Prenatal Exposure to Chemical Mixtures and Metabolic Syndrome Risk in Children

Abstract

Importance: Prenatal exposure to ubiquitous endocrine-disrupting chemicals (EDCs) may increase the risk of metabolic syndrome (MetS) in children, but few studies have studied chemical mixtures or explored underlying protein and metabolic signatures.

Objective: To investigate associations of prenatal exposure to EDC mixtures with MetS risk score in children and identify associated proteins and metabolites.

Design, setting, and participants: This population-based, birth cohort study used data collected between April 1, 2003, and February 26, 2016, from the Human Early Life Exposome cohort based in France, Greece, Lithuania, Norway, Spain, and the UK. Eligible participants included mother-child pairs with measured prenatal EDC exposures and complete data on childhood MetS risk factors, proteins, and metabolites. Data were analyzed between October 2022 and July 2023.

Exposures: Nine metals, 3 organochlorine pesticides, 5 polychlorinated biphenyls, 2 polybrominated diphenyl ethers (PBDEs), 5 perfluoroalkyl substances (PFAS), 10 phthalate metabolites, 3 phenols, 4 parabens, and 4 organophosphate pesticide metabolites measured in urine and blood samples collected during pregnancy.

Main outcomes and measures: At 6 to 11 years of age, a composite MetS risk score was constructed using z scores of waist circumference, systolic and diastolic blood pressures, triglycerides, high-density lipoprotein cholesterol, and insulin levels. Childhood levels of 44 urinary metabolites, 177 serum metabolites, and 35 plasma proteins were quantified using targeted methods. Associations were assessed using bayesian weighted quantile sum regressions applied to mixtures for each chemical group.

Results: The study included 1134 mothers (mean [SD] age at birth, 30.7 [4.9] years) and their children (mean [SD] age, 7.8 [1.5] years; 617 male children [54.4%] and 517 female children [45.6%]; mean [SD] MetS risk score, -0.1 [2.3]). MetS score increased per 1-quartile increase of the mixture for metals (β = 0.44; 95% credible interval [CrI], 0.30 to 0.59), organochlorine pesticides (β = 0.22; 95% CrI, 0.15 to 0.29), PBDEs (β = 0.17; 95% CrI, 0.06 to 0.27), and PFAS (β = 0.19; 95% CrI, 0.14 to 0.24). High-molecular weight phthalate mixtures (β = -0.07; 95% CrI, -0.10 to -0.04) and low-molecular weight phthalate mixtures (β = -0.13; 95% CrI, -0.18 to -0.08) were associated with a decreased MetS score. Most EDC mixtures were associated with elevated proinflammatory proteins, amino acids, and altered glycerophospholipids, which in turn were associated with increased MetS score.

Conclusions and relevance: This cohort study suggests that prenatal exposure to EDC mixtures may be associated with adverse metabolic health in children. Given the pervasive nature of EDCs and the increase in MetS, these findings hold substantial public health implications.

Figure 1.. Metabolic Syndrome (MetS) Risk and Estimated Posterior Weights of Exposure Mixture Groups on MetS Risk Score Using the Bayesian Weighted Quantile Sum Regression

Panel A shows β coefficient and 95% credible intervals for child MetS per quartile increase in prenatal chemical mixtures. Panel B shows the estimated posterior weights with 95% credible intervals (CrIs; presented as error bars) for MetS risk. Weights represent the relative contribution of each chemical to the overall group association. Within a chemical mixture group, the estimated weights total 1. Dotted horizontal lines indicate expected weights if all chemicals within a group contributed equally to the mixture. All models were adjusted for subcohort, parental country of birth, maternal age, maternal education level, maternal prepregnancy body mass index, parity, maternal smoking in pregnancy, and maternal fish intake in pregnancy. As indicates, inorganic arsenic; BPA, bisphenol A; BUPA, N-butyl paraben; Cd, cadmium; Co, cobalt; Cs, caesium; Cu, copper; DDE, dichlorodiphenyldichloroethylene; DDT, dichlorodiphenyltrichloroethane; DEP, diethyl phthalate; DETP, diethylthiophosphate; DMP, dimethyl phthalate; DMTP, dimethylthiophosphate; ETPA, ethyl paraben; HCB, hexachlorobenzene; Hg, total mercury; HMWPs, high-molecular weight phthalates; LMWPs, low-molecular weight phthalates; MBzP, monobenzylphthalate; MECPP, Mono-(2-ethyl-5-carboxypentyl) phthalate cyclodiphosphate; MEHHP, mono(2-ethyl-5-hydroxyhexyl) phthalate; MEHP, mono-2-ethylhexyl phthalate; MEOHP, mono(2-ethyl-5-oxohexyl) phthalate; MEP, monoethyl phthalate; MEPA, methyl paraben; MiBP, mono-iso-butyl phthalate; Mn, manganese; MnBP, mono-n-butyl phthalate; Mo, molybdenum; OC, organochlorine; oh-MiNP, mono-hydroxy-isononyl phthalate; OP, organophosphate; OXBE, oxybenzone; oxo-MiNP, mono-oxo-isononyl phthalate; Pb, lead; PBDEs, polybrominated diphenyl ethers; PCBs, polychlorinated biphenyls; PFAS, perfluoroalkyl substances; PFHxS, perfluorohexane sulfonate; PFNA, perfluorononanoic acid; PFOA, perfluoro-octanoic acid; PFOS, perfluoro-octane sulfonate; PFUNDA, perfluoroundecanoic acid; PRPA, propyl paraben; and TRCS, triclosan.

Figure 2.. Associations of Prenatal Chemical Mixtures With Metabolic Syndrome (MetS) Score Stratified by Sex

The dots denote the β estimate for MetS score per quartile increase in prenatal endocrine-disrupting chemical mixture exposure and the bars denote the 95% credible intervals from bayesian weighted quantile sum regression models. The horizontal dashed line at 0 line indicates the null. All models were adjusted for subcohort, parental country of birth, maternal age, maternal education level, maternal prepregnancy body mass index, parity, maternal smoking in pregnancy, and maternal fish intake in pregnancy. HMWPs indicate high-molecular-weight phthalates; LMWPs, low-molecular-weight phthalates; PBDEs, polybrominated diphenyl ethers; PCBs, polychlorinated biphenyls; PFASs, perfluoroalkyl substances; OC, organochlorine; OP, organophosphate.

Figure 3.. Scatterplot of Selected Proteins and Metabolites Associated With at Least 1 Prenatal Chemical Mixture and Child Metabolic Syndrome (MetS) Risk Score

Each point corresponds to a protein or serum or urine metabolites. The x-axis shows the β coefficient of the associations of prenatal mixture with child omics expressed as percent change of omics levels per quartile increase of the exposure mixture (only associations with a % change >5% are shown). The y-axis shows the β coefficient of the associations of child omics with child MetS risk score expressed per doubling of omics levels. This analysis has been restricted to chemical mixtures significantly associated with MetS risk. Dotted vertical and horizontal lines denote the null. All models were adjusted for subcohort, parental country of birth, maternal age, maternal education level, maternal prepregnancy body mass index, parity, maternal smoking in pregnancy, and maternal fish intake in pregnancy. α-AAA indicates alpha-aminoadipic acid; APO, apolipoprotein; Asp, aspartate; C, acylcarnitines; CRP, C reactive protein; HMWPs, high-molecular-weight phthalates; Glu, glutamate; IL, interleukin; Ile, isoleucine; IL-1RA, interleukin 1 receptor antagonist; Leu, leucine; LMWPs, low-molecular-weight phthalates; LysoPC, lysophosphatidylcholines; MCP1, monocyte chemoattractant protein-1; Met.SO, methionine sulfoxide; OCs, organochlorines; PBDEs, polybrominated diphenyl ethers; PC, phosphatidylcholine; PFASs, perfluoroalkyl substances; SDMA, symmetric dimethylarginine.