GRP78/IRE1 and cGAS/STING pathway crosstalk through CHOP facilitates iodoacetic acid-mediated testosterone decline
Iodoacetic acid (IAA) is an emerging unregulated iodinated disinfection byproduct with high toxicity and widespread exposure. IAA has potential reproductive toxicity and could damage male reproduction. However, the underlying mechanisms and toxicological targets of IAA on male reproductive impairmen...
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Veröffentlicht in: | Journal of hazardous materials 2024-09, Vol.476, p.135101, Article 135101 |
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Zusammenfassung: | Iodoacetic acid (IAA) is an emerging unregulated iodinated disinfection byproduct with high toxicity and widespread exposure. IAA has potential reproductive toxicity and could damage male reproduction. However, the underlying mechanisms and toxicological targets of IAA on male reproductive impairment are still unclear, and thus Sprague-Dawley rats and Leydig cells were used in this work to decode these pending concerns. Results showed that after IAA exposure, the histomorphology and ultrastructure of rat testes were abnormally changed, numbers of Leydig cells were reduced, the hypothalamic-pituitary-testis (HPT) axis was disordered, and testosterone biosynthesis was inhibited. Proteomics analyses displayed that oxidative stress, endoplasmic reticulum stress, and steroid hormone biosynthesis were involved in IAA-caused reproductive injury. Antioxidant enzymes were depleted, while levels of ROS, MDA, 8-OHdG, and γ-H2A.X were increased by IAA. IAA triggered oxidative stress and DNA damage, and then activated the GRP78/IRE1/XBP1s and cGAS/STING/NF-κB pathways in Leydig cells. The two signaling pathways constructed an interactive network by synergistically regulating the downstream transcription factor CHOP, which in turn directly bound to and negatively modulated steroidogenic StAR, finally refraining testosterone biosynthesis in Leydig cells. Collectively, IAA as a reproductive toxicant has anti-androgenic effects, and the GRP78/IRE1 and cGAS/STING pathway crosstalk through CHOP facilitates IAA-mediated testosterone decline.
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•IAA damages testicular histomorphology and decreases Leydig cell numbers.•IAA disturbs the hypothalamic-pituitary-testis axis and reduces testosterone levels.•IAA activates the GRP78/IRE1 pathway and the cGAS/STING pathway in Leydig cells.•IAA triggers the GRP78/IRE1 and cGAS/STING pathway crosstalk through CHOP.•CHOP directly binds to and negatively regulates steroidogenic StAR in Leydig cells. |
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ISSN: | 0304-3894 1873-3336 1873-3336 |
DOI: | 10.1016/j.jhazmat.2024.135101 |