Abstract
Benzo(a)pyrene [B(a)P] is the toxic environmental Polycyclic Aromatic Hydrocarbon (PAH), that exerts male reproductive dysfunctions. In this study the molecular mechanism of B(a)P induced Leydig cell steroidogenic dysfunctions and its protective mechanism of action with a natural Aryl hydrocarbon receptor (AhR) antagonist and anti-oxidant, Resveratrol (Res) has been investigated. B(a)P exposure induced ROS mediated steroidogenic imbalance via activation of p38MAPK and repression of testosterone level as well as other steroidogenic enzymes like CYPIIA1, 3β-HSD, 17β-HSD expressions. B(a)P exposure decreased StAR protein expression along with increased DAX-1, a transcriptional repressor of StAR gene. Along with that B(a)P decreased the expression of SF-1 that acts as a transcriptional inducer of StAR gene expression. The study has established Resveratrol as a potential agent combating the deleterious effect of B(a)P on Leydig cell steroidogenesis. Resveratrol treatment resulted significant protection against B(a)P by scavenging ROS and modulating the transcriptional regulation of anti-oxidant enzymes. Furthermore, Resveratrol also prevented stress kinase like p38 MAPK activation and increased StAR protein expression through the reduction of DAX-1 expression. Moreover, the testosterone production was efficiently restored with Resveratrol treatment. ChIP assay also revealed that resveratrol improved SF-1expression which further increased the StAR gene expression. Resveratrol acted efficiently against B(a)P, through its anti-oxidative properties as well as inhibits p38MAPK and increased steroidogenesis and StAR expression through the modulation of SF-1 gene expression.
Highlights
Leydig cells comprise the major endocrine compartment of testis and produce testosterone, the major male reproductive hormone, by the process of steroidogenesis
The findings have shown that B(a)P exposure significantly decreased (p ≤ 0.001) testicular and serum testosterone level (Figures 1A,B)
At molecular level CYP11A1, Steroidogenic Acute Regulatory (StAR), 3β HSD, and 17β HSD are strongly involved with the process of steroidogenesis
Summary
Leydig cells comprise the major endocrine compartment of testis and produce testosterone, the major male reproductive hormone, by the process of steroidogenesis. Several investigations have proposed that environmental toxicants induce adverse effects on male reproductive health [1, 2]. These environmental toxicants possess endocrine disrupting properties. They interfere with the process of steroidogenesis and prevent testosterone production [3]. B(a)P is an environmental PAH that act as an endocrine disruptor [4]. Ligand bound AhR acts as a ligand-activated transcription factor and induces the transcription of cytochrome enzymes associated with phase I xenobiotic and drug metabolism (like CYP1A1). The mode of action of B(a)P in Leydig cells is not properly elucidated
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