The manuscript of Wei CF et al.1 presents an ambitious and timely investigation of prenatal exposure to multiple metals and their potential interactions with genetic variants in relation to birth size, grounded in folate metabolism as a central biological pathway underlying the study hypothesis. This work aligns with the growing scientific interest in environmental mixtures, the developmental origins of health and disease, and gene–environment interactions. Using data from the Taiwan Birth Panel Study (TBPS), the authors analyzed 324 mother–infant pairs with cord blood measurements of 16 metals, including essential metals (zinc [Zn], molybdenum [Mo], copper [Cu], manganese [Mn], selenium [Se], and cobalt [Co]) and non-essential metals (arsenic [As], barium [Ba], beryllium [Be], cadmium [Cd], gallium [Ga], mercury [Hg], lead [Pb], antimony [Sb], thorium [Th], and uranium [U]), in relation to anthropometric outcomes at birth (birth weight, birth length, and head circumference). The study further examines interactions with 13 biologically selected single nucleotide polymorphisms related to fetal growth, folate metabolism, and metal processing, including rs1801133 (MTHFR), rs2236225 (MTHFD1), rs1805087 (MTR), rs1801394 (MTRR), rs234714 (CBS), rs4911259 (DNMT3B), rs4680 (COMT), rs1979277 (SHMT1), rs10830963 (MTNR1B), rs1351394 and rs1042725 (HMGA2), rs6845999 (HHIP), and rs905938 (ZBTB7B). Analytical approaches for the statistical analysis include multivariable linear regression, Bayesian kernel machine regression (BKMR), and quantile g-computation (QGC), which are well-suited to addressing the complexity of correlated metal mixtures.

While the literature on gene–metal interactions and birth size remains limited, prior studies have reported effect modification of prenatal Hg–birth weight associations by GST polymorphisms.2 In this context, the present study contributes to the limited evidence by extending gene–environment interaction research to a broader set of metals and genetic pathways relevant to fetal growth. Overall, the manuscript reports several notable findings, including opposing associations of prenatal Ba and Zn exposures with birth size, highlighting the contrasting effects of essential and non-essential metals during fetal development. Beyond single-metal analyses, the study further identifies multiple gene–metal interactions influencing birth size, particularly involving Co and genetic variants related to folate and metal metabolism, as well as genotype-specific effects of metal mixtures on birth size. By integrating mixture modeling with gene–environment interaction analyses, the study moves beyond single-exposure approaches and provides methodologically and conceptually thought-provoking insights relevant to precision-oriented research on prenatal metal-related exposure.