Sodium benzoate exposure disrupts HPG-axis in male rats: insights into oxidative stress, hormonal dysregulation, histopathology and kisspeptin/RFRP-3 expression

Abstract

The reproductive effects related to sodium benzoate (SB) are increasingly recognized as concerns for public health. To elucidate the underlying mechanistic pathway in SB-induced reproductive impairment, we evaluated its dose-dependent effects by assessing the key elements of HPG- axis, encompassing wide range of doses from dietary to presumably harmful levels. Thirty-five adult male rats (Sprague-Dawley) split into seven groups (n = 5/group); control, SB10, SB50, SB100, SB500, SB1000mg/kg and the co-treated group (SB + EB). SB and distilled water were gavage for 90 consecutive days. The co-treated group received SB500 from day one, while estradiol benzoate (EB; 40 µg/kg) was given at mid-study onward till completion of experiment. Biochemical parameters, sperm parameters, reproductive hormones, gonadal histopathology, hypothalamic kisspeptin and RFRP-3 expression were assessed. SB produced a concentration-dependent reduction in the testis, accessary sex organs weight, antioxidant activities (SOD, POD, CAT and GSH), testosterone and FSH levels. Testicular ROS, TBARs and plasma LH levels were significantly raised compared to control. Fertility parameters underwent a significant decline in SB rats. Notably, kisspeptin showed dose-related decline, while RFRP-3 upregulated in SB rats. Morphometric indices of seminiferous tubules highlighted apparent alterations and marked traces of histopathology were noticed in test groups. EB treatment restored kisspeptin hence stabilized hormones and improved fertility parameters were seen in co-treated rats. SB exposure significantly disrupts HPG-axis via neuroendocrine dysregulation and inducing testicular cytotoxicity, with oxidative stress serve as the key mediator of these effects. It underscores the dire need for careful usage and future studies of its long-term reproductive safety.

Graphical abstract