Associations between metal/metalloid exposure during pregnancy and placental growth characteristics: Findings from the Hangzhou birth cohort study II

Previous studies have suggested that metal/metalloid (hereafter referred to as metal) exposure may influence placental growth by affecting gene expression in the placenta. However, no epidemiological studies have been conducted to validate the relationships between metals exposure, placental gene expression, and placental growth at the population level. This study aims to investigate these relationships based on Hangzhou birth cohort study II (HBCS-II). Totally, 1025 participants were derived from HBCS-II. Thirteen metals levels in the placenta were measured using inductively coupled plasma mass spectrometry. Placental growth characteristics were assessed, including placental weight, chorionic disc area, placental eccentricity, and distance from cord insertion site to the nearest edge of placenta (DCIEP). The relationships between metals exposure and placental growth characteristics were examined using the elastic net model combined unpenalized linear regression model. Placental gene expression levels were analyzed through RNA sequencing and real-time polymerase chain reaction (RT-qPCR), and mediation analysis was conducted to investigate whether placental gene expression could mediate the relationship between metal exposure and placental growth. Notably, the results showed that a unite increase in Ln-transformed cadmium (Cd) levels was associated with a reduction of 16.4 g [95% confidence interval (CI): 31.2, −1.5] in placental weight, 13.9 cm² (95%CI: 20.0, −7.8) in chorionic disc area, and 0.3 cm (95%CI: 0.55, −0.06) in DCIEP. Through RNA sequencing followed by validation, significant associations were observed between placental Cd level and increased expression of placental genes, including TNFAIP2, OLAH, FLT4, SH3PXD2A, LIMCH1, BCL6, SLCO2A1, and CPSF1. Additionally, increased placental TNFAIP2, OLAH, FLT4, SH3PXD2A and LIMCH1 expression was linked to reduced placental weight. Moreover, SH3PXD2A was associated with decreased chorionic disc area. Mediation analysis showed that placental Cd level was associated with a 12.0 g (95%CI: 23.8, −2.7) decrease in placental weight mediated through the upregulation of FTL4 gene expression. The study provides evidence of the association between placental Cd exposure and decreased placental weight, and the FLT4 gene may play a mediating role in this relationship. Future experiment studies should be performed to validate the results.