Li Zeyu, Zhang Mingyu, Hong Xiumei, Wang Guoying, Choi Giehae, Nadeau Kari C, Buckley Jessie P, Wang Xiaobin
Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Environ Int. 2024 Dec;194:109144. doi: 10.1016/j.envint.2024.109144. Epub 2024 Nov 15.
Prenatal per- and polyfluoroalkyl substance (PFAS) exposures are associated with adverse offspring health outcomes, yet the underlying pathological mechanisms are unclear. Cord blood metabolomics can identify potentially important pathways associated with prenatal PFAS exposures, providing mechanistic insights that may help explain PFAS' long-term health effects.
The study included 590 mother-infant dyads from the Boston Birth Cohort. We measured PFAS in maternal plasma samples collected 24-72 h after delivery and metabolites in cord plasma samples. We used metabolome-wide association studies and pathway enrichment analyses to identify metabolites and pathways associated with individual PFAS, and quantile-based g-computation models to examine associations of metabolites with the PFAS mixture. We used False Discovery Rate to account for multiple comparisons.
We found that 331 metabolites and 18 pathways were associated with ≥ 1 PFAS, and 38 metabolites were associated with the PFAS mixture, predominantly amino acids and lipids. Amino acids such as alanine and lysine and their pathways, crucial to energy generation, biosynthesis, and bone health, were associated with PFAS and may explain PFAS' effects on fetal growth restriction. Carnitines and carnitine shuttle pathway, associated with 7 PFAS and the PFAS mixture, are involved in mitochondrial fatty acid β-oxidation, which may predispose higher risks of fetal and child growth restriction and cardiovascular diseases. Lipids, such as glycerophospholipids and their related pathway, can contribute to insulin resistance and diabetes by modulating transporters on cell membranes, participating in β-cell signaling pathways, and inducing oxidative damage. Neurotransmission-related metabolites and pathways associated with PFAS, including cofactors, precursors, and neurotransmitters, may explain the PFAS' effects on child neurodevelopment. We observed stronger associations between prenatal PFAS exposures and metabolites in males.
This prospective birth cohort study contributes to the limited literature on potential metabolomic perturbations for prenatal PFAS exposures. Future studies are needed to replicate our findings and link prenatal PFAS associated metabolomic perturbations to long-term child health outcomes.
产前全氟和多氟烷基物质（PFAS）暴露与不良的后代健康结局相关，但潜在的病理机制尚不清楚。脐血代谢组学可以识别与产前PFAS暴露相关的潜在重要途径，提供有助于解释PFAS长期健康影响的机制性见解。
该研究纳入了来自波士顿出生队列的590对母婴。我们测量了分娩后24 - 72小时收集的母体血浆样本中的PFAS以及脐血血浆样本中的代谢物。我们使用全代谢组关联研究和通路富集分析来识别与个体PFAS相关的代谢物和通路，并使用基于分位数的g计算模型来检验代谢物与PFAS混合物的关联。我们使用错误发现率来处理多重比较。
我们发现331种代谢物和18条通路与≥1种PFAS相关，38种代谢物与PFAS混合物相关，主要是氨基酸和脂质。丙氨酸和赖氨酸等氨基酸及其对能量生成、生物合成和骨骼健康至关重要的通路与PFAS相关，可能解释PFAS对胎儿生长受限的影响。肉碱和肉碱穿梭通路与7种PFAS和PFAS混合物相关，参与线粒体脂肪酸β氧化，这可能使胎儿和儿童生长受限以及心血管疾病的风险更高。脂质，如甘油磷脂及其相关通路，可通过调节细胞膜上的转运蛋白、参与β细胞信号通路和诱导氧化损伤来导致胰岛素抵抗和糖尿病。与PFAS相关的神经传递相关代谢物和通路，包括辅因子、前体和神经递质，可能解释PFAS对儿童神经发育的影响。我们观察到产前PFAS暴露与男性代谢物之间的关联更强。
这项前瞻性出生队列研究为关于产前PFAS暴露潜在代谢组学扰动的有限文献做出了贡献。未来需要进行研究来重复我们的发现，并将产前PFAS相关的代谢组学扰动与儿童长期健康结局联系起来。
