Aryl hydrocarbon receptor signaling in male fertility: Protective role of resveratrol and disruptive effects of CH223191 in adult male rats

TL;DR

Resveratrol improves male rat fertility by protecting against oxidative stress, while blocking the AhR receptor harms sperm quality and testicular health.

Contribution

This study demonstrates that resveratrol modulates AhR signaling to enhance male reproductive function and identifies AhR's critical role in fertility.

Findings

Resveratrol increased sperm motility, survival, viability, and antioxidant capacity while reducing DNA fragmentation and oxidative stress.

AhR inhibition with CH223191 caused severe testicular degeneration, reduced sperm quality, and elevated oxidative stress.

Resveratrol upregulated AhR gene expression, while CH223191 significantly downregulated it.

Abstract

The aryl hydrocarbon receptor (AhR) plays a pivotal role in spermatogenesis through its regulatory functions in redox balance and gene expression. This study aimed to investigate the effects of resveratrol (RES), a polyphenolic AhR modulator, and CH223191, a selective AhR antagonist, on male reproductive function in rats by assessing sperm quality, oxidative stress, testicular histopathology, and AhR gene expression.

Forty adult male rats were randomly divided into four groups: (i) Control, (ii) dimethyl sulfoxide (vehicle), (iii) RES (100 mg/kg i.p., twice weekly), and (iv) AhR¯ (CH223191, 10 mg/kg i.p., twice weekly), treated for 60 days. Post-treatment, sperm motility, survival, viability, and DNA fragmentation were evaluated. Total antioxidant capacity (TAC), malondialdehyde (MDA) levels, testicular histopathology, and AhR gene expression quantitative polymerase chain reaction (qPCR) were analyzed.

RES significantly enhanced sperm motility, survival, and viability, reduced DNA fragmentation, and increased TAC while decreasing MDA levels. Histologically, RES preserved normal testicular architecture. In contrast, AhR inhibition through CH223191 led to marked reductions in sperm quality, elevated oxidative stress, increased DNA fragmentation, and severe testicular degeneration. qPCR analysis revealed upregulation of AhR expression in the RES group (fold change: +23.1%) and significant downregulation in the AhR¯ group (fold change: −72.6%), indicating differential modulation of AhR signaling pathways.

RES positively modulates AhR activity, safeguarding testicular structure and enhancing sperm quality through antioxidant and anti-apoptotic mechanisms. Conversely, AhR antagonism disrupts spermatogenesis, underscoring the receptor’s essential role in male fertility. These findings suggest the therapeutic potential of AhR-targeting agents like RES in ameliorating male reproductive dysfunctions associated with oxidative stress and xenobiotic exposure.

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