Work

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

Year: 2025

Type: article

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 (Li 2 CO 3 ) 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 Li 2 CO 3 exposure contributes to NTDs. Pregnant mice were intraperitoneally injected with Li 2 CO 3 (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 Li 2 CO 3 exposure. The results revealed that treatment with Li 2 CO 3 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 Li 2 CO 3 -treated embryos with NTDs. Li 2 CO 3 exposure disturbed ER homeostasis in the developing brain. Interestingly, inositol supplementation partially rescued ciliogenesis impairment in lithium-treated NIH3T3 cells. Li 2 CO 3 exposure disrupted primary ciliary development and ER homeostasis in the embryonic neural tube. Maintaining adequate maternal inositol levels during Li 2 CO 3 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. • Maternal Li₂CO₃ exposure-induced NTDs primarily exhibited exencephaly on GD10.5. • Li₂CO₃ exposure caused significant shortening of primary cilia in embryonic brain tissue with NTDs. • Li₂CO₃ exposure increased HSP90AB1 levels, perturbing endoplasmic reticulum homeostasis. • Inositol supplementation partially rescued the shortening of cilia induced by Li₂CO₃.

Source: Ecotoxicology and Environmental Safety

DOI: 10.1016/j.ecoenv.2025.118200