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

Authors：Yu-Feng Zhang , Hua-Long Zhu , Xiao-Feng Xu , Jin Zhang , Qing Ling, Shuang Zhang , Wei Chang , Yong-Wei Xiong , De-Xiang Xu , Hua Wang

Source：Environ Pollut. 2023 Jul 1;328:121602.

DOI: 10.1016/j.envpol.2023.121602.

Abstract：

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.

摘要：

环境污染物镉（Cd）可导致胎盘非选择性自噬激活和胎儿生长受限（FGR）。然而，胎盘噬脂（一种选择性自噬）在镉诱导的 FGR 中的作用尚不清楚。本研究利用病例对照研究、动物实验和原代人类胎盘滋养层细胞培养来探讨胎盘噬脂作用在 Cd 诱导的 FGR 中的作用。我们发现胎盘噬脂与全因FGR有关。同时，妊娠期镉暴露诱导FGR和胎盘噬脂。通过药物和基因手段（Atg5-/小鼠）抑制胎盘噬脂会加剧镉引起的FGR。相反，激活胎盘噬脂功能可缓解镉刺激的FGR。随后，我们发现 Atg5 依赖性噬脂作用的激活会降解脂滴以产生游离胆固醇，并促进胎盘孕酮（P4）的合成。妊娠期补充 P4 能明显逆转 Cd 诱导的 FGR。总之，激活Atg5依赖的胎盘噬脂作用可改善Cd诱导的FGR。