Lithium carbonate exposure disrupts neurodevelopment by perturbing primary cilia and ER homeostasis

Abstract

Lithium, which is widely used in medicine and batteries, has become increasingly prevalent in the environment, raising concerns about its impact on human health. Lithium carbonate (Li2CO3) is a common treatment and relapse prevention method for bipolar disorder. It can freely cross the placental barrier; however, lithium treatment is accompanied by side effects, particularly in women of reproductive age. Among these, neural tube defects (NTDs) have the most severe impact on nervous system development; however, their underlying mechanisms remain unclear. This study explored the potential mechanisms by which Li2CO3 exposure contributes to NTDs. Pregnant mice were intraperitoneally injected with Li2CO3 (360 mg/kg), which mimicked high-exposure scenarios such as an unintended pregnancy during lithium therapy or exposure to industrial contamination. Embryos were assessed for morphological changes, primary cilia length, and endoplasmic reticulum (ER) homeostasis using histological analysis, scanning electron microscopy, PCR array analysis, immunofluorescence, and quantitative real-time PCR. Network and bioinformatics analyses were used to identify primary molecular targets and pathways. We also evaluated the effects of inositol supplementation on cilia during Li2CO3 exposure. The results revealed that treatment with Li2CO3 at 360 mg/kg induced exencephaly in some embryos, reduced primary cilia length, and dysregulated cilia-associated gene expression in the neural tube. PCR Array, network metabolism, and immunofluorescence analyses revealed that HSP90AB1, a critical regulator of ER homeostasis, was upregulated in Li2CO3-treated embryos with NTDs. Li2CO3 exposure disturbed ER homeostasis in the developing brain. Interestingly, inositol supplementation partially rescued ciliogenesis impairment in lithium-treated NIH3T3 cells. Li2CO3 exposure disrupted primary ciliary development and ER homeostasis in the embryonic neural tube. Maintaining adequate maternal inositol levels during Li2CO3 exposure before and during pregnancy prevents NTDs. These findings help in better understanding and reassessing the risks associated with lithium, especially in terms of maternal and fetal health.

Keywords

• Lithium
• Neurodevelopment
• Pregnancy
• inositol
• primary cilia
• endoplasmic reticulum homeostasis