Role of low-dose cadmium exposure to the pathogenesis of gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is caused by the imbalance between insulin-resistance hormones and insulin secretion. The association between prenatal cadmium (Cd) exposure and GDM remains unclear. Furthermore, how Cd contributes to GDM, especially in the perspective of placental development, is largely unknown. In this study, we aimed to define the association of blood Cd concentrations with GDM incidence based on a birth cohort (462 GDM cases and 924 matched controls), and unravel the mechanism of low-dose Cd in GDM development by applying trophoblast organoids and syncytiotrophoblasts (STB) models. The results showed that the mean plasma Cd concentration during early pregnancy for GDM cases and controls were 0.37 and 0.12μg/l, respectively, and increasing Cd concentrations were associated with an increased risk of GDM (odds ratio = 2.15; 95%CI: 1.84, 2.50). 0.08μM (the 95th percentile plasma Cd concentration of the study cohort) Cd promoted WNT signaling and ACSM1 gene expression in STB, which facilitate the STB differentiation and fatty acid beta oxidation in mitochondria, respectively. Mitochondrial respiration capacity was increased upon Cd treatment, the main fuel of which was glucose, Insulin-resistance hormone synthesis was elevated in Cd treated STB, indicating that the resulting lipid substrate did not, or at least not mainly contribute to tricarboxylic acid cycle, but to steroid hormone production, which might promote the GDM development.