Effects of neuron autophagy induced by arsenic and fluoride on spatial learning and memory in offspring rats

Abstract

There are numerous studies showing that exposure to arsenic (As) or fluoride (F) damages the nervous system, but there is no literature investigating the effects of combined As and F exposure to induce autophagy on neurotoxicity in the offspring. In this study, we developed a rat model of As and/or F exposure through drinking water from before pregnancy to 90 days postnatal. The offspring rats were randomly divided into nine groups. Sodium arsenite (NaAsO₂) (0, 35, 70 mg/L) and Sodium fluoride (NaF) (0, 50, 100 mg/L) were designed according to 3 × 3 factorial design. Our results suggested that the presence of F might antagonize the excretion of total As in urine, and As-F co-exposure led to severe pathological damage in brain tissue and reduced spatial learning and memory ability. At the same time, the experiments showed that As and F increased Beclin1 expression and LC3B ratio to activate autophagy; both P62 and Lamp2 expression were increased, suggesting that autophagy lysosomal degradation was blocked; SYN and JIP1 expression were significantly decreased, disrupting synaptic structure and function. Axonal autophagosome reverse transport regulation might be affected by combined As-F exposure, exacerbating neuronal synaptic damage and inducing neurotoxicity. Further analysis showed that there was an interaction between As and F exposure-induced changes in autolysosome-related proteins in the hippocampus, which showed antagonism, and the antagonism of the high As combined exposure groups were stronger than that of the low As combined exposure groups. In conclusion, our study showed that combined As and F exposure might induce reverse transport impairment of autophagy on axons, leading to autophagy defects, which in turn led to disruption of synaptic morphology and function, induced neurotoxicity, and there was an interaction between As and F, the type of its combined effect was antagonism.

Keywords: Arsenic; Autophagy lysosome; Fluoride; Interaction; Neurotoxicity.