Activation of Atg5-dependent placental lipophagy ameliorates cadmium-induced fetal growth restriction

Cadmium (Cd), an environmental contaminant, can result in placental non-selective autophagy activation and fetal growth restriction (FGR). However, the role of placental lipophagy, a selective autophagy, in Cd-induced FGR is unclear. This work uses case-control study, animal experiments and cultures of primary human placental trophoblast cells to explore the role of placental lipophagy in Cd-induced FGR. We found association of placental lipophagy and all-cause FGR. Meanwhile, pregnancy Cd exposure induced FGR and placental lipophgay. Inhibition of placental lipophagy by pharmacological and genetic means (Atg5-/- mice) exacerbated Cd-caused FGR. Inversely, activating of placental lipophagy relieved Cd-stimulated FGR. Subsequently, we found that activation of Atg5-dependent lipophagy degrades lipid droplets to produce free cholesterol, and promotes placental progesterone (P4) synthesis. Gestational P4 supplementation significantly reversed Cd-induced FGR. Altogether, activation of Atg5-dependent placental lipophagy ameliorates Cd-induced FGR.