Effects of low-level lead exposure on hematological parameters and the possible underlying mechanisms

Lead (Pb) is a pervasive hematotoxicant without safety exposure limits. However, the hematological effects and mechanisms of low-level Pb exposure have not yet been much investigated. To systematically elucidate the effects of low-level Pb exposure on hematological parameters and to further explore the underlying mechanisms. We recruited 41545 low-level Pb-exposed occupational subjects (among which, 767 had been included in a detailed substudy, and 4407 had been followed up to establish a cohort), along with 816 coke oven workers and 160 community adults. We first evaluated the cross-sectional and longitudinal associations of Pb exposure with hematological parameter-related outcomes. Then, we used RNA sequencing technology and mediation analysis to explore the possible mechanisms of gene expression and related biologic processes in Pb hematotoxicity. We consistently observed a positive association of Pb exposure with hemoglobin (Hb) in all cross-sectional studies (P < 0.05). We further found that in cohort study, 1-standard deviation (SD) increase in whole blood Pb (Bpb) was associated with 0.080-SD elevation in Hb change levels and 186.5% increased risk of clinically-abnormal Hb elevation, respectively (P < 0.001). These effects were significantly influenced by age and sex (P_interaction< 0.030). We further identified 369 mRNAs associated with both Pb and Hb (false discovery rate-adjusted P < 0.1), and found that their genes were mainly enriched in genetic damage-related pathways. Among multiple genetic damage biomarkers, 8-hydroxy-2-deoxyguanosine (8-OHdG) mediated 15.80% of the Pb-Hb association (P < 0.05). Further serial-multiple mediation analysis suggested two significant paths: Pb→DOCK2/PLEKHM3→8-OHdG→Hb, which accounted for 11.36% and 14.39% of total effect size, respectively. Low-level Pb exposure might induce increases in Hb levels by upregulating the expressions of DOCK2 and PLEKHM3 and influencing oxidative DNA damage, suggesting the hematologic toxicity of low-level Pb exposure and potential mechanisms that are worthy of further investigation.