Quantitative relationships of FAM50B and PTCHD3 methylation with reduced intelligence quotients in school aged children exposed to lead: Evidence from epidemiological and in vitro studies

Abstract

At present, the application of DNA methylation (DNAm) biomarkers in environmental health risk assessment (EHRA) is more challenging due to the unclearly quantitative relationship between them. We aimed to explore the role of FAM50B and PTCHD3 at the level of signaling pathways, and establish the quantitative relationship between them and children's intelligence quotients (IQs). DNAm of target regions was measured in multiple cell models and was compared with the human population data. Then the dose-response relationships of lead exposure with neurotoxicity and DNAm were established by benchmark dose (BMD) model, followed by potential signaling pathway screening. Results showed that there was a quantitative linear relationship between children's IQs and FAM50B/PTCHD3 DNAm (DNAm between 51.40 % - 78.78 % and 31.41 % - 74.19 % for FAM50B and PTCHD3, respectively), and this relationship was more significant when children's IQs > 90. The receiver operating characteristic (ROC) and calibration curves showed that FAM50B/PTCHD3 DNAm had a satisfying accuracy and consistency in predicting children's IQs, which was confirmed by sensitivity analysis of gender and CpG site grouping data. In cell experiments, there was also a quantitative linear relationship between FAM50B DNAm and reactive oxygen species (ROS) production, which was mediated by PI3K-AKT signaling pathway. In addition, the lead BMD of ROS was close to that of FAM50B DNAm, suggesting that FAM50B DNAm was a suitable biomarker for the risk assessments of adverse outcomes induced by lead. Taken collectively, these results suggest that FAM50B/PTCHD3 can be applied to EHRA and the prevention/intervention of adverse effects of lead on children's IQs.