Testicular protective effects of hesperidin against chemical and biological toxicants

Abstract

Introduction

The function of the male reproductive system can be damaged by various biological and chemical compounds. Notably, the testis is known to be highly affected by these agents.^1–4 In the testicular parenchyma, seminiferous tubules composed of Sertoli cells have a central role in spermatogenesis. Sertoli cells supply the essential nutrition for the differentiation of immature germ cells to spermatozoa.⁵

Between the lumina of seminiferous tubules and the lumina of interstitial capillaries, there is a blood-testis barrier which is created from various structures Sertoli cells, basal lamina of the seminiferous tubule, myoid cells, lymphatic endothelium, capillary basal lamina, and the capillary endothelium.⁶ These barrier structures inhibit or decline the passage of drug/chemical agents between the bloodstream and the fluid inside the seminiferous tubules. The transepithelial permeability and substance exchange are affected by the distances between the barrier structures.⁶

Of note, the testis function is under hormonal regulation mediated by other secretory organs, including the hypothalamus and pituitary. The hypothalamus secretes Gonadotropin-releasing hormone (GnRH) that provokes the secretion of the pituitary hormones, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), which participate in normal spermatogenesis. LH induces Leydig cells to produce testosterone that impacts the activity of Sertoli cells and is essential for appropriate spermatogenesis. FSH also stimulates Sertoli cells to orchestrate the spermatogenic cell maturation.

Further, GnRH is controlled by Leydig cell-mediated steroidogenesis through Leydig cell-Sertoli cell interactions.^7,8

Toxic agents can adversely impact the male reproductive system mainly via activating oxidative stress affecting the seminiferous epithelia, spermatogenesis, sperms, and the testis. Toxic agents lead to the excessive generation of reactive oxygen species (ROS), such as hydroxyl radicals, hydrogen peroxide, and superoxide anions.⁹ ROS exert a cytotoxic effect and oxidative damage to nucleic acids, proteins, and membrane lipids.¹⁰

Flavonoids are phenolic substances mainly presented in medicinal herbs, fruit, and vegetables and exert useful biological features, such as antioxidant, anti-inflammatory, anticarcinogen, and antiproliferative effects as well as inhibiting multidrug resistance and protecting against chemotherapy-mediated damage.^11–16 Hesperidin is a pharmacologically active phytoflavone abundantly present in citrus fruits such as lemons and oranges.¹⁷ Hesperidin is known to exert anti-carcinogenic,¹⁸ anti-inflammatory,¹⁹ anti-oxidant,²⁰ analgesic, antiviral,²¹ anti-coagulant, hypolipidemic, and hypoglycemic impacts.²² Hesperidin can elevate cellular antioxidant defense by eliminating free radicals and ROS. In addition, hesperidin exerts an anti-inflammatory impact by suppressing the thioredoxin (Trx)-interacting protein (Txnip) /the nucleotide-binding oligomerization structural domain-like receptor protein 3 (NLRP3), MAPK, and NF-κB pathways. It upregulates the expression of heme oxygenase 1 (HO-1), suppresses the activation of Txnip and its binding to NLRP3, and inhibits the binding of NLRP3 to downstream caspase-1 and apoptosis-associated speck-like protein containing a CARD domain (ASC), thereby suppressing activation of inflammatory body and downregulating IL-1β cytokine. Hesperidin suppresses hydrogen peroxide-induced phosphorylation of ERK, c-Jun amino-terminal kinases (JNK), p38, NF-κB, and NF-κB inhibitory protein (IκB). It also impedes IκB degradation, inhibits activation of the NF-κB signaling pathway, and downregulates TNF-α and IL-1β as well as the inflammatory mediators IL-6 and iNOS. Additionally, hesperidin inhibits MAPK kinase/ERK phosphorylation in the MAPK signaling pathway and downregulates matrix metalloproteinase 9 (MMP-9) expression, thus reducing inflammation. Hesperidin can also induce apoptosis and cell cycle arrest by activating cancer cells' tumor suppressor protein P53 pathway. Anti-microbial properties of hesperidin are provided by activation of the host immune system, disruption of bacterial membranes, and interference with microbial enzymes.²³

Recently, hesperidin has been found to exert protective effects against natural and chemical toxins-induced organ toxicities, such as liver toxicity.²⁴ Herbal formulations of hesperidin have shown good safety, with no side effects and/or toxicities. Notably, the acute oral toxicity testing showed that hesperidin has an LD50 (lethal dose 50%) of more than 2,000 mg/kg in experimental animals.^25,26

Considerable evidence has implicated the testicular protective effects of hesperidin against the toxicological impacts of pharmaceutical drugs as well as biological and chemical agents, and in the present review, we discussed, for the first time, the reported studies (Table 1).

Testicular protective effects of hesperidin against environmental toxicants

Phthalates, particularly di(2-ethylhexyl)phthalate (DEHP), are frequently employed in the production of biomedical devices, food packaging materials, plasticizers, and cosmetics. DEHP simply enters inside the ground, air, and water; thus, it can enter the food and the human body.²⁷ DEHP can disrupt the endocrine system activity by exerting deleterious impacts on the hormonal balance, leading to reproductive system deformation and malfunction in humans and animals. Interestingly, phthalate has been found to have higher toxic effects on the reproductive system in male subjects compared with female subjects.²⁸ Mechanistically, DEHP shows testicular toxicity by inhibiting β-hydroxysteroid dehydrogenases (β-HSD), dominantly 3β-HSD, which have the central role in testosterone biosynthesis in testicular Leydig cells.^29,30 In addition, oxidative stress is another important mechanism underlying DEHP-associated testicular malfunction.³¹ Of note, DEHP generates ROS that could injure DNA, disrupt the blood testis barrier, and promote leakage of germ cell-specific proteins from seminiferous tubules, leading to decreased levels of testosterone, testicular atrophy, and spermatogenesis impairment.³²

Hesperidin was found to exert a dose-dependent protective effect against the environmental contaminant DEHP-induced testicular toxicity and restore testicular function. In rats, hesperidin administration (25 or 50 mg/kg) could ameliorate DEHP-induced testicular toxicity through activating antioxidant enzymes as well as modulating the levels of testicular 3β-HSD, serum testosterone, testicular malondialdehyde (MDA), plasma fatty acid-binding protein-9, and Bax/Bcl2 ratio.³³ In addition, epigenetic regulation via microRNAs (miRs) is known to be the key mediator contributing to the anti-oxidant responses through regulating the expression of genes that participated in stress resistance,³⁴ such as sirtuin 1 that is downregulated by two oxidative stress-responsive miRs, including miR-126-3p and miR-180a.^35,36 Hesperidin could decrease the aberrant expression of testicular miR-126-3p and miR-181a in DEHP-treated rats, and increase the expression of sirtuin 1 and its targets involved in the oxidative-stress pathway, including superoxide dismutase (SOD), heme oxygenase, and nuclear factor-erythroid 2-related factor2.³³

Benzo[α]pyrene (BaP) is a polycyclic aromatic hydrocarbon that shows mutagenic, teratogenic, and carcinogenic properties. It has also shown testicular toxicity in animal models.^37,38 BaP-mediated testicular toxicity has been detected and approved by histological and biochemical analysis. It was found to reduce the relative weight of the testis and promote necrobiotic and pyknosis alterations as well as the nuclei chromatolysis of the spermatocytes in the seminiferous tubules.³⁹ BaP was also found to significantly collapse the function of the epididymis as detected via reduced sperm number and motility and delayed sperm generation.³⁹ In addition, BaP could decrease the testicular activities of glutathione-S-transferase (GST), SOD, and lactate dehydrogenase (LDH-X). Besides, it was shown to diminish reduced glutathione (GSH) levels in the testicular but elevate the levels of MDA.³⁹

Interestingly, hesperidin administration was found to prevent all the histological and biochemical alterations promoted by BaP.³⁹ It could enhance the epididymal function and decline the injurious effects of BaP on the seminiferous tubules. Thus, hesperidin exerts preventive impacts against BaP-induced testicular toxicity, which such protection attributes, at least in part, to its antioxidant activities.³⁹

Heavy metals are the other important environmental toxicants that can adversely affect the function of the male reproductive system. Heavy metals act as the oxidative agents that increase ROS production and reduce antioxidant capacity, leading to oxidative stress promotion damage in testicular tissue, resulting in low-quality semen and infertility.^40–43 Lead (Pb) is one of the most penetrative and hazardous heavy metals. The main sources of Pb exposure exerting severe damage to vital organs are traditional medicines, cosmetics, electronic wastes, coal combustion, gasoline, Pb-contaminated water, and Pb-based paints from older buildings.^44–46 Pb toxicity is a critical environmental health issue with destructive impacts on the human body, represented by a range of clinical manifestations that are dependent on the duration and route of exposure as well as the absorbed dose.^47,48 In the case of the male reproductive system Pb exposure adversely impacts the quality of sperm and semen with unknown mechanisms. Notably, a significant inverse association has been found between increased levels of Pb with main parameters of semen, and biomarkers of sperm activity.^49,50 Importantly, a close association has been also found between the impaired function of the male reproductive system and Pb-promoted oxidative stress with consequent antioxidant deficiency.^51–53 In Pb-exposed rats, hesperidin treatment (100 mg/kg) was found to markedly restore Pb-promoted reduction in testicular and epididymis weights as well as in semen parameters, reproductive hormones, and testicular markers of oxidative stress, along with elevating MDA levels and improving testicular histopathological parameters.⁵⁴ Overall, these results show the preventive role of hesperidin on Pb-promoted testicular damage, which is acquired by suppressing oxidative stress and modulating the production of reproductive hormones.⁵⁴

Sodium fluoride (NaF) is a famous fluorinated compound widely employed in various fields, especially dentistry and in some situations in tap water fluoridation systems to hamper caries.⁵⁵ NaF has also been employed as a wood preservative and an insecticide as well as in glass manufacturing. Of note, the major origin of fluoride exposure and water contamination with fluoride is groundwater. Importantly, the adverse health impacts of NaF have been found worldwide.⁵⁶ Excess fluoride exposure can lead to tooth and bone fluorosis, elevated rates of bone fractures and nephrolithiasis, decreased birth rates, thyroid dysfunction, and poor intellect in children.⁵⁷ It can also be associated with testicular degeneration,⁵⁸ renal damage,⁵⁹ neuronal damage,⁶⁰ and myocardial calcification.⁶¹ The most severe adverse impacts of NaF are attributed to the production of ROS in mammalian cells.⁶² Over-intake of fluoride has been found to result in oxidative stress,⁶³ alter gene expression, and modulate various signaling pathways involved in cell proliferation and apoptosis, including the mitogen-activated protein kinase (MAPK)⁶⁴ and nuclear factor kappa B (NF-kB).⁶⁵ Although various mechanisms underlying fluoride toxicity have been reported, oxidative stress has been found as a critical mechanism in mediating fluoride-promoted organ-specific diseases.⁶² Fluoride intensifies oxidative stress in mammalian cells by inducing an imbalance between ROS production and endogenous anti-oxidants, resulting in oxidative stress and inhibiting the function of various anti-oxidant enzymes, including glutathione peroxidase (GPx), catalase (CAT), and SOD.⁶⁶ Of note, administration of hesperidin at doses of 100 and 200 mg/kg was found to result in a notable reduction in oxidative stress, apoptosis, and endoplasmic reticulum stress in testicular tissues of NaF-treated rats,⁶⁷ suggesting a protective role of hesperidin against NaF-induced toxicity in the male reproductive system.

Tributyltin chloride (TBT) is another famous endocrine-disrupting compound that impacts the activity of the endocrine organs and subsequently leads to dangerous health problems.^68,69 TBT is mainly employed as a stabilizer in the production of plastic devices and as a catalyst in polyvinyl chloride tools. TBT is also employed in manufacturing food storage containers and as a preservative substance for leather, paper, textiles, and wood.^70,71 The consumption of TBT-contaminated drinks and food is the main route of human exposure to TBT. The food from aquatic sources such as fish, seafood, and fishery products contains high levels of TBT. Canned beverages and foods can be also a major source of TBT.^72,73 Humans may also be exposed to TBT by direct skin contact with different substances, such as pesticides, catalysts, cleansing products, polish, and disinfectants.⁷⁴ Experimental studies showed a remarkable reduction in the number of proliferating spermatogenic cells, testicular weight, plasma testosterone, as well as levels of LH and FSH in TBT-exposed rats.⁷⁵ Importantly, hesperidin administration significantly ameliorated the mentioned parameters and enhanced male fertility,⁷⁵ suggesting it as a promising protective agent against TBT-induced reproductive in susceptible subjects.

Bisphenol A (BPA) is the most abundant chemical produced worldwide,⁷⁶ broadly employed in numerous human exposure products such as medical supplies, baby feeding bottles, food packages, thermal papers, and electronic equipment.^77,78 BPA has shown endocrine-disrupting impacts causing testicle injury. Experimental studies showed a significant reduction in epididymal sperm count and testicular weight in BPA-exposed adult male rats.⁷⁹ BPA can attach to oestrogen receptors and defect semen quality and spermatogenesis.⁸⁰ BPA results in the excessive generation of ROS, such as hydroxyl radicals, hydrogen peroxide, and superoxide anions in the body,⁹ leading to an elevation in apoptotic and necrotic cells in both testicles and semen.⁸¹ BPA exposures are found to reduce the levels of testosterone and interfere with sexual behavior and reproduction.^82,83 Notably, hesperidin administration with BPA in rats decreased oxidative stress and apoptosis leading to beneficial therapeutic impacts on spermatogenesis and reproductive hormones (FSH, LH, and testosterone) as well as steroidogenic enzymes.⁸⁴ These results indicate that hesperidin treatment declines oxidative damage and apoptosis in the testicles of BPA-treated rats, while it exerts regulatory impacts on steroidogenic enzymes, spermatogenesis, and plasma reproductive hormones.

Testicular protective effects of hesperidin against drug induced-toxicity

Some findings show hesperidin could alleviate the toxicity from drug-induced oxidative stress in the male reproductive system, as discussed in the following.

Finasteride, one of the current main drugs applied for the treatment of benign prostate cancer, is accompanied by undesirable adverse impacts by oxidative stress-associated mechanisms, including the production of ROS and free radicals. The adverse impacts include ejaculatory disorder immunosuppression and alopecia, reduced libido, erectile impairment, and elevated risk of impotence.^85,86 It was shown that hesperidin administration (100 mg/kg) exerts protective effects against finasteride-promoted oxidative injury on testicular tissues in rats.⁸⁷ Of note, hesperidin was found to alleviate finasteride-mediated testicular injury by inhibiting oxidative stress parameters, improving antioxidant status, enhancing sperm indices and changes in the activities of marker enzymes, as well as suppressing the finasteride binding to molecular targets.⁸⁷

Cisplatin is an anticancer agent commonly applied for the chemotherapy of different cancer types.^88,89 However, its clinical application is mainly restricted by significant adverse impacts on various organs, such as hematological, neurological, renal, gastrointestinal, and reproductive systems.^89,90 Cisplatin was found to result in histopathological injuries, the significant elevation of lipid peroxidation, and reduction of enzymatic (SOD, CAT, and GPx) and non-enzymatic (GSH) antioxidants in the testis tissue, as well as a significant reduction in plasma levels of testosterone and sperm motility in rats.⁹¹ Notably, hesperidin administration (50 mg/kg) was found to markedly prevent the side impacts of cisplatin. Hesperidin showed protective impacts against cisplatin-promoted toxicity in the reproductive system relying on its antioxidant activities.⁹¹ Therefore, hesperidin may exert promising useful effects on cisplatin-mediated reproductive system damage in cancer patients.

Methotrexate is another anticancer drug that exerts a toxic effect on the male reproductive system. Methotrexate has been found to cause a significant decrease in the size of spermatogenic cells, the diameter of seminiferous tubules, and the reproductive organ weight, as well as harsh degradation of seminiferous epithelium and dilations in the interstitial region.^92,93 Methotrexate-induced toxicity is known to be due to induction of oxidative stress.⁹⁴ Notably, methotrexate elevates free radical formation by inhibiting antioxidant enzymes, modulating pro-inflammatory cytokines, and activating immune cells.^95,96 Activation of immune cells by pro-inflammatory cytokines results in increased ROS production, causing overproduction of ROS, and leading to elevated levels of pro-oxidant LP.^96,97 In methotrexate-treated rats, sperm density and motility, the activities of antioxidant enzymes CAT, GPx, and SOD as well as the levels of GSH were found to be decreased, while the levels of pro-inflammatory cytokines TNF-α and IL-1β, as well as levels of pro-oxidant MDA, were found to be increased.⁹⁸ In addition, the regular morphology of spermatogenic cells was deformed, and seminiferous tubules underwent degeneration and necrosis. It was shown that the hesperidin administration could improve spermatological parameters, and reduce necrotic and degenerative alterations in methotrexate-treated rats,⁹⁸ suggesting the protective effect of hesperidin against the destructive impact of methotrexate in the male reproductive system.

Cyclophosphamide (CP) is another non-specific anticancer agent showing remarkable adverse impacts. CP can adversely affect male fertility both peripherally and centrally by downregulation of the hypothalamic–pituitary–gonadal axis by impacting gonadotropin secretion, testicular steroidogenesis, testosterone production, and eventually spermatogenesis.^99,100 In addition, CP can result in testicular degeneration through direct induction of testicular oxidative stress and DNA damage.^101,102 In the CP-treated rats, the administration of hesperidin remarkably enhanced the plasma concentration of testicular GPx, prolactin, testosterone, FSH, and LH, with a decrease in the concentrations of iNOS, p53, and MDA.¹⁰³ In addition, a notably increased expression of hypophyseal GnRHr, testicular CYP19A1 enzymes, GLP-1, IL10, and PPAR-1, as well as a remarkable reduction in the expression of in testicular P53 and IL1β, were also found in hesperidin administrated rats.¹⁰³

Vanadium is a transition metal with broad industrial use. It is employed in the synthesis of steel, ceramics, electronics, pesticides, and chemicals. Besides, vanadium substances at low doses represent different therapeutic applications, such as antiretroviral, lipid-lowering, anticarcinogenic, and antidiabetic.^104–106 Despite its clinical use, there are well-known experimental findings that show the toxic impacts of vanadium on the male reproductive system,.^107,108 Vanadium was found to provoke DNA fragmentation in sperms and significantly reduce serum levels of testosterone as well as the number and motility of sperms in the rat.¹⁰⁹ Further, it could also induce a comparable elevation in the atypical morphology of sperms and detrimental alterations in the testis histology.¹⁰⁹ In addition, vanadium was also found to promote oxidative stress, as indicated via a significant elevation in levels of testicular MDA and reduced activity of antioxidant enzymes such as catalase and SOD.¹⁰⁹ Of note, co-administration of hesperidin (25–50 mg/kg) profoundly improved the sperm parameters and histological alterations by enhancing the antioxidant levels in rat testis, showing that hesperidin can protect the rat testis against vanadium-promoted oxidative injury.¹⁰⁹

Sildenafil citrate, also called Viagra, is a special treatment for curing erectile dysfunction.¹¹⁰ The clinical use of sildenafil is restricted due to various adverse impacts. In the rat testicular tissue, treatment with sildenafil citrate has been found to significantly reduce the catalase activity and total antioxidant capacity, and increase the levels of NO, ROS, and MDA.¹¹¹ In addition, sildenafil citrate was found to induce unusual histopathological patterns in the testes.¹¹¹ Notably, hesperidin administration was found to alleviate the harmful impacts of sildenafil citrate on testicular performance, attenuate oxidative stress, and recover blood parameters.¹¹¹

Testicular protective effects of hesperidin against biological toxicants

Diabetes is a metabolic disorder characterized by hyperglycemia, oxidative stress, and ROS production. Long-term injuries, dysfunctions, and failures of various organs, such as the male reproductive system, have been detected in diabetic patients.^112,113 Glucose metabolism plays an important role in the spermatogenesis process and, subsequently, in sperm activity, motility, and fertilization. Diabetes reduces the quality and motility of sperm, elevating sperm abnormality and DNA injury of sperm cells.¹¹⁴ Such adverse impacts may also be mediated by oxidative stress resulting from elevated ROS production. Notably, it has been found that experimentally induced diabetes using streptozotocin (STZ) could exert harmful effects on male fertility. In rats, STZ-induced diabetes could significantly elevate MDA levels and reduce the enzymatic activity of antioxidants (GSH-Px, SOD, CAT) and levels of nonenzymatic antioxidant GSH.¹¹⁵ Of note, hesperidin administration could markedly reduce oxidative stress and elevate enzymatic activities of antioxidants and levels of nonenzymatic antioxidants because of the antioxidant effect.¹¹⁵ In addition, STZ-induced diabetes could elevate levels of DNA damage in testicular tissue, and hesperidin administration markedly reduced levels of DNA damage in the testes of diabetic male rats. Moreover, hesperidin administration could markedly restore reduced sperm motility as well as rates of abnormal and dead sperms in the male reproductive system induced by diabetes in rats.¹¹⁵

Abamectin (ABM) is a compound from the avermectin family, which is fermented naturally by Streptomyces avemitilis.¹¹⁶ AMB is frequently employed as a pesticide because of its potent anthelmintic and insecticidal properties.¹¹⁷ It can easily pass through the blood–brain barrier and directly activate the glutamate and/or γ-aminobutyric acid-gated chloride channels, leading to neurotoxicity and, consequently, causing paralysis and death.¹¹⁸ ABM has also been found to exert toxicity on testicles and adversely impact fertility.¹¹⁹ Notably, the main factor mediating the toxicity mechanism of ABM is oxidative stress that elevates free oxygen radicals causing apoptosis and toxicity.^116,117 The results obtained from the experimental studies on the rat revealed that ABM could promote oxidative stress, and induce inflammation, apoptosis, and autophagy. Of note, hesperidin administration exerted antioxidant impacts by activating the enzyme activity of SOD, CAT, GPx, and glutathione levels in testis tissue and reduced lipid peroxidation.¹²⁰ Hesperidin was also found to suppress the JAK2/STAT3 signaling pathway by inhibiting the expression of IL-6 cytokines.¹²⁰ Overall, hesperidin significantly prevents the destruction mediated by ABM in testicular tissue, mechanistically through anti-autophagic, antiapoptotic, anti-inflammatory, and antioxidant effects.¹²⁰

Etoposide [40-demethylepipodo-phyllotoxin-9-(4,6-O-ethylidene)-b-d-glucopyranoside] is a semisynthetic derivative of podophyllotoxin, a natural substance isolated from the rhizomes and roots of the plants, Podophyllum peltatum. Etoposide can directly promote DNA strand breaks and suppress the topoisomerase II and is employed as monotherapy or combination therapy regimens for the treatment of various cancers, such as lymphoma, acute leukemia, testicular cancer, and small cell lung cancer.¹²¹ Importantly, chronic exposure to etoposide can affect spermatogenesis through degenerative alterations in spermatogonia and early spermatocytes, nuclear changes and cytoplasmic vacuolation in Sertoli cells, the presence of large spermatids with multinuclei.¹²² It can also induce DNA strand breaks in the sperm,¹²³ and adversely affect fertility by elevating pre/post-implantation loss and unusual progeny.^121,124 Hesperidin was found to exert protective effects against etoposide-induced oxidative damage on reproductive system parameters in male rats.¹²⁵ Of note, etoposide was found to significantly decrease the gene expression and plasma levels of LH, FSH, and testosterone, decline the sperm count and activity, and elevate abnormal sperms with reduced fertility rate, number, and weight of birth in rats.¹²⁵ Notably, hesperidin treatment alleviated the adverse effects of etoposide by restoring the parameter rates to normal values.¹²⁵

Conclusion and future perspective

In recent years, there have been numerous experimental studies showing that hesperidin can protect the male reproductive system from the toxic effects of environmental toxicants such as phthalates, benzo[α]pyrene, heavy metals, sodium fluoride, tributyltin chloride, and bisphenol A, as well as drugs and biological agents such as finasteride, cisplatin, methotrexate, cyclophosphamide, vanadium, sildenafil citrate, streptozotocin, abamectin, and etoposide. Such protective effects of hesperidin are attributed to its antioxidant, anti-inflammatory, and anti-apoptotic activities, as well as modulating the production of reproductive hormones. The antioxidant property of hesperidin was evidenced through an increase in the levels of GPx, GST, CAT, SOD, and GSH, as well as heme oxygenase and nuclear factor-erythroid 2-related factor2 in the testicular along with a decrease in the levels of MDA and ROS. Hesperidin was also found to exert anti-apoptotic impact through a reduction in the Bax/Bcl-2 ratio as well as the levels of NF-kB, Bad, and caspase 3. In addition, its anti-inflammatory activity was reflected by a decrease in the levels of IL-6, IL-1β, and TNF-α. Of note, hesperidin can also regulate steroidogenic enzymes, spermatogenesis, and reproductive hormones such as FSH, LH, and testosterone.

Although there are growing preclinical reports, the lack of human trials on the protective activities of hesperidin against toxicants-induced dysfunctionality of the male reproductive system is a notable limitation, that should be further considered. Hesperidin can be attended, in the near future, as a promising therapeutic agent to treat testicular-related disorders, although well-arranged human trials in patients with reproductive system failure are required to be conducted. Altogether, the current review study indicates that hesperidin is a promising protective agent against toxicants-induced reproductive system failure.

Author contributions

L.Y. and J.W. contributed to the conception and design of the study. D.D. and Y.Z. performed data acquisition, and prepared the first draft. Y.L. and W.X. revised the draft critically for important intellectual content. All authors read and approved the final version to be submitted.

Funding

Not applicable.

Conflict of interest statement

The authors have no relevant financial or non-financial interests to disclose.

Data availability

Data sharing does not apply to this article as no datasets were generated or analyzed during the current study.

References