Environmental Factors-Induced Oxidative Stress: Hormonal and Molecular Pathway Disruptions in Hypogonadism and Erectile Dysfunction

Abstract

Hypogonadism is an endocrine disorder characterized by inadequate serum testosterone production by the Leydig cells of the testis. It is triggered by alterations in the hypothalamic-pituitary-gonadal axis. Erectile dysfunction (ED) is another common disorder in men that involves an alteration in erectile response-organic, relational, or psychological. The incidence of hypogonadism and ED is common in men aged over 40 years. Hypogonadism (including late-onset hypogonadism) and ED may be linked to several environmental factors-induced oxidative stresses. The factors mainly include exposure to pesticides, radiation, air pollution, heavy metals and other endocrine-disrupting chemicals. These environmental risk factors may induce oxidative stress and lead to hormonal dysfunctions. To better understand the subject, the study used many keywords, including "hypogonadism", "late-onset hypogonadism", "testosterone", "erectile dysfunction", "reactive oxygen species", "oxidative stress", and "environmental pollution" in major online databases, such as SCOPUS and PUBMED to extract relevant scientific information. Based on these parameters, this review summarizes a comprehensive insight into the important environmental issues that may have a direct or indirect association with hypogonadism and ED in men. The study concludes that environmental factors-induced oxidative stress may cause infertility in men. The hypothesis and outcomes were reviewed critically, and the mechanistic approaches are applied through oxidant-sensitive pathways. This study also provides reccomendations on future therapeutic interventions and protective measures against such adverse environmental factors-induced hypogonadism and ED.

Keywords: air pollution; endocrine-disrupting chemicals; erectile dysfunction; heavy metals; hypogonadism; infertility; pesticide; radiation; testosterone.

Figure 1

Endocrine regulation of testosterone metabolism and spermatogenesis, and the possible attack points of ROS-induced pathologies. Normal physiology of testosterone metabolism and spermatogenesis is regulated by the hormones secreted by the hypothalamus, pituitary gland and Leydig cells. The pituitary gland produces LH and FSH in response to GnRH secreted by the hypothalamus. LH stimulates the Leydig cells to produce testosterone, and FSH upregulates the production of ABP in the Sertoli cells. Testosterone binds to ABP and brings about the functional response required for spermatogenesis. ROS stimulates the HPA axis, thereby mediating the adrenal cortex to synthesize cortisol, which inhibits the action of LH. ROS also upregulate the production of inhibin and estradiol and downregulates the concentration of testicular sialic acid—all these negatively affect the action of testosterone. Increased production of LTH resulting from excessive ROS generation may also create hindrance in the HPG axis. ROS may directly affect the HPG axis by inhibiting the production of FSH or stimulate the generation of cytokines, such as TNF-α, IL-1β and IL-6, which in turn block the HPG axis. Red arrows represent the increase and decrease of respective substances, which negatively affects the HPG axis. (GnRH: gonadotropin-releasing hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone; ABP: androgen-binding protein; CRH: corticotropin-releasing hormone; ACTH: adrenocorticotropic hormone; LTH: luteotropic hormone; TNF-α: tumor necrosis factor-alpha; IL-1β: interleukin- 1 beta; IL-6: interleukin 6; HPG: hypothalamic–pituitary–gonadal; HPA: hypothalamic–pituitary–adrenal; ROS: reactive oxygen species).

Figure 2

Probable mechanism of association of pesticide-induced ROS with hypogonadism and ED. Diazinon enhances LTH levels, which in turn lowers the activity of LH. Diazinon also stimulates producing serotonin that inhibits the action of both LH and FSH, thereby decreasing testosterone levels. Chlorpyrifos can reduce the activity of AChE in the hypothalamus. Consequently, the entire HPG axis is disrupted, leading to reduced testosterone production. Chlorpyrifos also reduces the concentration of sialic acid, which then inhibits Leydig cells. Cypermethrin disrupts the HPG axis by inhibiting the activity of the hypothalamus. Organophosphorus pesticides diazinon and chlorpyrifos, as well as pyrethroid pesticide cypermethrin, cause a decline in the antioxidant enzyme activity, thereby enhancing ROS generation. ROS causes lipid peroxidation and DNA damage, which inhibits the activity of Leydig cells, followed by reduced testosterone synthesis. Reduction in testosterone levels brings about the inactivity of the NOS enzyme, which ultimately leads to ED. Red arrows represent the increase and decrease of the respective substances, which have a negative impact on testosterone production, leading to hypogonadism and ED. (LTH: luteotropic hormone, AChE: acetylcholinesterase, GnRH: gonadotropin-releasing hormone, LH: luteinizing hormone, FSH: follicle-stimulating hormone, SOD: superoxide dismutase, NOS: nitric oxide synthase, ED: erectile dysfunction, ROS: reactive oxygen species).

Figure 3

Probable mechanism of association of radiation-induced ROS with hypogonadism and ED. Nonionizing radiations damage the Leydig cells, which reduces testosterone synthesis and subsequent inhibition of spermatozoa. Such radiations negatively affect sperm parameters, including count, motility, morphology, viability and motility. Nonionizing radiations also stimulate NO activity, which along with ROS, brings about lipid peroxidation and damage to testicular tissues. These tissues are also damaged by apoptosis mediated by elevated ROS levels. Nonionizing radiation-induced ROS further causes DNA damage and decreases the concentration of histone kinase along with a reduction of SOD and glutathione peroxidase activity. Whereas ionizing radiations cause a decline in testosterone production by damaging Leydig cells and by inhibiting the activity of steroidogenic enzymes. Such radiations enhance LDH activity, which results in cellular damage. Damage to the penile smooth muscles and reduced ICP may cause ED. ED is also caused by decreased cGMP levels and damage to the corpus cavernosum, which are brought about by ionizing radiation-induced oxidative stress. Red arrows represent the increase and decrease of the respective substances and sperm parameters beyond harmful levels. (NO: nitric oxide, SOD: superoxide dismutase, LDH: lactate dehydrogenase, ICP: intracavernosal pressure, ODO: oxadiazoloquinoxalin-1-one, cGMP: cyclic guanosine monophosphate, ED: erectile dysfunction, ROS: reactive oxygen species).

Figure 4

Probable mechanism of association of ROS induced by air pollutants (heavy metals Cd and Pb, and PM2.5) with hypogonadism and ED. Heavy air pollutant Cd increases NO and decreases LDH activity to inhibit spermatogenesis. It also lowers DLD and cAMP levels, which reduces testosterone. Cd decreases antioxidant enzymes along with a decrease in total antioxidant capacity. Through these mechanisms, Cd increases ROS production, which in turn causes lipid peroxidation, testicular necrosis, fibrosis and reduced testicular size. These factors, together with lowered levels of testosterone, contribute to the cause of infertility. Another heavy metal Pb reduces testosterone levels and estradiol, which leads to the inhibition of spermatogenesis. PM2.5 downregulates GnRH activity, thereby declining LH and FSH levels. Reduction in LH inhibits the action of Leydig cells, thereby lowering testosterone production. PM2.5 also induces ED by damaging penile arteries, reducing the ICP/MAP ratio and inhibiting endothelial NO activity. PM2.5 further stimulates the generation of ROS that can damage DNA and spermatogenic cells. PM2.5-induced ROS may also have a negative impact on sperm quality, particularly motility, viability, functioning and membrane fluidity. Red arrows represent the increase and decrease of the respective substances and sperm parameters beyond harmful levels. (NO: nitric oxide, LDH: lactate dehydrogenase, DLD: dihydrolipoamide dehydrogenase, cAMP: cyclic adenosine monophosphate, TAC: total antioxidant capacity, GnRH: gonadotropin-releasing hormone, LH: luteinizing hormone, FSH: follicle-stimulating hormone, ICP: intracavernosal pressure, MAP: mean arterial pressure, ED: erectile dysfunction ROS: reactive oxygen species).

Figure 5

Probable mechanism of association of ROS induced by BPA, phthalates, PFAS and PCB with hypogonadism and ED. BPA downregulates the production of LH, FSH and steroidogenic enzymes along with upregulation of ROS, which, in turn, causes a decline in testosterone levels followed by inhibition of spermatogenesis. BPA-mediated ROS generation may also suppress testosterone activity and spermatogenic processes directly. Phthalates cause damage to testicular tissues and lower the levels of LH and FSH, which further reduces testosterone levels. ROS generation by phthalates may bring about the apoptosis of Sertoli cells and germ cells, ultimately inhibiting spermatogenesis. Lowered testosterone levels also result in diminished sexual desire and reduce spontaneous erection, which may lead to ED. PFAS, such as PFOS and PFOA, may also cause damage to Leydig cells leading to reduced testosterone levels. PFOS and PFOA may induce cortisol production, which leads to ROS generation, ultimately resulting in suppression of the hormonal activity of Leydig cells. PCBs damage testicular tissues and lower the activity of LH and FSH together with reducing the steroidogenic enzymes, which may lead to lowered testosterone levels. PCBs can also reduce the levels of antioxidant enzymes, and resulting in oxidative stress induces lipid peroxidation in Leydig cells, thus lowering the level of testosterone. PCB-induced reduction of testosterone may also give rise to ED. Red arrows represent the increase and decrease of the respective substances, which negatively impact testosterone level, thereby inhibiting spermatogenesis and causing hypogonadism and ED. (BPA: bisphenol A, PFAS: perfluoroalkyl substances, PFOS: perfluorooctanesulfonic acid, PFOA: perfluorooctanoic acid, PCB: polychlorinated biphenyls, LH: luteinizing hormone, FSH: follicle-stimulating hormone, ED: erectile dysfunction, ROS: reactive oxygen species).