Cadmium inhibits differentiation of human trophoblast stem cells into extravillous trophoblasts and disrupts epigenetic changes within the promoter region of the HLA-G gene.

Cadmium (Cd) is a toxic heavy metal widely distributed in the environment. Maternal whole-blood Cd levels during pregnancy are positively associated with the risk of early preterm birth. We hypothesized that Cd inhibits trophoblast differentiation, resulting in the development of hypertensive disorders of pregnancy and a high risk of early preterm birth. Using the CT27 human trophoblast stem cell line, we found that exposing these cells to 0.1-0.4 µM Cd inhibited their differentiation into extravillous cytotrophoblasts (EVTs). Supporting this finding, we found that expression of the metal-binding protein metallothionein, which suppresses the toxicity of Cd, is low in EVTs. We also found that Cd exposure changes the methylation status of the promoter region of the HLA-G gene, which is specifically expressed in EVTs. Together, these results suggest that Cd inhibits placental formation by suppressing trophoblast differentiation into EVTs. This suppression may underlie the increased risk of gestational hypertension in women with high whole-blood Cd levels.