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
Authors: Hamed M , Akhigbe R 
Published: June 2022

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