Exploring the associations between phthalate exposure and cardiometabolic risk factors clustering among children: The potential mediating role of insulin-resistant-related genes DNA methylation

The relationship between childhood phthalates (PAEs) exposure, DNA methylation, and cardiometabolic risk (CMR) factors is not well understood. Children were included from a longitudinal cohort 2018-2020 in Xiamen, China. A nest case-control study was additionally conducted, and methylation in lysyl oxidase-like 3 (LOXL3) and solute Carrier Family 6 Member 19 (SLC6A19) were measured. Generalized linear models were used to estimate the associations between PAEs exposure and CMR factors, and mediation analyses of DNA methylation were conducted. The longitudinal study included 835 children aged 7-11 years, and the nest case-control study included 120 cases and 120 controls. Exposure to high PAEs was correlated with increased CMR scores at baseline (β=0.299, 95%CI=0.114, 0.485) and the final visit (β=0.202, 95%CI=0.008, 0.397). In nest case-control study, higher mono-n-butyl phthalate (MnBP) exposure was related with elevated triglycerides (TG) (β=0.283, 95%CI=0.025, 0.540). A decrement of methylation of CpG 33.34 of LOXL3 was found in response to MnBP exposure (β=-0.014, 95%CI=-0.027, -0.001). Furthermore, increase methylation of LOXL3_CpG 33.34 and SLC6A19_CpG 11.12 was related to reduced TG. De-methylation of LOXL3_CpG 33.34 and SLC6A19_CpG 11.12 could mediate MnBP-TG pathways. Childhood exposure to PAEs was associated with increased CMR scores, and mediation of PAE exposure on childhood cardiometabolic health by LOXL3 and SLC6A19 de-methylation was observed. Phthalates (PAEs) are known to disrupt childhood health and can cause epigenetic changes. Positive associations between childhood PAEs exposure with increased cardiometabolic risk (CMR) factors scores were found in longitudinal survey. In the nested case-control study, the demethylation of insulin-resistant-related LOXL3 and SLC6A19, induced by PAEs exposure, partially mediated the impact of mono-n-butyl phthalate (MnBP) exposure on the increased triglycerides (TG). The present study provides epidemiological insights of the association between early PAEs exposure and childhood cardiometabolic health, and highlights the potential epigenetic role of DNA methylation in mediating these effects.