Androgen Receptor (AR) Depletion Underlies the Reproductive Dysfunctions in Male Rats Exposed to Alcohol and Combination Antiretroviral Therapy (cART)

Abstract

The prevalence of alcohol abuse and HIV/AIDS is high in males of reproductive age; unfortunately, a high incidence of alcohol intake has been reported in HIV/AIDS patients including those on combination antiretroviral therapy (cART). Incidentally, alcohol and cART use have each been implicated in male reproductive dysfunction. Therefore, the interactive effects of alcohol and cART on reproductive hormone levels, testicular connective tissue, and androgen receptor and Ki-67 expression were evaluated in HIV naïve adult male Sprague Dawley rats. Adult male rats were divided into four groups: control, alcohol (A), cART, and A+cART. Animals were terminated after 90 days of treatment; then, the blood and testis were extracted for analysis. Special staining for testicular connective tissue, immunoassay for reproductive hormones, and immunohistochemistry for androgen receptor and Ki-67 were conducted. The study found significantly ( $p<0.05$ ) increased thickness of seminiferous tubule basement membrane in the cART group and testicular capsule in the A+cART group. Collagen, reticulin, and elastin fibers decreased significantly in all the treated groups, except for reticulin in the testis of A group animals. With exception of luteinizing hormone in the cART group, all the treated groups had significantly elevated levels of luteinizing and follicle-stimulating hormones, but no significant ( $p>0.05$ ) difference was found in their testosterone and inhibin B levels. The number of Sertoli and Leydig cells expressing androgen receptor reduced significantly in all the treated groups, except for A group’s number of Sertoli cells expressing androgen receptor. Further, in all the treated groups, Ki-67 expression significantly reduced relative to control. In this study, with exception of seminiferous tubule basement membrane, all study parameters were greatly altered in the A+cART group; we suggest that the exacerbated androgen receptor depletion recorded in the A+cART group might have led to the observed severe testicular structural alteration and spermatogenesis derangement.