Lead exposure induced transgenerational developmental neurotoxicity by altering genome methylation in Drosophila
Heavy metal toxicity is a worldwide health problem. Lead exposure is of particular concern due to the adverse effects of low concentrations on cognitive development in children. Although the mechanism of lead neurotoxicity has been well studied, the analysis and molecular mechanism of the transgenerational effects of lead exposure-induced neurotoxicity are lacking. To address this, Drosophila, a powerful developmental animal model, was exposed to lead acetate. We found that Pb exposure during the developmental stage affected the neurodevelopment of F0 fruit flies, resulting in a loss of the correlation between the motor terminal area and muscle fiber area and the increased frequency of ß-lobe midline crossing phenotype in Mushroom bodies. We also found that Pb exposure led to an increase in BRP expression, suggesting an increase in synaptic vesicle release sites and a decrease in synaptic vesicle protein SYN expression in F0 generation. This explained the results of our electrophysiological data that Pb exposure led to an increase in the amplitude of evoked excitatory junctional potential (EJP) and an increase in the frequency of spontaneous excitatory junctional potential (mEJP). Our results further confirmed that the developmental neurotoxicity of parental Pb exposure has a transgenerational effect. Neurodevelopmental defects, abnormalities in synaptic function, and repetitive behavior also were observed in the F3 offspring of F0 exposed to lead. Our Medip-seq analysis showed that Pb exposure altered the DNA methylation levels of many neurodevelopmentally associated genes (eg, hppy, nrg, baz, and spn) in the F3 offspring of the F0 generation with Pb exposure. Our findings suggest that epigenetic mechanisms may underlie the transgenerational inheritance of acquired phenotypic traits resulting from exposure to environmental factors. Overall design: To investigate the effect of lead exposure on the genome methylation ,we use MeDIPSeq to explore differentially enriched region between lead exposure group and control group.