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 RORA-AS1, PLCD3, 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.

目前，针对产前邻苯二甲酸酯（phthalate）暴露与瘦素（leptin）的关联，以及DNA甲基化（DNA methylation）的介导作用的相关研究仍较为匮乏。本研究依托一项中国出生队列开展，随访周期覆盖妊娠阶段至儿童早期。随访期间共纳入160对母婴完成检测，检测内容涵盖孕产妇三个孕期的尿液邻苯二甲酸酯浓度、脐血DNA甲基化水平，以及儿童血浆瘦素水平。本研究发现，孕产妇尿液中特定邻苯二甲酸酯代谢物水平与儿童早期血浆瘦素水平呈负相关，其中孕晚期的单(2-羧基丙基)酯（MiBP，校正百分比变化[95%置信区间（CI）]：-6.62 [-11.73, -1.22]）、孕中期的单正丁基邻苯二甲酸酯（MnBP，-7.81 [-14.26, -0.87]）、邻苯二甲酸二丁酯代谢物总和（ΣDBP，-9.62 [-16.77, -1.84]）以及低分子量邻苯二甲酸酯代谢物总和（ΣLMWP，-11.58 [-21.06, -0.96]）的关联尤为显著。同样，邻苯二甲酸酯混合暴露在孕中晚期也与儿童早期瘦素水平呈现更为显著的负相关。中介分析筛选出两个CpG位点（CpG）可显著介导邻苯二甲酸酯暴露与瘦素水平之间的关联，这些位点注释至RORA-AS1、PLCD3等基因。分子对接实验进一步证实，MiBP与DNA甲基转移酶（DNA methyltransferases）具有较强的结合亲和力与良好的空间互补性，为MiBP与DNA甲基化的关联提供了分子层面的理论依据。综上，孕产妇产前暴露于MiBP、MnBP、ΣDBP、ΣLMWP以及混合邻苯二甲酸酯，与儿童早期较低的血浆瘦素水平相关，其潜在机制可能与多位点DNA甲基化改变有关。