Environmental exposures associated with behavioral outcomes and their link to endogenous metabolites in children born very preterm
- 1Emory Rollins School of Public Health
Abstract
BackgroundChildren born very preterm (VPT) are at elevated risk for adverse neurobehavioral outcomes and are vulnerable to environmental exposures. We used untargeted metabolomics analysis to identify environmentally relevant metabolites associated with childhood behavioral problems and to characterize related endogenous metabolic pathways.
MethodsWe studied 226 children born <30 weeks gestation in a multi-site cohort study. Urine collected at age 4 was profiled using untargeted ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC-HRMS). Associations between 30 exogenous environmental metabolites and behavioral problems score at age 4 were evaluated cross-sectionally using multivariable linear regression, followed by metabolome-wide association and pathway enrichment analyses.
ResultsThree exogenous metabolites were nominally associated with child behavior problems. Specifically, 2-(Acetylamino)-3-(2henylthiol)propanoic acid was positively associated with overall ({beta}=1.42, p=0.006), externalizing ({beta}=1.50, p=0.006), and internalizing ({beta}=1.34, p=0.021) behavior problems. Diethofencarb was positively associated with overall ({beta}=0.34, p=0.018) and externalizing ({beta}=0.39, p=0.010) behavior problems, while protocatechuic acid was inversely associated with internalizing problems ({beta}=-0.68, p=0.027). No associations remained significant after false discovery rate (FDR) correction. Nevertheless, these metabolites were associated with 151, 131, and 530 endogenous metabolic features, respectively, at FDR<0.05, highlighting perturbations in lipid metabolism, mitochondrial energetics, inflammatory signaling, amino acid metabolism, and neuroactive pathways.
ConclusionsEnvironmental metabolites associated with behavior problems were linked to broad endogenous metabolic differences relevant to neurodevelopment. These findings highlight potentially modifiable environmental influences, including exposures related to combustion-derived pollutants, pesticides, and dietary sources, that may contribute to behavioral vulnerability among children born very preterm.
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BibTeX
@misc{patel2026environmental,
title = {{Environmental exposures associated with behavioral outcomes and their link to endogenous metabolites in children born very preterm}},
author = {P. Patel and Y. Tan and D. Liang and M. Camerota and C. Marsit and B. M. Lester and T. Everson},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.25.26364017},
url = {https://www.medrxiv.org/content/10.64898/2026.09.25.26364017v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Environmental exposures associated with behavioral outcomes and their link to endogenous metabolites in children born very preterm
AU - P. Patel
AU - Y. Tan
AU - D. Liang
AU - M. Camerota
AU - C. Marsit
AU - B. M. Lester
AU - T. Everson
PY - 2026
DA - 2026/09/25
PB - medRxiv
DO - 10.64898/2026.09.25.26364017
UR - https://www.medrxiv.org/content/10.64898/2026.09.25.26364017v1
AB - BackgroundChildren born very preterm (VPT) are at elevated risk for adverse neurobehavioral outcomes and are vulnerable to environmental exposures. We used untargeted metabolomics analysis to identify environmentally relevant metabolites associated with childhood behavioral problems and to characterize related endogenous metabolic pathways. MethodsWe studied 226 children born <30 weeks gestation in a multi-site cohort study. Urine collected at age 4 was profiled using untargeted ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC-HRMS). Associations between 30 exogenous environmental metabolites and behavioral problems score at age 4 were evaluated cross-sectionally using multivariable linear regression, followed by metabolome-wide association and pathway enrichment analyses. ResultsThree exogenous metabolites were nominally associated with child behavior problems. Specifically, 2-(Acetylamino)-3-(2henylthiol)propanoic acid was positively associated with overall ({beta}=1.42, p=0.006), externalizing ({beta}=1.50, p=0.006), and internalizing ({beta}=1.34, p=0.021) behavior problems. Diethofencarb was positively associated with overall ({beta}=0.34, p=0.018) and externalizing ({beta}=0.39, p=0.010) behavior problems, while protocatechuic acid was inversely associated with internalizing problems ({beta}=-0.68, p=0.027). No associations remained significant after false discovery rate (FDR) correction. Nevertheless, these metabolites were associated with 151, 131, and 530 endogenous metabolic features, respectively, at FDR<0.05, highlighting perturbations in lipid metabolism, mitochondrial energetics, inflammatory signaling, amino acid metabolism, and neuroactive pathways. ConclusionsEnvironmental metabolites associated with behavior problems were linked to broad endogenous metabolic differences relevant to neurodevelopment. These findings highlight potentially modifiable environmental influences, including exposures related to combustion-derived pollutants, pesticides, and dietary sources, that may contribute to behavioral vulnerability among children born very preterm.
ER -