes. There was a strong positive correlation between testicular malondialdehyde and MAP2K6 expression level as well as a strong positive correlation between CXCR4 gene expression and the C-kit area %. In conclusion, SeNPs can be considered as a potential therapy for a lead-induced testicular injury., (© 2022 Wiley Periodicals LLC.)

Cyclophosphamide is an antitumor agent that causes disorders in fertility. This study aimed to evaluate the protective effects of Spirulina platensis against Cyclophosphamide-induced testicular toxicity. 42 male Wistar rats were randomly divided into six groups. Experimental groups included three groups. The first experimental group received Cyclophosphamide at a dose of 5 mg/kg body weight (BW) orally. The second and third experimental groups received 5 mg/kg BW Cyclophosphamide and 500 and 1,000 mg/kg BW S. platensis orally, respectively. The control groups included a control group, and two S. platensis control groups. Following 28 days, two flow cytometry techniques were used to determine sperm apoptosis and testicular protein expression of tumor protein (p53) and B-cell lymphoma 2 (Bcl-2). p53 is a tumor suppressor protein that causes the cell to enter the apoptosis cycle after DNA damage and Bcl-2 is an anti-apoptotic protein that acts through the mitochondrial pathway of apoptosis. FITC-Annexin V assay was used for sperm apoptosis evaluation. For protein expression assay, primary and secondary antibodies staining were performed. The Cyclophosphamide group showed a significant increase in sperm apoptosis compared to the control group. Cyclophosphamide significantly increased p53 and decreased Bcl-2 expression compared to the control group. S. platensis co-treated groups exhibited a significant decrease in sperm apoptosis compared to the Cyclophosphamide group. Moreover, S. platensis co-treated groups displayed a significant decreasing in p53 and increasing in Bcl-2 expression compared to the Cyclophosphamide group. The results of this study indicated that S. platensis protected rats against Cyclophosphamide-induced reproductive toxicity. PRACTICAL APPLICATIONS: Cyclophosphamide is the chemotherapy agent used to treat different cancers. Cyclophosphamide has side effects on the male reproductive system. Spirulina plantesis has a protective effect because of its antioxidant and anti-apoptotic properties. Co-administration of Spirulina plantesis with Cyclophosphamide reduces sperm apoptosis also decreases P53 protein expression and increases Bcl-2 protein expression. This study validated the anti-apoptotic potential of Spirulina plantesis against Cyclophosphamide-induced male reproductive toxicity., (© 2021 Wiley Periodicals LLC.)

Testicular toxicity is an adverse reaction of the effective chemotherapy drug cisplatin (CIS). Our previous study found that grape seed proanthocyanidin extract (GSPE) had a protective effect on CIS-induced testicular toxicity. However, the protective mechanism of GSPE against CIS-induced testicular toxicity remains unknown. In this study, we aimed to investigate whether GSPE can reduce CIS-induced testicular toxicity and its potential mechanism in rats. The results showed that GSPE ameliorated CIS-induced the apoptosis of testicular cells and inhibited the protein levels of Bad, Cyt c, caspase-9, caspase-3, caspase-12, GRP78, CHOP, IRE1α, p-IRE1α, XBP-1S, PERK, p-PERK, eIF2α, and p-eIF2α. Besides, GSPE reversed the downregulation of PI3K, p-PI3K, Akt, p-Akt, mTOR, and p-mTOR protein expression induced by CIS. These results indicated that GSPE can improve CIS-induced testicular cells apoptosis via activating PI3K/Akt/mTOR and inhibiting Bad/Cyt c/caspase-9/caspase-3 pathways. And GSPE relieved endoplasmic reticulum stress-mediated apoptosis via inhibiting PREK/eIF2α and IRE1α/XBP-1S/caspase-12 pathways. In conclusion, the evidence suggested that GSPE can act as a protective agent against testicular toxicity induced by CIS. PRACTICAL APPLICATIONS: Testicular toxicity was a well-known adverse effect of cisplatin (CIS) in cancer treatment. Grape seed proanthocyanidin extract (GSPE) has been reported to serve as one of the most therapeutic potentials agents. In present study, we explored the regulatory effects of GSPE on the apoptosis induced by CIS, which involved testicular apoptosis mechanisms in rats. Our results indicated that CIS caused testicular toxicity via PI3K/AKT/mTOR and ERS mediated apoptosis pathway in rats. This toxicity was attenuated by GSPE treatment via activated PI3K/Akt/mTOR pathway, and inhibiting Bad/CytC/caspase-9/caspase-3 as well as PREK/eIF2α, IRE1α/XBP-1S/caspase-12 pathways. Our findings suggest that GSPE may be a novel protective agent against testicular toxicity induced by CIS., (© 2021 Wiley Periodicals LLC.)

Parabens, alkyl ester derivatives from p-hydroxybenzoic acid, are extensively used as antimicrobial preservatives. Nonetheless, due to its widespread and massive employment, several studies highlighted the association between parabens and alterations in the reproductive system. This study aimed to relate the adverse effect of the most commonly used parabens in testis mitochondria with male fertility. From all the parabens used, propyl and butyl were the ones that most negatively decreased the respiratory control ratio. In the case of butyl, inhibitions of 20% and 60% were observed, respectively, at the lowest and highest concentration, when compared to the control group. The membrane potential was only significantly affected by propyl (14%) and butyl (31%), and at a concentration of 250 µM. Succinate dehydrogenase, cytochrome c oxidase, and ATPase activities showed a nonsignificant decrease. Cytochrome c reductase, on the other hand, showed statistically significant inhibitions for both propyl (56%) and butylparaben (55%). The susceptibility to the mitochondrial permeability transition pore (MPTP) opening was increased by all parabens, although this increase was markedly significant for propyl and butyl. These results show that the susceptibility of mitochondria to parabens is dependent on the alkyl chain length and parabens hydrophobicity, and the main mitochondrial target is Complex II-III and MPTP. Hence, this study demonstrates the contribution of parabens exposition to the inhibition of testis mitochondrial function and their putative noxious effect on the male reproductive system., (© 2020 Wiley Periodicals LLC.)

In the present study, the protective effects of chrysin (CHR) against testicular damage caused by lead acetate (PbAc) were examined. In this way, 30 min after rats were given 25 and 50 mg/kg/b.w CHR orally for seven consecutive days, 30 mg/kg/b.w PbAc was administered orally. In biochemical analysis of testicular tissue, it was found that PbAc-reduced antioxidant parameters [glutathione peroxidase (GPx), glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT)], while it increased lipid peroxidation, inflammatory markers [nuclear factor kappa-B (NF-κB), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE-2), and inducible nitric oxide synthase (iNOS)], and 8-hydroxy-2'-deoxyguanosine (8-OHdG). In the immunohistochemical examination, it was determined that PbAc increased the expression of tumor necrosis factor-α (TNF-α) and caspase-3. Accordingly, PbAc was found to cause a decrease in sperm motility and an increase in the percentage of dead sperm. However, it has been observed that CHR relieves oxidative stress due to its antioxidant properties, thus protecting against inflammation and apoptosis. It also allowed the CHR sperm parameters to return to control group levels. The results revealed that CHR could be a natural substance to be used in Pb-induced testicular toxicity. PRACTICAL APPLICATIONS: Lead (Pb) is an important environmental contaminant heavy metal. Pb is believed to reduce fertility in men. Oxidative stress plays a significant role in the damage caused by Pb to testicular tissue. CHR is an antioxidant substance that occurs naturally in various plants and has various pharmacological properties. In the present study, it was investigated whether CHR has a protective effect against testicular toxicity induced by PbAc. The results revealed that in rats, CHR protects the testicular tissue from PbAc toxicity by showing antioxidant, anti-inflammatory and anti-apoptotic effects, thus bringing sperm parameters closer to normal., (© 2020 Wiley Periodicals LLC.)

This study aimed to investigate the effect of curcumin (CUR) on doxorubicin (DOX)-induced testicular damage in male rats. Thirty-five adult male Wistar rats were used. Control group was received saline for 7 days. CUR group received CUR for 7 days. DOX group received single dose DOX on the 5th day. DOX+ CUR-100 group received 100 mg/kg/day CUR for 7 days and DOX injection on the 5th day. DOX + CUR-200 group received 200 mg/kg/day CUR for 7 days and DOX injection on the 5th day. DOX treatment decreased in sperm motility rate, live sperm percentages, cellular antioxidants, and increased malondialdehyde (MDA) levels, necrosis, degenerations, and slimming in seminiferous tubules, and DNA damages in testes by inducing oxidative stress. CUR treatment mitigated significantly these side effects when compared with DOX group in a dose-dependent manner. In conclusion, CUR treatment can be used in the mitigation of DOX-induced testicular toxicity., (© 2019 Wiley Periodicals, Inc.)

Permethrin (PM), a synthetic pyrethroid insecticide, has broad toxicity spectra. We aimed to investigate the effects of PM on the testes of adult albino rats, examine the recovery response and evaluate the efficacy of naringenin (NG) supplementation. Adult male albino rats were randomly assigned to five groups of six each: control, NG (50 mg/kg), PM (70 mg/kg), recovery (after subsequent withdrawal of PM) and NG-PM group. All treatments were given by oral gavage for 6 weeks and another 3 weeks for the recovery group. At the time of sacrifice, each testis was weighed. Biochemical analysis of epididymal sperm count and serum testosterone level was performed. Testes were processed for histological, ultrastructural and c-Kit immunohistochemical study. PM toxicity was evidenced by a highly significant decrease in testicular weight, epididymal sperm count and serum testosterone level compared to control. Furthermore, testicular structure abnormalities and reduced c-Kit immunoreactions were observed. Stoppage of PM in the recovery group partially reversed PM-induced changes. There was a mild decrease in testicular weight and biochemical parameters compared to control. The structure of seminiferous tubules was partially retained. The NG-PM group showed an overall improvement in testicular weight and biochemical alterations which were confirmed by light and electron microscopic examination. In conclusion, PM induced testicular toxicity, which was ameliorated by NG co-administration. However, stoppage of PM exposure was associated with partial recovery., (© 2016 The Authors. International Journal of Experimental Pathology © 2016 International Journal of Experimental Pathology.)