Fluoride induces spermatocyte apoptosis by IP3R1/MCU-mediated mitochondrial calcium overload through MAMs.
Level 5 - mechanism / opinion, no new human data
Preclinical in vivo animal and in vitro cell culture study with no human data.
PubMed 39929132 · doi:10.1016/j.jhazmat.2025.137514
What was done
Mice were exposed to sodium fluoride (NaF) at 25, 50, and 100 mg/L for 60 days, and GC-2spd cells were treated with 1.5, 2.0, and 2.5 mM NaF for 24 hours. Researchers conducted mitochondrial stress tests to assess respiration and ATP production. They evaluated endoplasmic reticulum (ER)-mitochondria contacts, mitochondrial calcium levels, and protein expression associated with mitochondria-associated ER membranes (MAMs) and apoptosis (IP3R1, GRP75, VDAC1, MCU, MFN1, MFN2, VAPB, PTPIP51, Cytochrome C, and Caspase-3). In vitro rescue experiments used the MCU inhibitor Ru360 and IP3R1 siRNA.
What was found
Fluoride exposure led to significant reductions in basal respiration, maximal respiration, and ATP production. It significantly increased ER-mitochondria contacts, mitochondrial calcium levels, and expression of IP3R1, GRP75, VDAC1, MCU, Cytochrome C, and Caspase-3, while decreasing MFN1, MFN2, VAPB, and PTPIP51. Intervention with Ru360 or IP3R1 siRNA restored mitochondrial membrane potential and reduced mitochondrial calcium levels and apoptosis. Exact numerical values, percentage changes, and baseline figures were not reported in the abstract.
Why it matters
The findings outline a specific mechanism—calcium transfer via the IP3R1-GRP75-VDAC1-MCU axis at MAMs—driving fluoride-induced spermatocyte apoptosis, pointing to potential molecular targets for addressing fluorosis-related reproductive toxicity.
Limits
The study is restricted to mouse models and an immortalized cell line, limiting direct translation to human reproductive health. The abstract does not disclose sample sizes (animal counts or assay replicates), effect sizes, or confidence intervals. In vitro fluoride concentrations may not reflect in vivo tissue exposures.
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