TET1 mitigates prenatal fluoride-induced cognition impairment by modulating Bcl2 DNA hydroxymethylation level.

Fluoride exposure during pregnancy commonly compromises fetal neurodevelopment and largely results in a broad spectrum of cognitive deficiencies in the adult offspring. However, the precise mechanisms underlying these effects remain to be fully elucidated. Herein, we investigate the impacts of fluoride on neural excitability and apoptosis, synaptic plasticity, and cognitive function, as well as possible underlying mechanisms. Our results indicated that exposure to a high sodium fluoride (100 mg/L) during pregnancy in the mouse can cause the cognitive deficits of their offspring, accompanied by a decrease in the expression of Tet-eleven translocation protein 1 (TET1), an enzyme responsible for DNA hydroxymethylation. Additionally, there is a reduction in the dendritic spine density and the expression of postsynaptic density protein-95 (PSD95) in the hippocampal regions of male offspring. Furthermore, in vitro fluoride treatment significantly exacerbates neuronal apoptosis and reduces the frequency of spikes in spontaneous action potential. More significantly, we also found that TET1 could directly bind to the promotor region of Bcl2, altering its DNA hydroxymethylation and Bcl2 expression. Intriguingly, Tet1 knock-out mice exhibited cognitive deficits similar to those observed in male animals exposed to high levels of fluoride. Furthermore, the down-regulation of TET1 protein, along with the consequent alteration in Bcl2 hydroxymethylation and increased neuronal apoptosis, are likely mechanisms underlying the impact of prenatal fluoride exposure on the neurodevelopment of male offspring. These findings provide novel insights into the molecular mechanisms by which fluoride exposure induces neurodevelopmental impairment of the male offspring.