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Fluoride-Induced Autophagy and Apoptosis in the Mouse Ovary: Genomic Insights into IL-17 Signaling and Gut Microbiota Dysbiosis.
| Journal of Agricultural and Food Chemistry | Ommati MM, Zuo Q, Sabouri S, Retana-Marquez S, Nategh Ahmadi H, Gholami A, Eftekhari A, Shojaei S, Lijuan L, Heidari R, Wang HW. |
Autophagy Developmental toxicity Apoptosis Ovary/Uterus Reproductive Toxicity Animal Study

Abstract

Chronic fluoride (F) exposure is linked to gonadotoxicity in females, yet the underlying molecular mechanisms remain unclear. This study investigated fluoride-induced reprotoxicity using advanced genomic profiling. RNA-seq analysis identified significant activation of autophagy, apoptosis, and IL-17 signaling pathways in fluoride-exposed female mice. To explore these mechanisms, F0 pregnant mice were exposed to deionized water (control) or 100 mg/L sodium fluoride (NaF) during gestation and throughout the F1 generation (n = 16 females/group), covering puberty to weaning and maturity. NaF exposure caused significant reductions in body weight, organ coefficients, and pathological indices, with increased ovarian autophagic vacuoles, mitochondrial injuries, and elevated serum/ovary LPS levels in F1 females. qRT-PCR, fluorescent staining, biochemical assays, and Western blotting confirmed the activation of IL-17 signaling, apoptosis, and autophagy. Moreover, 16S rRNA sequencing revealed gut microbiota dysbiosis in NaF-exposed F1 females, potentially exacerbating ovary injury via serum LPS elevation. The gut dysbiosis could justify deteriorated serum LPS levels and its connection to F-induced ovary injury. These findings provide mechanistic insights into fluoride-induced reprotoxicity, emphasizing the interplay of IL-17 signaling, autophagy, and apoptosis in disrupting cellular homeostasis and suggesting potential therapeutic targets.

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Supporting Information
Click to copy section link https://pubs.acs.org/doi/10.1021/acs.jafc.4c10165#_i25

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jafc.4c10165.

  • Table S1: Primer sequences used for RT-PCR. Figure S1: Experimental design schematic for animal studies. Figure S2: Metrics in F1-fluorosis female mice, including body weight, ovarian organ coefficient, and lipopolysaccharide levels. Figure S3: Serum and ovary fluoride levels in control and NaF-exposed mice. Figure S4: Overlap of gene sets, GO annotation analysis, and transcriptomic sample correlation in NaF-induced reprotoxicity. Figure S5: Collinearity and correlation analysis of gut microbiota at the phylum level in NaF-exposed mice. Figure S6: Graphical Abstract – Overview of Fluoride-Induced Autophagy, Apoptosis, IL-17 Signaling, and Gut Microbiota Dysbiosis in Ovary (PDF)
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