Frontiers in nutrition · 2026
Maternal copper levels moderate the neuroprotective effect of zinc on early childhood development: evidence from a birth cohort and proteomic profiling.
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Liu Chaoqun, Zhang Zhuoqing, Huang Mingtian, Cheng Hong, He Caitong, Zhou Likai, Zhang Yu, Zhang Jijie, Wei Sisi, Liang Tao, Yang Xiaobo
Аннотация
BACKGROUND & AIMS: The impact of maternal zinc-copper (Zn-Cu) homeostasis on offspring brain development remains underexplored. This study investigated the relationships between maternal zinc (Zn), copper (Cu), and the Cu/Zn ratio during mid-pregnancy and subsequent early childhood neurodevelopment, utilizing both a prospective birth cohort and an in vivo rodent model to elucidate the underlying biological mechanisms.
METHODS: This prospective cohort study recruited 725 mother-child pairs from the Guangxi Birth Cohort Study (GBCS). Multivariable linear regression models, restricted cubic splines (RCS), and formal interaction tests with stratified analyses were employed to evaluate the non-linear dose-response relationships and metal-metal interactions influencing the child's developmental quotient (DQ). To explore the underlying mechanisms and provide biological plausibility for the epidemiological findings, pregnant rats were divided into four dietary groups with varying Cu/Zn ratios. Offspring spatial cognitive behaviors were assessed via the Morris Water Maze (MWM), followed by high-throughput hippocampal proteomics.
RESULTS: Maternal Cu and the Cu/Zn ratio exhibited significant inverse non-linear associations with child neurodevelopment across multiple domains. Crucially, the neuroprotective potential of Zn was significantly moderated by maternal Cu status; Zn was positively associated with developmental scores under low Cu conditions, but this benefit was progressively attenuated at higher Cu levels. In the MWM test, despite comparable baseline spatial learning boundaries, the Medium Cu/Zn ratio group displayed significantly altered exploratory patterns during the spatial probe trials. Proteomic analysis revealed a universal downregulation of the glutamate transporter SLC1A3 and significant dysregulation of critical synaptic markers (including SYT1, KCC2, and MAP2) across all Cu/Zn imbalance groups.
CONCLUSIONS: The maternal mid-pregnancy Cu/Zn ratio is non-linearly associated with offspring neurodevelopment, potentially mediated by hippocampal synaptic protein alterations. These findings provide a preliminary conceptual framework advocating for personalized prenatal nutritional assessments, which should integrate dual-index monitoring and consider regional geochemical baselines to optimize intervention strategies.
METHODS: This prospective cohort study recruited 725 mother-child pairs from the Guangxi Birth Cohort Study (GBCS). Multivariable linear regression models, restricted cubic splines (RCS), and formal interaction tests with stratified analyses were employed to evaluate the non-linear dose-response relationships and metal-metal interactions influencing the child's developmental quotient (DQ). To explore the underlying mechanisms and provide biological plausibility for the epidemiological findings, pregnant rats were divided into four dietary groups with varying Cu/Zn ratios. Offspring spatial cognitive behaviors were assessed via the Morris Water Maze (MWM), followed by high-throughput hippocampal proteomics.
RESULTS: Maternal Cu and the Cu/Zn ratio exhibited significant inverse non-linear associations with child neurodevelopment across multiple domains. Crucially, the neuroprotective potential of Zn was significantly moderated by maternal Cu status; Zn was positively associated with developmental scores under low Cu conditions, but this benefit was progressively attenuated at higher Cu levels. In the MWM test, despite comparable baseline spatial learning boundaries, the Medium Cu/Zn ratio group displayed significantly altered exploratory patterns during the spatial probe trials. Proteomic analysis revealed a universal downregulation of the glutamate transporter SLC1A3 and significant dysregulation of critical synaptic markers (including SYT1, KCC2, and MAP2) across all Cu/Zn imbalance groups.
CONCLUSIONS: The maternal mid-pregnancy Cu/Zn ratio is non-linearly associated with offspring neurodevelopment, potentially mediated by hippocampal synaptic protein alterations. These findings provide a preliminary conceptual framework advocating for personalized prenatal nutritional assessments, which should integrate dual-index monitoring and consider regional geochemical baselines to optimize intervention strategies.