Sex-Specific Mechanisms of Fluoride-Induced Gonadal Injury: A Multi-Omics Investigation into Reproductive Toxicity and Gut Microbiota Disruption
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Le résumé fourni par la source
Fluoride, a common agricultural additive used to enhance plant resilience and pest control, poses toxicity risks when exposure surpasses safe thresholds, affecting ecosystems and human health. While its reproductive toxicity is recognized, the sex-specific and cross-generational effects remain underexplored. To address this gap, we employed an integrative approach combining transcriptomics (next-generation sequencing (NGS)), bioinformatic network analysis, gut microbiota sequencing, and in vivo functional assays. ICR mice (F0 generation), both male and female, were exposed to fluoride (100 mg/L in drinking water) for 35 days, continuing through gestation and offspring weaning. Our transcriptomic analysis revealed significant upregulation of autophagy (via the PI3K-AKT-mTOR pathway) and oxidative stress-induced mitochondrial dysfunction in gonadal tissue, with more pronounced effects observed in males. Further integrated analyses of transcriptomic and metabolomic data, supported by in vivo experiments, highlighted oxidative stress, mitochondrial dysfunction, and PI3K-AKT-mTOR pathway activation with stronger effects in males. The principal component analysis confirmed sex-specific transcriptome alterations, with males showing more substantial disruption. Additionally, 16S rRNA sequencing identified significant gut dysbiosis, particularly in males, with an increased Firmicutes/Bacteroidetes ratio and higher abundances of Oscillospirales and Anaerovoracaceae . Moreover, our study identified significant correlations between specific gut microbiota (e.g., Firmicutes, Proteobacteria ) and autophagy, oxidative stress, and mitochondrial dysfunction pathways, with notable sex-dependent differences. These findings suggest that gut microbiota may play a critical role in modulating fluoride-induced reproductive toxicity, particularly through their effects on oxidative stress and cellular homeostasis. The breakdown of the gut barrier and elevated serum/gonadal lipopolysaccharide (LPS) levels in fluoride-treated mice further established a link between gut dysbiosis and fluoride-induced reproductive toxicity. These findings underscore the importance of considering sex differences in xenobiotic-induced reproductive and developmental toxicity.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Sex-Specific Mechanisms of Fluoride-Induced Gonadal Injury: A Multi-Omics Investigation into Reproductive Toxicity and Gut Microbiota Disruption
- Date Crossref
- 16/01/2025
- Éditeur
- American Chemical Society (ACS)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Henan University of Science and Technology pays non établi dans la noticeUniversité ou école supérieure
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Shiraz University of Medical Sciences Pharmaceutical Sciences Research Center pays non établi dans la noticeUniversité ou école supérieure
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Shiraz University pays non établi dans la noticeUniversité ou école supérieure
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Universidad Autónoma Metropolitana pays non établi dans la noticeUniversité ou école supérieure
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Shanxi Agricultural University pays non établi dans la noticeUniversité ou école supérieure
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College of Animal Science and Technology Henan Key Laboratory of Environmental and Animal Product Safety pays non établi dans la noticeUniversité ou école supérieure
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Shiraz Agricultural University Department of Animal Science pays non établi dans la noticeUniversité ou école supérieure
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Autonomous Metropolitan University Department of Biology of Reproduction pays non établi dans la noticeUniversité ou école supérieure
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College of Animal Science and Veterinary Medicine pays non établi dans la noticeUniversité ou école supérieure
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College of Veterinary Medicine pays non établi dans la noticeUniversité ou école supérieure
Henan University of Science and Technology, Pharmaceutical Sciences Research Center — Shiraz University of Medical Sciences et Shiraz University, avec 7 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.