Gut microbiota dysbiosis is associated with the synaptic deficits and cognitive impairment induced by LCM mixtures within a proposed mechanistic framework consistent with the AOP concept.

Abstract

Liquid crystal monomers (LCMs), as emerging environmental contaminants, have poorly understood cognitive effects under realistic mixture exposure scenarios. This study integrated ecological and human exposure data to characterize LCM mixtures and assessed their neurotoxicity using in vitro and in vivo models. We found that long-term exposure to LCM mixtures at environmental levels more strongly inhibited viability in hippocampal HT22 cells and microglial BV2 cells than individual compounds, and was associated with memory deficits in mice accompanied by neuroinflammation and reduced hippocampal synaptic plasticity. Within an AOP-based mechanistic framework, LCM binding to Zonula occludens-1 (ZO-1) is proposed as a hypothesized molecular initiating event (MIE), which may contribute to gut barrier injury, colonic inflammation, and gut microbiota dysbiosis. Altered microbiota composition showed significant correlations with cognitive index. Fecal microbiota transplantation provided suggestive evidence for the role of gut dysbiosis in cognitive impairment, while probiotic supplementation administered concurrently with LCM exposure showed protective effects against the deficits by restoring microbial balance and suppressing inflammation. This study systematically outlines a putative mechanistic framework consistent with the AOP concept for LCM mixtures: an initial gut barrier injury, hypothesized to be triggered by ZO‑1 binding, may disturb the gut‑brain axis, thereby contributing to neuroinflammation, synaptic dysfunction, and cognitive decline. Our findings provide mechanistic insights into how environmental-level LCM mixtures impair cognitive health and suggest probiotics as a potential prevention strategy.