Histidine Metabolic Pathway Modifies the Relationships Between 6:2 Cl-PFESA Exposure and Preterm Birth

<b>Background</b>: Evidence linking chlorinated polyfluoroalkyl ether sulfonic acids (Cl-PFESAs) to preterm birth (PTB) is limited, and their relationships with the metabolome remain unexplored. <b>Aims:</b> Our study aimed to explore the role of the metabolome in the associations between Cl-PFESAs exposure and PTB. <b>Methods</b>: We conducted a nested case-control study in the Shenyang birth cohort, which included 206 spontaneous preterm birth cases and 206 full-term controls, matched for maternal age and pre-pregnancy BMI. We used conditional logistic regression models to analyze the associations between Cl-PFESAs exposure in umbilical cord blood and PTB. Moreover, the metabolomics of maternal blood (44 cases) between the preterm and control groups was analyzed using the interaction analysis. <b>Results</b>: We observed that a higher natural log-transformed 6:2 Cl-PFESA level was associated with greater odds of PTB in conditional multivariable-adjusted logistic regression models (OR = 1.738, 95% CI: 1.320, 2.287). The results of metabolomics pathway analysis showed that histidine metabolism pathways may modify the above risk. When stratified by histidine levels, the association between cord blood 6:2 Cl-PFESA and PTB was different. <b>Conclusions</b>: Intrauterine exposure to 6:2 Cl-PFESA was associated with increased PTB. Also, for the first time, our study illustrates that maternal plasma metabolite profiles may modify the associations of 6:2 Cl-PFESA with PTB. More research is needed to elucidate the mechanism underlying the reproductive toxicity of 6:2 Cl-PFESA in pregnant women following exposure.