Oxidative Stress-sensitive Pathways Research Articles

P-002 Zinc restores testicular integrity and function in HAART-treated male Wistar rats via modulation of Nrf2/NFkB pathway and downregulation of caspase 3 signaling

Abstract Study question Will zinc treatment attenuate highly active antiretroviral drugs (HAART)-induced testicular dysfunction when used concomitantly? Summary answer Zinc blunted HAART-induced reproductive toxicity by attenuating testicular and epididymal oxido-inflammatory injury via modulation of Nrf2/NFkB signaling and downregulation of caspase 3-mediated apoptosis. What is known already The use of HAART has been established to be effective in the management of HIV; however, it has also been reported to induce male reproductive dysfunction. Studies have revealed that HAART impairs fertility by reducing libido and inducing testicular and sperm damage via an oxidative stress-sensitive pathway. On the other hand, zinc has been shown to enhance reproductive function by improving testicular redox state. Till date, no study has reported the impact of zinc co-administration with HAART on testicular integrity and function, spermatogenesis and sperm quality, and sexual behaviour. Study design, size, duration This is a prospective experimental study using animal model. Forty sexually mature inbred male Wistar rats of comparable age and weight were used for the study. The study lasted 8 weeks. Participants/materials, setting, methods Animals were acclimatized for two weeks, then randomly assigned into four groups (n = 10). The control rats received 0.5mL of distilled water as vehicle, zinc-treated animals received zinc supplement, HAART-treated rats received a cock-tail of antiretroviral drugs (Efavirenz, Lamivudine, and Tenofovir), while the Zn + HAART-treated rats received treatment as zinc-treated as well as HAART-treated. The doses of drugs used were the Human Equivalent doses for rats. Main results and the role of chance Zinc blunted HAART-induced rise in testicular activities of gamma glutamyl transferase, lactate dehydrogenase activity, concentrations of lactate, and reduced testicular sorbitol dehydrogenase activity. Also, zinc ameliorated HAART-induced decline in the activities of testicular and epididymal superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase, as well as glutathione and Nrf2 concentrations, and rescued HAART-induced increase in testicular and epididymal concentrations of uric acid, malondialdehyde, 8-OHdG, xanthine oxidase and MPO activities, and TNF-α, IL-1β, and NF-kB levels. This was associated with dampening of HAART-led upregulation of caspase 3 activity by zinc. Furthermore, zinc alleviated HAART-led reduction in spermatogenesis and sperm quality, serum nitric oxide and penile cGMP, and circulatory levels of FSH, LH, and testosterone, as well as testicular concentrations of 3β-HSD, 17β-HSD, and testosterone. In addition, zinc prevented HAART-induced sexual dysfunction and poor fertility indices. Limitations, reasons for caution This study was conducted in a rat model; hence findings should be extrapolated to human with care. Thus, clinical trials are recommended to validate these findings. Wider implications of the findings For the first time, we demonstrated the protective role of zinc treatment on HAART-induced male reproductive dysfunction. These findings provide further mechanisms through which HAART induces male infertility, and the possible protective role of zinc. Trial registration number not applicable

P-001 L-arginine ameliorates maternal and pre-pubertal codeine exposure-induced dysregulation of testicular cytoprotective and spermatogenic genes and improves steroidogenesis in adult rat offspring

Abstract Study question Will maternal exposure to codeine cause transgenerational effect on testicular function and what role will pre-pubertal codeine-exposure and L-arginine treatment play? Summary answer L-arginine treatment blunted maternal and pre-pubertal codeine exposure-induced downregulation of testicular cytoprotective and spermatogenic genes and distortion of steroidogenesis. What is known already Codeine, a common drug of abuse, has been reported to impair male infertility by eliciting testicular and sperm damage via oxidative stress-sensitive pathway. On the other hand, L-arginine has been shown to improve testicular perfusion and testicular redox state, thus enhancing male reproductive function. However, no study has evaluated the effect of maternal codeine exposure and concurrent pre-pubertal codeine and L-arginine administration on male reproductive health viz a viz testicular steroidogenesis, spermatogenesis, and sperm quality. Study design, size, duration This is a prospective experimental study using animal model. Forty pre-pubertal female Wistar rats of comparable age and weight were used for the study. The study lasted two generations. Participants/materials, setting, methods Forty pre-pubertal female Wistar rats were randomized into vehicle-treated or codeine-treated. After 8 weeks of administration via gavage, animals were paired with stud male Wistar rats (1: 1). Administration continued throughout pregnancy and lactation. Male offsprings were weaned at post-natal day (PND) 21 and each cohort was randomized into vehicle treated, codeine-treated, L-arginine-treated, and codeine with L-arginine-treated. Offspring intervention commenced at PND 28 and lasted for 8 weeks. Main results and the role of chance Maternal codeine exposure caused increased testicular lactate dehydrogenase activity, concentrations of lactate and uric acid, and reduced testicular sorbitol dehydrogenase activity. In addition, maternal codeine exposure reduced testicular activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, and glutathione and Nrf2 concentrations, but increased testicular concentrations of malondialdehyde, 8OHdG, TNF-α, IL-1β, and NFkB, MPO and caspase 3 activities, and DNA fragmentation. Furthermore, codeine exposure reduced steroidogenic markers (3β-HSD, 17β-HSD, FSH, LH, and testosterone), indices of spermatogenesis, and sperm quality. This was associated with reduced expression of regulatory genes for spermatogenesis (mRNA of Ndrg4, Kit, Rhcg, Lrrc34, and Lgals1), and cytoprotection (mRNA SOD, mRNA GPx, and mRNA Nrf2), and increased mRNA TNF-α, mRNA NFkB, and mRNA caspase 3. The observed codeine-induced perturbations were worsened by pre-pubertal codeine exposure in offsprings damned by mothers with codeine exposure but blunted by L-arginine treatment. Limitations, reasons for caution This study is an animal model; therefore, findings should be extrapolated to human with care. Thus, human studies are recommended. Wider implications of the findings This study demonstrates for the first time the transgenerational effect of maternal codeine exposure, and the impact of concomitant pre-pubertal codeine use and L-arginine treatment. The present findings add to the available literature by providing further molecular mechanisms through which codeine impairs male reproductive function. Trial registration number not applicable