Prenatal Phthalate Exposure, Leptin in Early Childhood, and Mediating Role of DNA Methylation

Currently, research on the association of prenatal phthalate exposure with leptin, as well as the mediating role of DNA methylation, is insufficient. A birth cohort in China was conducted, followed by pregnancy to early childhood. During the follow-up period, measurements were conducted for 160 mother-child pairs, including maternal urinary phthalate concentrations in three trimesters, DNA methylation in cord blood, and leptin levels in children's plasma. The present study found that maternal urinary levels of specific phthalate metabolites, particularly MiBP (adjusted percent change [95% CI]; -6.62 [-11.73 to -1.22] in the third trimester], MnBP (adjusted percent change [95% CI]; -7.81 [-14.26 to -0.87] in the second trimester), ΣDBP (adjusted percent change [95% CI], -9.62 [-16.77 to -1.84] in the second trimester), and ΣLMWP (adjusted percent change [95% CI], -11.58 [-21.06 to -0.96] in the second trimester), were negatively associated with leptin levels in early childhood. Similarly, the phthalate mixture also showed a more prominent negative association with leptin levels in the second and third trimesters. Mediation analysis identified two CpGs that significantly mediated the association between phthalate exposure and leptin levels, annotated to genes including <i>RORA-AS1</i>, <i>PLCD3</i>, etc. Molecular docking further revealed that MiBP has a strong binding affinity and good spatial complementarity with DNA methyltransferases, providing a molecular basis for the association between MiBP and DNA methylation. In conclusion, prenatal exposure to MiBP, MnBP, ΣDBP, ΣLMWP, and mixed phthalates was associated with lower leptin levels in early childhood, possibly due to DNA methylation changes at multiple sites.