Highly Active Antiretroviral Therapy Alters Sperm Parameters and Testicular Antioxidant Status in Diet-Induced Obese Rats

Abstract

The efficacy of highly active antiretroviral therapy (HAART) has led to an increase demand for therapeutic use, thereby necessitating investigation into drug toxicity. This study was designed to investigate the in vivo effects of HAART on sperm parameters and testicular oxidative stress in lean and obese rats. Wistar rats (males, n = 40, weighing 180~200 g) were assigned randomly into 4 groups and treated accordingly for 16 weeks as follows: Control (C): lean group fed with standard rat chow; Diet induced obesity (DIO): obese animals fed a high caloric diet; C + ART: lean animals treated with HAART; DIO + ART: obese animals treated with HAART. An antiretroviral drug combination of Tenofovir, Emtricitabine and Efavirenz at a dose of 17, 26 and 50 mg/kg/day was administered for the latter 6 weeks via jelly cube feeding. At the end of the experimental period, sperm analysis was performed on sperm collected from the caudal epididymis, while the testis was homogenized for antioxidant enzyme and lipid peroxidation assays. Results showed that HAART significantly decreased sperm motility (p < 0.05) in both lean and obese animals, and viability (p < 0.05) in the DIO group. Testicular glutathione, catalase and superoxide dismutase were significantly decreased (p < 0.05), while Thiobarbituric acid reactive substances (TBARS) levels were significantly increased (p < 0.05) when the DIO+ART group was compared to Control group. Thus, the decreased sperm qualities associated with HAART might be as a result of increased testicular oxidative stress prominent in obese animals.

EFVb-HAART Increases Mortality, Locomotor Deficits and Reduces Reproductive Capacity in Drosophila melanogaster

“…Nevirapine and Efavirenz have been shown to cross the blood-brain barrier and cause significant inhibition in the activity of creatine kinase, which plays a vital role in imparting cell energy homeostasis in the brain [28]. Generally, one of the theories propounded to explain antiretroviral drug toxicities partly involves mitochondria oxidative stress induction [19,29], causing accelerated aging and lifespan reduction [30].…”

“…Some in vitro studies have shown the relationship between acetylcholine and fecundity [19,29]. Generally, the higher the activity of AChE, the lower the concentration of acetylcholine (ACh).…”

“…From our result, we recorded 100% emergence failure (P<0.001) when both genders were simultaneously exposed compared to unexposed group, significant reduction (P<0.001) in emergence of the group with only female exposed compared to control, and highly pronounced reduction (P<0.001) in emergence of a group with only male exposed. Similarly, it has been reported that significantly decreased AChE activity correlates positively with increased oxidative stress and acetylcholine concentrations which in turn impacts negatively on both male and female fertility [19,29,23]. Increased acetylcholine concentration via insecticides induced AChE inhibition, for example, impairs insects' spermatogenesis, sperm motility, and increased oxidative stress-induced oocyte damage [34,35] due to increased segregation errors orchestrated by premature loss of cohesion [36,37].…”

“…Besides the overproduction of reactive oxygen species (ROS) seen in in vitro cell cultures exposed to antiretroviral drugs [10,11,12,13], in vivo human studies have confirmed that antiretroviral drug exposure results to varying degrees of oxidative damage [12] as evidenced by increase in lipid peroxidation [14], decreased catalase activity [15], decreased superoxide dismutase (SOD) activity [16], decreased thiol contents [16,13], increased sperm nuclear fragmentation rate [17,18] and reduction in number of ovarian follicles [17]. Furthermore, in vivo studies in mice showed that exposure to EFV b -HAART significantly decreased sperm motility and viability, testicular glutathione, catalase, and superoxide dismutase but increases pro-oxidant like thiobarbituric acid reactive substance (TBARS) levels [19]. In view of the foregoing, the assessment of long term effects of EFV b -HAART has garnered increasing attention [2].…”

Current perspectives of CASA applications in diverse mammalian spermatozoa

“…Spermatozoa were retrieved from murine (Wistar and Sprague-Dawley rats (Rattus norvegicus) and C57 strain mice (Mus musculus)) and non-murine (naked mole-rat (Heterocephalus glaber)) animals postmortem after the animals had been humanely killed with a lethal dose of sodium pentobarbital, halothane or cervical dislocation. The testis and epididymis were subsequently removed and spermatozoa were harvested from the proximal cauda epididymis using a sperm isolation procedure as described by Maree (2011) for mouse and naked mole-rat and by Oyeyipo et al (2018) for rat.…”