Chronic fluorosis can cause injury to the central nervous system. Since fat mass and obesity-associated protein (FTO) connected with demethylation of N6-methyladenosine (m6A) plays a crucial role in maintaining brain function, we examined whether FTO might help resist the neurotoxicity of fluoride. Sprague-Dawley rats with chronic fluorosis and cultured nerve cells exposed to fluoride with overexpression or knockdown of FTO were employed. Morris water maze test was employed to assess learning and memory. Expressions of FTO, m6A, postsynaptic density protein 95 (PSD95) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) and its subunit GluR2 mRNA stability, and apoptosis and reactive oxygen species (ROS) were determined by Western blotting, RT-PCR, and biochemical methods, respectively. The results showed that the impaired learning and memory of rats with chronic fluorosis, and the decreased FTO, PSD95 and AMPARs, the elevated m6A and the disrupted synapse morphology as well as apoptosis in their brains were determined. Similar abnormal changes were further confirmed in primary neurons and SH-SY5Y cells exposed to fluoride, accompanied by a significant decline of GluR2 and high ROS. Notably, overexpression of FTO reduced m6A, enhanced GluR2 and attenuated neurotoxicity induced by fluoride, while knockdown had the opposite effects. FTO can alleviate the neurotoxicity induced by fluoride, in which the mechanism may be involved in its regulating m6A to enhance expression of GluR2.
Zeng et al. (Wed,) studied this question.