Association of maternal multiple serum metal/metalloid concentrations and metabolic gene polymorphisms with offspring skeletal defects: a multicenter case-control study

Skeletal defects (SDs) can be caused by various factors, including genetic and environmental factors, as well as gene-environment interactions. This study aimed to investigate the association of maternal serum concentrations of metals/metalloids and metabolic gene polymorphisms with offspring SDs risk, including their potential interactions. In this multicenter case-control study, 316 pregnant women with offspring SDs and 361 healthy controls were recruited from 49 hospitals in China. Serum concentrations of aluminum (Al), iron (Fe), zinc (Zn), selenium (Se), strontium (Sr), molybdenum (Mo), and cadmium (Cd) were measured. Genotyping of 63 single nucleotide polymorphisms (SNPs) across 30 metal/metalloid metabolism-related genes was performed on first- and second-trimester blood samples. Associations were assessed using logistic regression and generalized multifactor dimensionality reduction. Median maternal serum concentrations of Fe, Zn, Sr, and Mo were significantly lower in cases than controls (all P < 0.001), while Cd was higher (P = 0.017). Higher (second/third tertile) concentrations of Fe, Zn, Sr, and Mo were associated with a decreased risk of offspring SDs. Notably, the protective association was strongest for Mo (adjusted odds ratio, aOR = 0.10–0.15). In contrast, higher concentrations of Se and Cd were associated with an increased risk (aOR = 2.04–2.43). No significant associations were found between maternal metabolic SNPs and offspring SDs risk after false discovery rate correction, and no significant gene-metal/metalloid interactions were observed. The lowered maternal serum concentrations of the essential trace elements Fe, Zn, and Mo, as well as of the non-essential element Sr, were associated with an increased risk of offspring SDs, with Mo showing a particularly strong protective association. Cd showed a positive association, though its interpretation warrants caution. Larger-scale and prospective cohort studies on the effects of maternal serum concentrations of metals/metalloids and genetic polymorphisms on offspring SDs are warranted.