Activation of lipophagy ameliorates cadmium-induced neural tube defects via reducing low density lipoprotein cholesterol levels in mouse placentas

TL;DR

This study shows that activating lipophagy in mouse placentas can reduce neural tube defects caused by cadmium exposure by lowering LDL cholesterol levels.

Contribution

The study reveals that lipophagy activation mitigates cadmium-induced NTDs by reducing LDL-C levels in placentas.

Findings

Cd exposure causes NTDs and increases LDL-C levels in maternal and fetal tissues.

Lipophagy activation reduces LDL-C levels and alleviates Cd-induced NTDs in mice.

Lrp1 gene downregulation is linked to elevated LDL-C in Cd-exposed placentas.

Abstract

Neural tube defects (NTDs) represent a prevalent and severe category of congenital anomalies in humans. Cadmium (Cd) is an environmental teratogen known to cause fetal NTDs. However, its underlying mechanisms remain elusive. This study aims to investigate the therapeutic potential of lipophagy in the treatment of NTDs, providing valuable insights for future strategies targeting lipophagy activation as a means to mitigate NTDs.We successfully modeled NTDs by Cd exposure during pregnancy. RNA sequencing was employed to investigate the transcriptomic alterations and functional enrichment of differentially expressed genes in NTD placental tissues. Subsequently, pharmacological/genetic (Atg5-/- placentas) experiments confirmed that inducing placental lipophagy can alleviate Cd induced-NTDs. We found that Cd exposure caused NTDs. Further analyzed transcriptomic data from the placentas with NTDs which revealed significant downregulation of low-density lipoprotein receptor associated protein 1(Lrp1) gene expression responsible for positive regulation of low-density lipoprotein cholesterol (LDL-C) transport. Correspondingly, there was an increase in maternal serum/placenta/amniotic fluid LDL-C content. Subsequently, we have discovered that Cd exposure activated placental lipophagy. Pharmacological/genetic (Atg5-/- placentas) experiments confirmed that inducing placental lipophagy can alleviate Cd induced-NTDs. Furthermore, our findings demonstrate that activation of placental lipophagy effectively counteracts the Cd-induced elevation in LDL-C levels. Lipophagy serves to mitigate Cd-induced NTDs by reducing LDL-C levels within mouse placentas.

The online version contains supplementary material available at 10.1007/s10565-024-09885-2.

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