Protective effects of naringin on colistin-induced damage in rat testicular tissue: Modulating the levels of Nrf-2/HO-1, AKT-2/FOXO1A, Bax/Bcl2/Caspase-3, and Beclin-1/LC3A/LC3B signaling pathways.

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.

Piperine mitigates oxidative stress, inflammation, and apoptosis in the testicular damage induced by cyclophosphamide in mice.

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.

Effects of in utero benzo[a]pyrene exposure on the testis of rats during puberty and the protective effect of atorvastatin.

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.

Genotoxicity of bisphenol AF in rats: Detrimental to male reproductive system and probable stronger micronucleus induction potency than BPA.

Bisphenol AF (BPAF), as one of structural analogs of BPA, has been increasingly used in recent years. However, limited studies have suggested its adverse effects similar to or higher than BPA. In order to explore the general toxicity and genotoxicity of subacute exposure to BPAF, the novel 28-day multi-endpoint (Pig-a assay + micronucleus [MN] test + comet assay) genotoxicity evaluation platform was applied. Male rats were randomly distributed into seven main experimental groups and four satellite groups. The main experimental groups included BPAF-treated groups (0.5, 5, and 50 µg/kg·bw/d), BPA group (10 µg/kg·bw/d), two solvent control groups (PBS and 0.1% ethanol/99.9% oil), and one positive control group (N-ethyl-N-nitrosourea, 40 mg/kg bw). The satellite groups included BPAF high-dose recovery group (BPAF-HR), oil recovery group (oil-R), ENU recovery group (ENU-R), and PBS recovery group (PBS-R). All groups received the agents orally via gavage for 28 consecutive days, and satellite groups were given a recovery period of 35 days. Among all histopathologically examined organs, testis and epididymis damage was noticed, which was further manifested as blood-testis barrier (BTB) junction protein (Connexin 43 and Occludin) destruction. BPAF can induce micronucleus production and DNA damage, but the genotoxic injury can be repaired after the recovery period. The expression of DNA repair gene OGG1 was downregulated by BPAF. To summarize, under the design of this experiment, male reproductive toxicity of BPAF was noticed, which is similar to that of BPA, but its ability to induce micronucleus production may be stronger than that of BPA.

A novel alternative method for long-term evaluation of male reproductive toxicity and its recovery using a pre-pubertal mouse testis organ culture system.

Successful treatment of pediatric cancers often results in long-term health complications, including potential effects on fertility. Therefore, assessing the male reproductive toxicity of anti-cancer drug treatments and the potential for recovery is of paramount importance. However, in vivo evaluations are time-intensive and require large numbers of animals. To overcome these constraints, we utilized an innovative organ culture system that supports long-term spermatogenesis by placing the testis tissue between a base agarose gel and a polydimethylsiloxane ceiling, effectively mirroring the in vivo testicular environment. The present study aimed to determine the efficacy of this organ culture system for accurately assessing testicular toxicity induced by cisplatin, using acrosin-green fluorescent protein (GFP) transgenic neonatal mouse testes. The testis fragments were treated with different concentrations of cisplatin-containing medium for 24 h and incubated in fresh medium for up to 70 days. The changes in tissue volume and GFP fluorescence over time were evaluated to monitor the progression of spermatogenesis, in addition to the corresponding histopathology. Cisplatin treatment caused tissue volume shrinkage and reduced GFP fluorescence in a concentration-dependent manner. Recovery from testicular toxicity was also dependent on the concentration of cisplatin received. The results demonstrated that this novel in vitro system can be a faithful replacement for animal experiments to assess the testicular toxicity of anti-cancer drugs and their reversibility, providing a useful method for drug development.

Mitigative potential of kaempferide against polyethylene microplastics induced testicular damage by activating Nrf-2/Keap-1 pathway.

Polyethylene microplastics (PE-MPs) are one of the environmental contaminants that instigate oxidative stress (OS) in various organs of the body, including testes. Kaempferide (KFD) is a plant-derived natural flavonol with potential neuroprotective, hepatoprotective, anti-cancer, anti-oxidant and anti-inflammatory properties. Therefore, the present study was designed to evaluate the alleviative effects of KFD against PE-MPs-prompted testicular toxicity in rats. Fourty eight adult male albino rats were randomly distributed into 4 groups: control, PE-MPs-administered (1.5 mgkg-1), PE-MPs (1.5 mgkg-1) + KFD (20 mgkg-1) co-treated and KFD (20 mgkg-1) only treated group. PE-MPs intoxication significantly (P < 0.05) lowered the expression of Nrf-2 and anti-oxidant enzymes, while increasing the expression of Keap-1. The activities of anti-oxidants i.e., catalase (CAT), glutathione reductase (GSR), superoxide dismutase (SOD), hemeoxygene-1 (HO-1) and glutathione peroxidase (GPx) were reduced, besides malondialdehyde (MDA) and reactive oxygen species (ROS) contents were increased significantly (P < 0.05) following the PE-MPs exposure. Moreover, PE-MPs exposure significantly (P < 0.05) reduced the sperm motility, viability and count, whereas considerably (P < 0.05) increased the dead sperm number and sperm structural anomalies. Furthermore, PE-MPs remarkably (P < 0.05) decreased steroidogenic enzymes and Bcl-2 expression, while increasing the expression of Caspase-3 and Bax. PE-MPs exposure significantly (P < 0.05) reduced the levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone, whereas inflammatory indices were increased. PE-MPs exposure also induced significant histopathological damages in the testes. Nevertheless, KFD supplementation significantly (P < 0.05) abrogated all the damages induced by PE-MPs. The findings of our study demonstrated that KFD could significantly attenuate PE-MPs-instigated OS and testicular toxicity, due to its anti-oxidant, anti-inflammatory, androgenic and anti-apoptotic potential.

Assessment of the toxicity of different antiretroviral drugs and their combinations on Sertoli and Leydig cells.

The human immunodeficiency virus continues to pose a significant global public health challenge, affecting millions of individuals. The current treatment strategy has incorporated the utilization of combinations of antiretroviral drugs. The administration of these drugs is associated with many deleterious consequences on several physiological systems, notably the reproductive system. This study aimed to assess the toxic effects of abacavir sulfate, ritonavir, nevirapine, and zidovudine, as well as their combinations, on TM3 Leydig and TM4 Sertoli cells. The cell viability was gauged using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) and neutral red uptake (NRU) assays. Reactive oxygen species (ROS) production was assessed via the 2',7'-dichlorofluorescein diacetate (DCFDA) test, and DNA damage was determined using the comet assay. Results indicated cytotoxic effects at low drug concentrations, both individually and combined. The administration of drugs, individually and in combination, resulted in the production of ROS and caused damage to the DNA at the tested concentrations. In conclusion, the results of this study suggest that the administration of antiretroviral drugs can lead to testicular toxicity by promoting the generation of ROS and DNA damage. Furthermore, it should be noted that the toxicity of antiretroviral drug combinations was shown to be higher compared to that of individual drugs.

Sudachitin Alleviates Paraquat Instigated Testicular Toxicity in Albino Rats via Regulating Nrf-2/Keap-1, Inflammatory, Steroidogenic, and Histological Profile.

Paraquat (PQ) is a noxious herbicide which adversely affects the vital organs including male reproductive system. Sudachitin (SCN) is a naturally occurring flavonoid that demonstrates a wide range of biological potentials. The current study was designed to investigate the alleviative potential of SCN to avert PQ-induced testicular toxicity in rats. Forty-eight male rats (Rattus norvegicus) were apportioned into four groups including control, PQ (5 mg/kg), PQ + SCN (5 mg/kg + 30 mg/kg), and SCN (30 mg/kg) only treated group. Our findings elucidated that PQ treatment reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2) and its antioxidant genes as well as the activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSR) and glutathione peroxidase (GPx), while elevating the levels of reactive oxygen species (ROS), and malondialdehyde (MDA). Furthermore, PQ intoxication upregulated the expressions of Keap-1 while downregulating the expression of 3-beta hydroxysteroid dehydrogenase (3ß-HSD), 17-beta hydroxysteroid dehydrogenase (17ß-HSD), and steroidogenic acute regulatory protein (StAR). Moreover, sperm anomalies were increased following the exposure to PQ. Besides, PQ exposure decreased the levels of plasma testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) while increasing the levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), nuclear factor-kappa B (NF-κB), interleukin-1beta (IL-1ß), and cyclooxygenase-2 (COX-2). Additionally, PQ treatment escalated the expressions of cysteinyl aspartate-specific proteases-3 (Caspase-3) and Bcl-2-associated X-protein (Bax) while downregulating the expressions of B-cell lymphoma-2 (Bcl-2). Furthermore, PQ exposure disrupted the normal architecture of testicular tissues. However, SCN treatment remarkably protected the testicular tissues via regulating the aforementioned disruptions owing to its antioxidant, anti-inflammatory, and androgenic potential.

Protective effects of polysaccharide extracted from green alga Chaetomorpha linum against zinc and copper-induced testicular toxicity in male mice.

This study aimed to investigate the effects of copper (CuSO4) and zinc (ZnSO4) overload on male reproductive toxicity and the potential of a polysaccharide extracted from green alga Chaetomorpha linum (PS) in mitigating their toxicities. Adult male mice strain of 25 ± 2 g of weight was subdivided into eight groups. Group 1 served as control; group 2 received PS (200 mg/kg), and groups 3 and 4 received intraperitoneally zinc (60 mg/kg b.w) and copper (33 mg/kg b.w), respectively. Group 5 received both zinc (60 mg/kg b.w) and copper (33 mg/kg b.w), group 6 received zinc (60 mg/kg b.w) associated with PS (200 mg/kg), group 7 received copper (33 mg/kg b.w) associated with PS (200 mg/kg), and group 8 received zinc (60 mg/kg b.w) and copper (33 mg/kg b.w) associated with PS (200 mg/kg). Results suggested that ZnSO4 and CuSO4 significantly decreased the functional sperm parameters. Furthermore, extended exposure to these elements increased oxidative stress biomarkers, including malondialdehyde (MDA) as a measure of lipid peroxidation and advanced oxidation protein products (AOPP) indicating protein oxidative damage. This process also reduces the activity of antioxidant enzymes such as glutathione (GSH) and glutathione peroxidase (GPx), which neutralize and catalyze free radicals. Histopathological changes in mice testis were also studied. However, the co-treatments with PS significantly reduced these effects and promoted the reproductive parameters in male mice. In conclusion, PS exhibited protective effects against zinc and copper-induced reproductive toxicity, making it a potential adjuvant treatment for testicular toxicity.

Naringenin alleviate reproductive toxicity evoked by lead acetate via attenuation of sperm profile and biochemical alterations in male Wistar rat: Involvement of TGFß/AKT/mTOR pathway.

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-1ß, and TGFß, 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.

Lycopene ameliorates aflatoxin B1-induced testicular lesion by attenuating oxidative stress and mitochondrial damage with Nrf2 activation in mice.

Aflatoxin B1 (AFB1) is an extremely hazardous and unavoidable pollutant for cereals and feedstuff. AFB1 can cause testicular lesion, and how to alleviate its testicular toxicity has received much attention in recent years. Lycopene (LYC), a foodborne nutrient derived from red fruits and vegetables, has protective effects against sperm abnormality and testicular lesions. To confirm the beneficial effects and mechanisms of LYC on AFB1-induced testicular lesion, 48 male mice were exposed to 0.75 mg/kg AFB1 or/and 5 mg/kg LYC for consecutive 30 days. Results demonstrated the LYC significantly restored the lesions of testicular microstructure and ultrastructure, and sperm abnormalities in AFB1-exposed mice. Furthermore, LYC effectively attenuated AFB1-induced oxidative stress and mitochondrial damage, including ameliorative mitochondrial structural, and elevated mitochondrial biogenesis for maintaining mitochondrial function. Meanwhile, LYC resisted AFB1-induced mitochondrial-dependent apoptosis. In addition, LYC promoted nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, and upregulated the Nrf2 signaling pathway. Collectively, our findings demonstrate LYC ameliorates AFB1-induced testicular lesion by attenuating oxidative stress and mitochondrial damage, which is related to the activation of Nrf2.

Sildenafil aggravates adriamycin-induced testicular toxicity in rats; a preliminary investigation.

Male reproductive toxicity is a well-established side effect of the chemotherapeutic drug adriamycin (ADR). Sildenafil (SIL) is a phosphodiesterase inhibitor known to enhance the chemosensitivity of cancer cells to ADR. However, there is a scarcity of information on the effect of SIL on ADR-induced testicular toxicity. In this study, SIL (5, 10, or 20 mg/kg/day) was administered to male rats for 7 days, followed by a single intraperitoneal injection of ADR (20 mg/kg) on day 7. Control rats received either ADR, SIL, or normal saline for 7 days. Epididymal sperm were collected from the testes to assess the effects on sperm quality, quantity, and serum testosterone concentration was also determined. ADR treatment caused a decrease in sperm motility and elevated the percentage of sperms with tail defects which worsened in combination with SIL (20 mg/kg). Furthermore, ADR alone or in combination with SIL dose-dependently increased total sperm abnormalities. SIL (20 mg/kg) plus ADR also decreased sperm count and lowered testosterone level compared to ADR-only rats. In conclusion, exposure of rats to SIL before ADR treatment has the potential to worsen ADR-induced testicular toxicity.

Arrested Acetylene-Induced Pulmonary and Testicular Toxicity in Rats Through Treatment With Polyphenols.

Occupational exposure to potentially harmful substances is one of the dangers associated with industrial jobs. This study evaluated the modulatory influence of selected dietary polyphenols on the pulmonotoxic and testiculotoxic effects of crude acetylene, an industrial gas used in welding metals. Wistar rats were exposed to 58 000 ppm acetylene, 20 min daily for 30 days, in a 36 L glass inhalation chamber. Some acetylene-exposed animals were treated concurrently with 30 mg/kg quercetin, rutin, caffeic acid, ferulic acid, or coumaric acid. At the end of the treatment sessions, the levels of superoxide dismutase, reduced glutathione, glutathione peroxidase, lactate dehydrogenase, and hormonal markers in rats exposed to acetylene were significantly decreased, with a concomitant increase in lipid peroxidation, nitric oxide level, cholesterol concentration, and histopathological abnormalities. These damaging biochemical and histopathological changes were significantly ameliorated in animals administered the polyphenols. Quercetin showed greater ameliorative activity than rutin while the phenolic acids exhibited increasing levels of ameliorative activity in the order: caffeic acid > ferulic acid > coumaric acid. These results indicate that inhalation of crude acetylene is deleterious to the lungs and testes, and polyphenols provide protection against these detrimental effects.

Effects of naringin on oxidative stress, inflammation, some reproductive parameters, and apoptosis in acrylamide-induced testis toxicity in rat.

Acrylamide (ACR) is used in many fields such as cosmetics, paper, and textile industries. It also occurs at very high temperatures in some foods. Gonadotoxic effects of ACR have been found in experimental animals. Many studies use flavonoids to prevent the reproductive side effects of ACR. Naringin (NA) is a flavonoid and it has been determined by studies that it has no toxic effect on tissues. In our study, we aimed to determine the protective effect of NA against the damage of ACR on testicular tissue and the reproductive system in rats. In our study, 50 Spraque Dawley male rats weighing 220-250 grams were used. Control: Only intragastric saline was administered for 10 days. ACR: Animals received ACR (40 mg/kg, intraperitoneally) for 10 days. NA50+ACR: Animals were given NA for 10 days and each NA was one hour after the administration of ACR. NA100+ACR: Animals received NA for 10 days and one hour after each NA was given ACR. NA100: Animals were given NA for 10 days. At the end of the applications, the rats were euthanized by cervical dislocation under anesthesia. Serum FSH, LH, and Dihydrotestosterone levels were compared between the groups. In addition, oxidative stress, inflammation, expression of some reproductive enzymes, and apoptosis markers were determined in testicular tissues. When these parameters were compared between groups, ACR induced testicular dysfunction and tissue damage in rats. We determined that only the NA application did not cause tissue damage. and the administration of NA along with ACR significantly reduced ACR-induced testis toxicity.

Carvacrol reduces abnormal and dead sperm counts by attenuating sodium arsenite-induced oxidative stress, inflammation, apoptosis, and autophagy in the testicular tissues of rats.

Arsenic (As) is a highly toxic metalloid. Carvacrol (CAR) is the active ingredient of Lamiaceae plants and has various biological and pharmacological properties. The present study investigated the protective effects of carvacrol (CAR) against testicular toxicity induced by sodium arsenite (SA). Rats were given SA (10 mg/kg) and/or CAR (25 or 50 mg/kg) for 14 days. Semen analyzes showed that CAR increased sperm motility and decreased the percentage of abnormal and dead sperm. It was determined that the oxidative stress induced by SA decreased with the increase of Nrf-2 and HO-1 expressions, SOD, CAT, GPx, and GSH levels, and MDA levels decreased after CAR treatment. It was observed that autophagy and inflammation triggered by SA in testicular tissue were alleviated by suppressing the expressions of LC3A, LC3B, MAPK-14, NF-κB, TNF-α, IL-1ß, iNOS, and COX-2 biomarkers in rats given CAR. Also, CAR treatment suppressed SA-induced apoptosis by inhibiting Bax and Caspase-3 expressions in testicles and up-regulating Bcl-2 expression. Histopathological analyzes showed that rats given SA had deterioration in tubule structure and spermatogenesis cell line, especially a serious loss of spermatogonia cells, atrophy of seminiferous tubules, and deterioration of germinal epithelium. In the group given CAR, the germinal epithelium and connective tissue were in normal morphological structure and an increase in seminiferous tubule diameters was observed. As a result, it was determined that oxidative stress, inflammation, autophagy, and apoptosis induced by SA were suppressed by CAR, thus protecting the testicular tissue from damage and increasing semen quality.

Quercetin inhibits testicular toxicity induced by the mixture of three commonly used phthalates in rats.

BACKGROUND: Phthalates (PEs), such as butyl benzyl phthalate, dibutyl phthalate and di(2-ethylhexyl) phthalate, are one of the most widely used plasticizers, and humans are increasingly exposed to them. Phytochemical quercetin (Que) is a typical flavonoid with several biological effects, such as antioxidative and anti-inflammatory. The present study was designed to explore the effect of Que on testicular toxicity caused by the mixture of three commonly used PEs (MPEs), and the underlying mechanism. Forty male Sprague-Dawley rats were randomly and equally divided into five groups (n = 8). Rats in control the group were orally treated with the excipient. Rats in the MPEs group were orally administered with 900 mg kg-1 day-1 MPEs, whereas rats in the MPEs+L-Que, MPEs+M-Que and MPEs+H-Que groups were simultaneously treated with 900 mg kg-1 day-1 MPEs and, respectively, 10, 30 and 90 mg kg-1 day-1 Que for 30 days. RESULTS: Compared with the control group, the testes weight, epididymides weight, serum testosterone, luteinizing hormone, follicle-stimulating hormone and estradiol levels, and anogenital distance in the MPEs group were significantly decreased (P < 0.05). The testicular tissues were injured with atrophy of seminiferous tubules, hyperplasia of Leydig cells and arrest of spermatogenesis in the MPEs group. Testicular steroidogenic proteins (StAR, P450scc, CYP17A1 and 17ß-HSD, P450arom) were up-regulated, whereas P-element-induced wimpy testis proteins (PIWIL1 and PIWIL2) were down-regulated in the MPEs group (P < 0.05). However, the alterations of these parameters were inhibited in the MPEs+M-Que and MPEs+H-Que groups. CONCLUSION: MPEs disturbed steroid hormone metabolism and caused testicular injuries. Que could inhibit testicular toxicity of MPEs, which might relate to the improved regulation of steroid hormone metabolism. © 2022 Society of Chemical Industry.

Effect of troxerutin on the expression of genes regulating mitochondrial biogenesis and microRNA-140 in doxorubicin-induced testicular toxicity.

Background: Application of doxorubicin (DOX) in cancer patients is limited due to its dose-dependent toxicity to nontarget tissues such as testis and subsequent infertility. Due to limitation of our knowledge about the mechanisms of DOX toxicity in the reproductive system, reduction of DOX-induced testicular toxicity remains an actual and primary clinical challenge. Considering the potentials of troxerutin (TXR) in generating a protective phenotype in many tissues, we aimed to examine the effect of TXR on DOX-induced testicular toxicity by evaluating the histological changes and the expression of mitochondrial biogenesis genes and microRNA-140 (miR-140). Materials and Methods: Twenty-four adult male Wistar rats (250-300 g) were divided in groups with/without DOX and/or TXR. DOX was injected intraperitoneally at 6 consecutive doses over 12 days (cumulative dose: 12 mg/kg). TXR (150 mg/kg/day; orally) was administered for 4 weeks before DOX challenge. One week after the last injection of DOX, testicular histopathological changes, spermatogenesis activity, and expression of mitochondrial biogenesis genes and miR-140 were determined. Results: DOX challenge significantly increased testicular histopathological changes, decreased testicular expression profiles of sirtuin 1 (SIRT-1) and nuclear respiratory factor-2 (NRF-2), and increased expression of miR-140 (P < 0.05 to P < 0.01). Pretreatment of DOX-received rats with TXR significantly reversed testicular histopathological changes, spermatogenesis activity index, and the expression levels of SIRT-1, peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC-1α), NRF-2, and miR-140 (P < 0.05 to P < 0.01). Conclusion: Reduction of DOX-induced testicular toxicity following TXR pretreatment was associated with upregulation of SIRT-1/PGC-1α/NRF-2 profiles and better regulation of miR-140 expression. It seems that improving microRNA-mitochondrial biogenesis network can play a role in the beneficial effect of TXR on DOX-induced testicular toxicity.

Selenium nanoparticles alleviate lead acetate-induced toxicological and morphological changes in rat testes through modulation of calmodulin-related genes expression.

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.

Bisphenol A exposure causes testicular toxicity by targeting DPY30-mediated post-translational modification of PI3K/AKT signaling in mice.

Bisphenol A (BPA), one of the chemicals with the highest volume of production worldwide, has been demonstrated to cause testicular toxicity via different pathways. However, there is little evidence concerning the mechanism of BPA exposure induced histone modification alterations, especially regarding the effect on the histone H3 lysine 4 (H3K4) epigenetic modification. Our results demonstrated a new epigenetic regulation of BPA exposure on testicular damage using both cell culture and mouse models. With BPA treatment, disordered and shrunken seminiferous tubules and poor sperm quality were observed in vivo, and mouse spermatogonial germ cell proliferation was inhibited in vitro. BPA attenuated PI3K expression inducing phospho-AKT inhibition in vivo and in vitro. DPY30 was the only downregulated subunit in BPA and MEK2206 (AKT inhibitor) treated cells, which contributed to reducing H3K4me3 recruitment at the PIK3CA transcriptional start site (TSS) in BPA treated cells. The toxicity caused by BPA exposure was relieved after the transduction of adenoviruses expressing DPY30 transgenes, which resulted in the stimulation of PI3K/AKT with H3K4me3 enriched at the PI3KCA TSS. DPY30 promoted cell glycolysis via AMPK and proliferation through AKT/P21. DPY30 was mainly located in the round and elongated spermatids for energy accumulation in mature sperm in AD-DPY30-treated mice which showed higher sperm quality. Overall, our results indicated that BPA exposure causes testicular toxicity through a DPY30-mediated H3K4me3 epigenetic modification, which serves to regulate the PI3K/AKT/P21 pathway.

Ameliorative effects of a curcumin vitamin E nanocomposite coated with olive oil against cadmium chloride-induced testicular damage.

In the current study, we synthesized and prepared a curcumin and vitamin E nanocomposite coated with olive oil (CEONC). Curcumin, vitamin E, and olive oil are fundamental organic antioxidants, and forming nanoparticles from these components endows them with special characteristics. We investigated the protective effect of CEONC on reproductive toxicity induced by cadmium chloride (CdCl2 ) in male rats. Forty rats (170-180 g) were randomly assigned to four groups: Group 1 (control) received oral distilled water; Group 2 intraperitoneal injection with CEONC (30 mg/kg); Group 3 received oral CdCl2 (5 mg/kg); and Group 4 received CdCl2 (5 mg/kg) followed by CEONC (30 mg/kg) for 4 weeks. After 50 days, we terminated the experiment and assessed male reproductive hormones, sperm motility, viability and morphology, and testes histopathology and conducted a comet assay. The results revealed that co-administration of CEONC with CdCl2 exposure increased reproductive hormone levels, improved sperm motility and viability, prevented sperm morphological changes, recovered the testicular histology, and decreased DNA damage in the testicular tissue compared to rats exposed to CdCl2 alone. CEONC administration produced no adverse effects and enhanced all sperm parameters. Our findings demonstrate that CEONC is a potential treatment for preventing reproductive damage induced by cadmium exposure.