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Although lead associated with intelligence decline in children has long been reported, studies combining intelligence determination, molecular mechanisms exploration, and biomarker screen are quite rare. In this study, based on 333 children aged 9-11, we determined the role of DNA methylation (DNAm) in the relationship of lead exposure with children's intelligence. DNAm was measured from children's blood DNA specimens, and mediation analysis was performed to identify DNAm biomarkers mediating the lead-intelligence relationship. We identified forty-three differentially methylated regions (DMRs), and two fragments ( FAM50B1 and PTCHD3 ) significantly mediated the lead-intelligence relationship, with contribution rates of 30.36% ( p = 0.010) and 60.36% ( p &lt; 0.001), respectively. In addition, blood lead levels (BLLs) lower than 100 μg/L still adversely affected children's IQs and DNAm of the two fragments. Our data suggests that DNAm mediates lead-associated cognitive delay in children and blood lead reference value for school-aged children (100 μg/L) should be revised, and the candidate biomarkers can be used in related neurological diseases in future.

DNA Methylation Biomarkers of IQ Reduction are Associated with Long-term Lead Exposure in School Aged Children in Southern China