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  3. Prenatal exposure to environmental metal mixtures and social development in early childhood: Evidence from a birth cohort and mechanistic study

Prenatal exposure to environmental metal mixtures and social development in early childhood: Evidence from a birth cohort and mechanistic study

  • Environ Res. 2025 Oct 17:287:123154. doi: 10.1016/j.envres.2025.123154.
Susu Wang 1,  Tai Ren 1,  Yun Zhou 2,  Chunping Hu 3,  Xiaogang Yu 1,  Junxia Liu 1,  Xin Liu 1,  Kan Shao 2,  Yuanyuan Li 4,  Chong-Huai Yan 1,  Wei-Guang Li 5,  Fei Li 6
Affiliations

Affiliations

  • 1 Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
  • 2 Department of Environmental and Occupational Health, School of Public Health, Indiana University, Bloomington, IN, 47405, United States.
  • 3 Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Shaanxi, 710054, China; Shaanxi Key Laboratory of Spine Bionic Treatment, Shaanxi, 710054, China.
  • 4 Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 5 Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; Department of Rehabilitation Medicine, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China. Electronic address: feili@shsmu.edu.cn.
  • 6 Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China. Electronic address: liwg@fudan.edu.cn.
PMID: 41110787 DOI: 10.1016/j.envres.2025.123154
Abstract

Objectives: Neurodevelopmental disorders, particularly autism spectrum disorder (ASD), are increasingly linked to prenatal exposure to environmental heavy metal mixtures. This study aimed to evaluate the neurodevelopmental risks of such mixtures by integrating human cohort data, zebrafish behavioral assays, and omics analyses, thereby advancing mechanistic and mixture-based risk assessment frameworks.

Methods: We applied a multi-level design: (i) a prospective population-based cohort (Shanghai Birth Cohort, n = 941) assessing prenatal exposure to lead (Pb), cadmium (Cd), mercury (Hg), and arsenic (As) measured in cord blood, with neurodevelopmental outcomes evaluated at ages 2 and 4; (ii) embryonic zebrafish models (0-5 dpf) exposed to a human-relevant mixture (Mix N) to assess locomotor and social behaviors, as well as dose-response relationships; (iii) zebrafish transcriptomic and metabolomic analyses to uncover molecular mechanisms, with emphasis on lipid and steroid metabolism; and (iv) the Similar Mixture Approach (SMACH) integrating evidence across species for risk assessment.

Results: Mean cord blood concentrations of Pb, Cd, Hg, and As were 13.560, 0.051, 2.237, and 2.478 μg/L, respectively. Prenatal exposure to the mixture significantly impaired motor and social functions, with Pb contributing most to motor deficits and Cd to social dysfunction. Zebrafish assays confirmed dose-dependent decreases in locomotor activity and social preference. Integrated omics analyses identified substantial disruption of lipid and steroid metabolic pathways, particularly involving the Peroxisome Proliferator-activated Receptor (PPAR) signaling cascade. SMACH-based risk estimation suggested that over 51.7 % of children in the cohort may have experienced prenatal exposure levels associated with measurable neurodevelopmental risk.

Conclusions: Prenatal exposure to heavy metal mixtures may compromise early neurodevelopment via PPAR-mediated lipid metabolic dysregulation. These findings provide mechanistic evidence, highlight the vulnerability of early life to combined exposures, and support translational, mixture-informed frameworks for risk assessment and prevention.

Keywords

ASD-Like behaviors; Environmental heavy metal mixtures; Health risk assessment; Lipid metabolism; Neurodevelopment; PPAR signaling.

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