3-Acetyldeoxynivalenol induces pyroptosis in leydig cells via METTL3-mediated N6-methyladenosine modification of NLRP3
3-acetyldeoxynivalenol (3-ADON), an acetylated derivative of deoxynivalenol, is a prevalent contaminant found in food products contaminated with mycotoxins. While the toxicological effects of 3-ADON on human and animal health are well-documented, its specific impact on the reproductive system remain...
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Elsevier
2025-01-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651324016257 |
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| author | Yangyun Wang Chaoliang Shi Wei Jiao Xiaoxiang Wan |
| author_facet | Yangyun Wang Chaoliang Shi Wei Jiao Xiaoxiang Wan |
| author_sort | Yangyun Wang |
| collection | DOAJ |
| description | 3-acetyldeoxynivalenol (3-ADON), an acetylated derivative of deoxynivalenol, is a prevalent contaminant found in food products contaminated with mycotoxins. While the toxicological effects of 3-ADON on human and animal health are well-documented, its specific impact on the reproductive system remains underexplored. In this study, we comprehensively examined the toxicological effects of 3-ADON on TM3 Leydig cells through both in vivo and in vitro experimental models. Our results demonstrate that 3-ADON exposure leads to substantial testicular damage in vivo and significantly reduces cell viability while increasing mortality in TM3 cells in vitro (P = 0.012). Mechanistic investigations further revealed that 3-ADON exposure triggers pyroptosis in TM3 cells, as evidenced by upregulation of NLRP3, activation of caspase-1, ASC, and GSDMD. Moreover, 3-ADON treatment resulted in a significant upregulation of METTL3 expression and increased global mRNA m6A modification levels. m6A sequencing and functional assays established that METTL3-mediated m6A modification of NLRP3 mRNA enhances its stability and expression. RNA immunoprecipitation (RIP) assays further demonstrated that IGF2BP1 selectively recognizes m6A-modified NLRP3 mRNA, contributing to its stabilization. Notably, IGF2BP1 was found to inhibit the recruitment of the BTG2/CCR4-NOT complex by competitively binding to PABPC1, thereby preventing the deadenylation of NLRP3 mRNA and maintaining its expression. Additionally, we identified that METTL3 also methylates and stabilizes c-MyB mRNA, which subsequently binds to the promoter region of NLRP3, thereby enhancing its transcription. Collectively, our findings reveal a novel mechanism by which 3-ADON exerts its reproductive toxicity, underscoring the pivotal role of METTL3-mediated m6A modifications in regulating Leydig cell dysfunction. |
| format | Article |
| id | doaj-art-f6cbb1d3adb04edf8a2fc70ea115b2da |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-f6cbb1d3adb04edf8a2fc70ea115b2da2025-02-12T05:29:39ZengElsevierEcotoxicology and Environmental Safety0147-65132025-01-012901175493-Acetyldeoxynivalenol induces pyroptosis in leydig cells via METTL3-mediated N6-methyladenosine modification of NLRP3Yangyun Wang0Chaoliang Shi1Wei Jiao2Xiaoxiang Wan3Corresponding author.; Department of Urology, The Fifth People's Hospital of Shanghai, Fudan University, 200240, ChinaDepartment of Urology, The Fifth People's Hospital of Shanghai, Fudan University, 200240, ChinaDepartment of Urology, The Fifth People's Hospital of Shanghai, Fudan University, 200240, ChinaDepartment of Urology, The Fifth People's Hospital of Shanghai, Fudan University, 200240, China3-acetyldeoxynivalenol (3-ADON), an acetylated derivative of deoxynivalenol, is a prevalent contaminant found in food products contaminated with mycotoxins. While the toxicological effects of 3-ADON on human and animal health are well-documented, its specific impact on the reproductive system remains underexplored. In this study, we comprehensively examined the toxicological effects of 3-ADON on TM3 Leydig cells through both in vivo and in vitro experimental models. Our results demonstrate that 3-ADON exposure leads to substantial testicular damage in vivo and significantly reduces cell viability while increasing mortality in TM3 cells in vitro (P = 0.012). Mechanistic investigations further revealed that 3-ADON exposure triggers pyroptosis in TM3 cells, as evidenced by upregulation of NLRP3, activation of caspase-1, ASC, and GSDMD. Moreover, 3-ADON treatment resulted in a significant upregulation of METTL3 expression and increased global mRNA m6A modification levels. m6A sequencing and functional assays established that METTL3-mediated m6A modification of NLRP3 mRNA enhances its stability and expression. RNA immunoprecipitation (RIP) assays further demonstrated that IGF2BP1 selectively recognizes m6A-modified NLRP3 mRNA, contributing to its stabilization. Notably, IGF2BP1 was found to inhibit the recruitment of the BTG2/CCR4-NOT complex by competitively binding to PABPC1, thereby preventing the deadenylation of NLRP3 mRNA and maintaining its expression. Additionally, we identified that METTL3 also methylates and stabilizes c-MyB mRNA, which subsequently binds to the promoter region of NLRP3, thereby enhancing its transcription. Collectively, our findings reveal a novel mechanism by which 3-ADON exerts its reproductive toxicity, underscoring the pivotal role of METTL3-mediated m6A modifications in regulating Leydig cell dysfunction.http://www.sciencedirect.com/science/article/pii/S01476513240162573-AcetyldeoxynivalenolLeydig cellsPyroptosisMETTL3IGF2BP1NLRP3 |
| spellingShingle | Yangyun Wang Chaoliang Shi Wei Jiao Xiaoxiang Wan 3-Acetyldeoxynivalenol induces pyroptosis in leydig cells via METTL3-mediated N6-methyladenosine modification of NLRP3 Ecotoxicology and Environmental Safety 3-Acetyldeoxynivalenol Leydig cells Pyroptosis METTL3 IGF2BP1 NLRP3 |
| title | 3-Acetyldeoxynivalenol induces pyroptosis in leydig cells via METTL3-mediated N6-methyladenosine modification of NLRP3 |
| title_full | 3-Acetyldeoxynivalenol induces pyroptosis in leydig cells via METTL3-mediated N6-methyladenosine modification of NLRP3 |
| title_fullStr | 3-Acetyldeoxynivalenol induces pyroptosis in leydig cells via METTL3-mediated N6-methyladenosine modification of NLRP3 |
| title_full_unstemmed | 3-Acetyldeoxynivalenol induces pyroptosis in leydig cells via METTL3-mediated N6-methyladenosine modification of NLRP3 |
| title_short | 3-Acetyldeoxynivalenol induces pyroptosis in leydig cells via METTL3-mediated N6-methyladenosine modification of NLRP3 |
| title_sort | 3 acetyldeoxynivalenol induces pyroptosis in leydig cells via mettl3 mediated n6 methyladenosine modification of nlrp3 |
| topic | 3-Acetyldeoxynivalenol Leydig cells Pyroptosis METTL3 IGF2BP1 NLRP3 |
| url | http://www.sciencedirect.com/science/article/pii/S0147651324016257 |
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