In-utero co-exposure to toxic metals and micronutrients on childhood risk of overweight or obesity: new insight on micronutrients counteracting toxic metals

Abstract

Background/objectives: Low-level, in-utero exposure to toxic metals such as lead (Pb) and mercury (Hg) is widespread in the US and worldwide; and, individually, was found to be obesogenic in children. To address the literature gaps on the health effects of co-exposure to low-level toxic metals and the lack of intervention strategy, we aimed to investigate the association between in-utero co-exposure to Hg, Pb, cadmium (Cd) and childhood overweight or obesity (OWO) and whether adequate maternal micronutrients (selenium (Se) and folate) can be protective.

Subjects/methods: This study included 1442 mother-child pairs from the Boston Birth Cohort, a predominantly urban, low-income, Black, and Hispanic population, who were enrolled at birth and followed prospectively up to age 15 years. Bayesian kernel machine regression (BKMR) was applied to estimate individual and joint effects of exposures to metals and micronutrients on childhood OWO while adjusting for pertinent covariables. Stratified analyses by maternal OWO and micronutrient status were performed to identify sensitive subgroups.

Results: In this sample of understudied US children, low-level in-utero co-exposure to Hg, Pb, and Cd was widespread. Besides individual positive associations of maternal Hg and Pb exposure with offspring OWO, BKMR clearly indicated a positive dose-response association between in-utero co-exposure to the three toxic metals and childhood OWO. Notably, the metal mixture-OWO association was more pronounced in children born to mothers with OWO; and in such a setting, the association was greatly attenuated if mothers had higher Se and folate levels.

Conclusions: In this prospective cohort of US children at high-risk of toxic metal exposure and OWO, we demonstrated that among children born to mothers with OWO, low-level in-utero co-exposure to Hg, Pb, and Cd increased the risk of childhood OWO; and that adequate maternal Se and folate levels mitigated the risk of childhood OWO.

Clinical trial registry number and website where it was obtained: NCT03228875.

Fig. 1.. Associations of toxic metal and micronutrient exposures with child OWO, stratified or combined by maternal pre-pregnancy OWO (N = 1442), using conventional regression analysis.

Adjusted for maternal age, BMI, race/ethnicity, marital status, education level, parity, breastfeeding type, smoking status, fish intake, child’s sex, low birthweight, and preterm status. (A) Children born to mothers without OWO (N=687). Children born to mothers with T1 biomarker were the reference groups. (B) Children born to mothers with OWO (N=755). Children born to mothers with T1 biomarker were the reference groups. (C) Children born to mothers without OWO with T1 biomarker were the reference groups. Refer to Table S4 and S5 for p-values.

Fig. 2.. Univariate dose-response function (95% Credible Intervals, CrIs) of toxic metal (Hg, Pb, Cd) and micronutrient (Se, folate) exposures with child overweight or obesity (OWO).

(A) Children born to mothers with OWO (N=755). (B) Children born to mothers without OWO (N=687). The univariate dose-response functions were assessed by fixing the remaining exposures at their median values and including maternal age, BMI, race/ethnicity, marital status, education level, parity, breastfeeding type, smoking status, fish intake, child’s sex, low birthweight, and preterm status as the covariates. The x-axis was limited to a range from −2 to 2, which reflects the z-score. Refer to the Supplement for the full range plot (Fig. S10). 95% CrIs are indicated by the shaded areas.

Fig. 3.. Bivariate dose-response function of toxic metal (Hg, Pb, Cd) and micronutrient (Se, folate) exposures on child overweight or obesity (OWO) among children born to mothers with OWO.

The bivariate dose-response function was obtained by plotting the dose-response function of a single predictor (exposure 1) when the second predictor (exposure 2) was fixed at various quantiles as labeled, while the remaining predictors were fixed to their median values. Maternal age, BMI, race/ethnicity, marital status, education level, parity, breastfeeding type, smoking status, fish intake, child’s sex, low birthweight, and preterm status were included as the covariates. The x-axis was limited to a range from −2 to 2, which reflects the z-score. Refer to the Supplement for the full range plot (Fig. S11).

Fig. 4.. Overall effect (95% Credible Intervals, CrIs) of toxic metals (Hg, Pb, Cd) on child overweight or obesity (OWO) among children born to mothers with OWO, stratified by maternal Se (Panel A) and folate levels (Panel B).

The overall effect (95% CrIs) of toxic metals (Hg, Pb, Cd) on child OWO is defined as the difference in the response when all the exposures are fixed at a specific quantile (ranging from 0.10 to 0.90), as compared to when all the exposures are fixed at their median value. Maternal age, BMI, race/ethnicity, marital status, education level, parity, breastfeeding type, smoking status, fish intake, child’s sex, low birthweight, and preterm status were included as the covariates. (A) Red group shows the overall effect on OWO risk among children whose mothers have OWO and have Se levels in T1, while the blue group shows the overall effect among children of mothers with OWO and with Se levels in T2–T3. (B) Red group shows the overall effect on OWO risk among children whose mothers have OWO and have folate levels in T1, while the blue group shows the overall effect among children of mothers with OWO and with folate levels in T2–T3. Note: Although the blue and red groups in (A) and (B) have the same quantiles (from 0.10 to 0.90), the blue group was slightly right-shifted to make the two sets of CrIs more clearly visible.