Journal
TOXICOLOGICAL SCIENCES
Volume 171, Issue 1, Pages 32-45Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfz139
Keywords
in utero exposure; benzalkonium chloride; sterols; lipids; neurodevelopment; multiomics
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Funding
- University of Washington Environmental Pathology/Toxicology Training Program (National Institutes of Health (NIH)) [T32 ES007032-39]
- NIH National Institute of Child Health and Human Development [R01HD092659]
- Interdisciplinary Center for Exposures, Diseases, Genomics and Environment (UW EDGE) [NIH P30ES007033]
- Sheldon D. Murphy Endowment
- Department of Medicinal Chemistry
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Lipids are critical for neurodevelopment; therefore, disruption of lipid homeostasis by environmental chemicals is expected to have detrimental effects on this process. Previously, we demonstrated that the benzalkonium chlorides (BACs), a class of commonly used disinfectants, alter cholesterol biosynthesis and lipid homeostasis in neuronal cell cultures in a manner dependent on their alkyl chain length. However, the ability of BACs to reach the neonatal brain and alter sterol and lipid homeostasis during neurodevelopment in vivo has not been characterized. Therefore, the goal of this study was to use targeted and untargeted mass spectrometry and transcriptomics to investigate the effect of BACs on sterol and lipid homeostasis and to predict the mechanism of toxicity of BACs on neurodevelopmental processes. After maternal dietary exposure to 120mg BAC/kg body weight/day, we quantified BAC levels in the mouse neonatal brain, demonstrating for the first time that BACs can cross the blood-placental barrier and enter the developing brain. Transcriptomic analysis of neonatal brains using RNA sequencing revealed alterations in canonical pathways related to cholesterol biosynthesis, liver X receptor-retinoid X receptor (LXR/RXR) signaling, and glutamate receptor signaling. Mass spectrometry analysis revealed decreases in total sterol levels and downregulation of triglycerides and diglycerides, which were consistent with the upregulation of genes involved in sterol biosynthesis and uptake as well as inhibition of LXR signaling. In conclusion, these findings demonstrate that BACs target sterol and lipid homeostasis and provide new insights for the possible mechanisms of action of BACs as developmental neurotoxicants.
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