Early-life metal exposure and child growth and development

Cadmium, lead and arsenic are toxic metals, the exposure to which occurs primarily through food and drinking water. While many studies are available about their health effects in adults, studies in children and adolescents are more limited, especially for cadmium. The overall aim of this thesis was to assess if early-life metal exposure, especially cadmium, but also lead and arsenic, may affect children’s growth and pubertal development at school-age.

This research was conducted in a large mother-child cohort in a rural area called Matlab, in southern Bangladesh. The cohort was nested in a randomized food and micronutrient supplementation trial called MINIMat (Maternal and Infant Intervention, Matlab), which was established in 2001-2003. Women were recruited during early pregnancy and their children were followed up repeatedly from birth up to the age of 15 years. Urine and/or blood samples were collected from the mothers during pregnancy and from the children at several time points to assess their exposure to metals and to measure various health-related biomarkers. The children’s weight and height were measured during infancy, childhood and adolescence, and pubertal development in late childhood and adolescence.

In Paper I, we investigated if early-life cadmium exposure was associated with changes in bone-related biomarkers at 9 years of age (n=504), as cadmium has been linked to bone toxicity in adults. Using adjusted linear regression analyses, we found that both children’s urinary cadmium (reflecting life-long exposure) and erythrocyte cadmium (reflecting the last few months) were associated with decreased levels of vitamin D3, a hormone involved in calcium homeostasis and with importance for bone mineralization. We also observed that childhood cadmium exposure was associated with changes in biomarkers of bone remodeling. Urinary cadmium was associated with an increase of both osteocalcin (biomarker of bone formation) and urinary deoxypyridinoline (DPD, biomarker of bone resorption). Interestingly, when stratifying the models by gender, we found that urinary cadmium was associated with an increase of osteocalcin in girls, but with a decrease of osteocalcin in boys, suggesting a dysregulation of the feedback mechanisms in bone remodeling in boys.

We also observed a tendency of an inverse association between urinary cadmium and weight-for-age Z-score (WAZ) at 9 years, but the confidence intervals were wide. Therefore, in order to ascertain this association, we investigated this in a larger subset of children in the MINIMat cohort in Paper II (n=1530). We also explored associations with the children’s lead and arsenic exposure. In this larger sample, we found that concurrent urinary cadmium was inversely associated with WAZ and possibly also with height-for-age Z-score (HAZ) at 10 years, and that the associations were stronger in boys. We also found that short-term lead exposure, measured in urine, was associated with decreased WAZ and HAZ in boys, while neither maternal nor childhood arsenic exposure was associated with any measure of size, despite a very large variation in the arsenic exposure. In longitudinal analyses from birth to 10 years, we found that maternal erythrocyte cadmium in early pregnancy was associated with decreased WAZ in boys.

As cadmium and lead are reported endocrine disruptors, we investigated if the exposure to these two metals was associated with changes of timing of menarche in girls in Paper III (n=935). Using survival analysis, we observed that an increased exposure to cadmium during childhood was associated with a delay in menarche. The potential impact of lead was less clear.

To conclude, this research provides important evidence that early-life exposure to dietary cadmium can adversely affect child growth and pubertal development at exposure levels relevant for millions of children around the world. This emphasizes the need for further research in children and adolescents and that research on children should be considered in updates of the international health risk assessment of cadmium.

List of scientific papers

I. Malin Igra A, Vahter M, Raqib R, Kippler M. Early-Life Cadmium Exposure and Bone-Related Biomarkers: A Longitudinal Study in Children. Environmental Health Perspectives. 2019 Mar;127(3):37003.
https://doi.org/10.1289/EHP3655

II. Malin Igra A, Warnqvist A, Rahman SM, Ekström EC, Rahman A, Vahter M, Kippler M. Environmental metal exposure and growth to 10 years of age in a longitudinal mother-child cohort in rural Bangladesh. Environment International. 2021 Nov;156:106738.
https://doi.org/10.1016/j.envint.2021.106738

III. Malin Igra A, Rahman A, Johansson ALV, Pervin J, Svefors P, El Arifeen S, Vahter M, Persson LÅ, Kippler M. Early-life environmental exposure to cadmium and lead and age at menarche: a longitudinal mother-child cohort study in Bangladesh. [Submitted]