High-Risk HPV with Multiple Infections Promotes CYP2E1, Lipoperoxidation and Pro-Inflammatory Cytokines in Semen of Asymptomatic Infertile Men

Abstract

High-risk human papillomavirus (HR-HPV) infection, followed by chronic inflammation and oxidative stress, is a major risk factor of male infertility. In this study, we explored the potential impact of high-risk (HR) HPV genotypes in single infection (SI) and multiple infections (MI) that promote CYP2E1 expression, oxidative damage and pro-inflammatory cytokines, possibly contributing to sperm damage and male infertility. Semen samples from 101 infertile military men were studied. We analyzed seminal parameters, namely, HPV genotyping, cytochrome P450 2E1 (CYP2E1), oxidative stress biomarkers (total antioxidant capacity (TAC), catalase (CAT) and superoxide dismutase (SOD)), lipid peroxidation (LPO), 8-hydroxiguanosine (8-OHdG) and pro-inflammatory cytokines (IFN-γ, IL-1β, IL-4, IL-6 and IL-8). Eighty-one men (80.2%, 81/101) were positive for HPV infection, and MI-HR-HPV was higher than SI-HR-HPV (63% vs. 37%). HPV-52 was the most frequently detected type (18.5%), followed by HPV-33 (11.1%), and the most frequent combination of genotypes detected was HPV-33,52 (11.1%), followed by HPV-18,31 (6.2%). The group with infected samples presented lower normal morphology and antioxidant levels compared to non-infected samples. In concordance, the infected group showed high levels of LPO, IFN-γ, IL-1β, IL-4 and IL-6 and downregulation of CAT and SOD enzymes. Interestingly, changes in motility B, low levels of TAC, overexpression of CYP2E1, LPO and IL-8 levels were higher in MI-HR-HPV than SI-HR-HPV, suggesting that HPV infection promotes a chronic inflammatory process and a toxic and oxidative microenvironment, which increases with MI-HPV infections.

Human Papilloma Virus and Male Infertility: An Analysis Following World Health Organization 2021 Guidelines

“…Similar evidence of a higher DFI being a genotype-dependent impairment has already been described in the literature by Capra et al 20 and Boeri et al 18 . This data is also in agreement with Perez-Soto et al 37 , who, as previously mentioned, found in hrHPV infected sperms high levels of ROS, cause of DNA damage. Although the comparison of lrHPV and hrHPV positive samples did not reveal signi cant differences in slow and rapid motility parameters, it could be hypothesised that a wider sample could bring out signi cant differences in rapid progressive motility, whose p-value is particularly close to statistical signi cance.…”

“…As concerns sperm morphology, HPV-positivity appears to be correlated with substantial morphological abnormalities, involving with the highest statistical signi cance the neck and the midpiece, as emerged by our multivariate analysis. These ndings join numerous studies already describing an HPV-induced deterioration of overall sperm morphology 13,15,20,[35][36][37] . Furthermore, in HPV-positive samples, correlation analysis between morphological defects of the neck and midpiece and rapid progressive motility revealed a highly statistically signi cant positive correlation.…”

“…Recently, Perez-Soto et al 37 described an association between hrHPV infection, high levels of oxidative stress and sperm cell impairment. Indeed, their ndings highlighted that HPV-positivity was correlated with an overexpression of the cytochrome P450 2E1 gene, related in turn to an elevated ROS production and an oxidation-induced damage of polyunsaturated fatty acids, of which spermatozoa plasma membrane is rich.…”

Oxidative Stress Biomarkers in Male Infertility: Established Methodologies and Future Perspectives

“…However, an excess of ROS leads to OS, causing structural and functional damage to sperm cells, including lipid peroxidation, protein oxidation, and DNA damage, resulting in compromised male fertility and a risk of genetic mutations in offspring [2,3]. Elevated ROS concentrations, found in seminal fluid samples from infertile men, are often due to pathological conditions or environmental factors such as infections, smoking, alcoholism, and diet [4][5][6][7].…”

Emerging paradigms: unmasking the role of oxidative stress in HPV-induced carcinogenesis

“…Similarly, elevated levels of cytokines were accompanied by OS marker (lipid peroxidation) and decreased levels of catalase and superoxide dismutase antioxidant enzymes in high-risk HPV patients. These results imply that HPV infection triggers a persistent inflammatory reaction and plays a role in generating an oxidative environment [ 80 ].…”