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Identification of Environmental Quaternary Ammonium Compounds as Direct Inhibitors of Cholesterol Biosynthesis.

ABSTRACT: In this study, we aim to identify environmental molecules that can inhibit cholesterol biosynthesis, potentially leading to the same biochemical defects as observed in cholesterol biosynthesis disorders, which are often characterized by congenital malformations and developmental delay. Using the Distributed Structure-Searchable Toxicity (DSSTox) Database Network developed by EPA, we first carried out in silico screening of environmental molecules that display structures similar to AY9944, a known potent inhibitor of 3?-hydroxysterol-?(7)-reductase (DHCR7)-the last step of cholesterol biosynthesis. Molecules that display high similarity to AY9944 were subjected to test in mouse and human neuroblastoma cells for their effectiveness in inhibiting cholesterol biosynthesis by analyzing cholesterol and its precursor using gas chromatography-mass spectrometry. We found that a common disinfectant mixture, benzalkonium chlorides (BACs), exhibits high potency in inhibiting DHCR7, as suggested by greatly elevated levels of the cholesterol precursor, 7-dehydrocholesterol (7-DHC). Subsequent structure-activity studies suggested that the potency of BACs as Dhcr7 inhibitors decrease with the length of their hydrocarbon chain: C10?>?C12???C14?>?C16. Real-time qPCR analysis revealed upregulation of the genes related to cholesterol biosynthesis and downregulation of the genes related to cholesterol efflux, suggesting a feedback response to the inhibition. Furthermore, an oxidative metabolite of 7-DHC that was previously identified as a biomarker in vivo was also found in cells exposed to BACs by liquid chromatography-mass spectrometry. Our findings suggest that certain environmental molecules could potently inhibit cholesterol biosynthesis, which could be a new link between environment and developmental disorders.

SUBMITTER: Herron J

PROVIDER: S-EPMC4880132 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Identification of Environmental Quaternary Ammonium Compounds as Direct Inhibitors of Cholesterol Biosynthesis.

Herron Josi J Reese Rosalyn C RC Tallman Keri A KA Narayanaswamy Rohini R Porter Ned A NA Xu Libin L

Toxicological sciences : an official journal of the Society of Toxicology 20160226 2

In this study, we aim to identify environmental molecules that can inhibit cholesterol biosynthesis, potentially leading to the same biochemical defects as observed in cholesterol biosynthesis disorders, which are often characterized by congenital malformations and developmental delay. Using the Distributed Structure-Searchable Toxicity (DSSTox) Database Network developed by EPA, we first carried out in silico screening of environmental molecules that display structures similar to AY9944, a know ...[more]

PMID: 26919959

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Project description:Disinfectant quaternary ammonium compounds (Quats) have diverse uses in a variety of consumer and commercial products, particularly cleaning products. With the emergence of the COVID-19 pandemic, they have become a primary tool to inactivate the SARS-CoV-2 virus on surfaces. Disinfectant Quats have very low vapor pressure, and following the use phase of the products in which they are found, disposal is typically "down-the-drain" to wastewater treatment systems. Consequently, the potential for the greatest environmental effect is to the aquatic environment, from treated effluent, and potentially to soils, which might be amended with wastewater biosolids. Among the earliest used and still common disinfectant Quats are the alkyl dimethyl benzyl ammonium chloride (ADBAC) compounds and the dialkyl dimethyl ammonium chloride (DDAC) compounds. They are cationic surfactants often found in consumer and commercial surface cleaners. Because of their biocidal properties, disinfectant Quats are heavily regulated for human and environmental safety around the world. Consequently, there is a robust database of information regarding the ecological hazards and environmental fate of ADBAC and DDAC; however, some of the data presented are from unpublished studies that have been submitted to and reviewed by regulatory agencies (i.e., EPA and European Chemicals Agency) to support antimicrobial product registration. We summarize the available environmental fate data and the acute and chronic aquatic ecotoxicity data for freshwater species, including algae, invertebrates, fish, and plants using peer-reviewed literature and unpublished data submitted to and summarized by regulatory agencies. The lower limit of the range of the ecotoxicity data for disinfectant Quats tends to be lower than that for other surface active agents, such as nonionic or anionic surfactants. However, ecotoxicity is mitigated by environmental fate characteristics, the data for which we also summarize, including high biodegradability and a strong tendency to sorb to wastewater biosolids, sediment, and soil. As a result, disinfectant Quats are largely removed during wastewater treatment, and those residues discharged in treated effluent are likely to rapidly bind to suspended solids or sediments, thus mitigating their toxicity.

Project description:Quaternary ammonium compounds (QACs) have been extensively used in the community, healthcare facilities, and food chain, in concentrations between 20 and 30,000 mg/L. Enterococcus faecalis and Enterococcus faecium are ubiquitous in these settings and are recognized as nosocomial pathogens worldwide, but QACs' activity against strains from diverse epidemiological and genomic backgrounds remained largely unexplored. We evaluated the role of Enterococcus isolates from different sources, years, and clonal lineages as hosts of QACs tolerance genes and their susceptibility to QACs in optimal, single-stress and cross-stress growth conditions. Only 1% of the Enterococcus isolates included in this study and 0.5% of publicly available Enterococcus genomes carried qacA/B, qacC, qacG, qacJ, qacZ, qrg, bcrABC or oqxAB genes, shared with >60 species of Bacillota, Pseudomonadota, Actinomycetota, or Spirochaetota. These genes were generally found within close proximity of antibiotics and/or metals resistance genes. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) of benzalkonium chloride (BC) and didecyldimethylammonium chloride ranged between 0.5 and 4 mg/L (microdilution: 37°C/20 h/pH = 7/aerobiosis) for 210 E. faecalis and E. faecium isolates (two isolates carrying qacZ). Modified growth conditions (e.g., 22°C/pH = 5) increased MICBC/MBCBC (maximum of eightfold and MBCBC = 16 mg/L) and changed bacterial growth kinetics under BC toward later stationary phases in both species, including in isolates without QACs tolerance genes. In conclusion, Enterococcus are susceptible to in-use QACs concentrations and rarely carry QACs tolerance genes. However, their potential gene exchange with different microbiota, the decreased susceptibility to QACs under specific environmental conditions, and the presence of subinhibitory QACs concentrations in various settings may contribute to the selection of particular strains and, thus, require a One Health strategy to maintain QACs effectiveness. IMPORTANCE Despite the increasing use of quaternary ammonium compounds (QACs), the susceptibility of pathogens to these antimicrobials remains largely unknown. Enterococcus faecium and Enterococcus faecalis are susceptible to in-use QACs concentrations and are not main hosts of QACs tolerance genes but participate in gene transfer pathways with diverse bacterial taxa exposed to these biocides. Moreover, QACs tolerance genes often share the same genetic contexts with antibiotics and/or metals resistance genes, raising concerns about potential co-selection events. E. faecium and E. faecalis showed increased tolerance to benzalkonium chloride under specific environmental conditions (22°C, pH = 5), suggesting that strains might be selected in settings where they occur along with subinhibitory QACs concentrations. Transcriptomic studies investigating the cellular mechanisms of Enterococcus adaptation to QACs tolerance, along with longitudinal metadata analysis of tolerant populations dynamics under the influence of diverse environmental factors, are essential and should be prioritized within a One Health strategy.

Dataset Information

Identification of Environmental Quaternary Ammonium Compounds as Direct Inhibitors of Cholesterol Biosynthesis.

Publications

Identification of Environmental Quaternary Ammonium Compounds as Direct Inhibitors of Cholesterol Biosynthesis.

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