4 METHYLCYCLOHEXANE METHANOL MSDS PDF

The large-scale chemical spill on January 9, from coal processing and cleaning storage tanks of Freedom Industries in Charleston affected the drinking water supply to , people in Charleston, West Virginia metropolitan, while the short-term and long-term health impacts remain largely unknown and need to be assessed and monitored. There is a lack of publically available toxicological information for the main contaminant 4-methylcyclohexanemethanol 4-MCHM. Particularly, little is known about 4-MCHM metabolites and their toxicity. This study reports timely and original results of the mechanistic toxicity assessment of 4-MCHM and its metabolites via a newly developed quantitative toxicogenomics approach, employing proteomics analysis in yeast cells and transcriptional analysis in human cells. These results suggested that, although 4-MCHM is considered only moderately toxic based on the previous limited acute toxicity evaluation, 4-MCHM metabolites were likely more toxic than 4-MCHM in both yeast and human cells, with different toxicity profiles and potential mechanisms.

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The large-scale chemical spill on January 9, from coal processing and cleaning storage tanks of Freedom Industries in Charleston affected the drinking water supply to , people in Charleston, West Virginia metropolitan, while the short-term and long-term health impacts remain largely unknown and need to be assessed and monitored.

There is a lack of publically available toxicological information for the main contaminant 4-methylcyclohexanemethanol 4-MCHM. Particularly, little is known about 4-MCHM metabolites and their toxicity. This study reports timely and original results of the mechanistic toxicity assessment of 4-MCHM and its metabolites via a newly developed quantitative toxicogenomics approach, employing proteomics analysis in yeast cells and transcriptional analysis in human cells. These results suggested that, although 4-MCHM is considered only moderately toxic based on the previous limited acute toxicity evaluation, 4-MCHM metabolites were likely more toxic than 4-MCHM in both yeast and human cells, with different toxicity profiles and potential mechanisms.

In the yeast library, 4-MCHM mainly induced chemical stress related to transmembrane transport and transporter activity, while 4-MCHM metabolites of S9 mainly induced oxidative stress related to antioxidant activity and oxidoreductase activity.

On January 9, , approximately 10, US gal 38, L of chemicals used in coal processing and cleaning leaked from the storage tanks of Freedom Industries, about 1. In March , 4-MCHM was found to be absorbed on the activated carbon filters and onto plastic water pipes; therefore, it likely continued to be released into water over a relatively long period of time after the spill.

According to information provided by Freedom Industries, the leaked tank contained It has been patented for use in air fresheners 10 and a frothing agent for coal processing and cleaning.

A limited number of reports, including the report released by Eastman Chemical Co. A structure—activity relationship SAR analysis suggested that 4-MCHM might result in effects on the development of offspring and might be an eye and skin irritant. However, little is yet known about 4-MCHM metabolites and their toxicity.

A WHO study of alicyclic primary alcohols suggested that 4-MCHM would primarily be metabolized to its corresponding carboxylic acid: 4-methylcyclohexanecarboxylic acid CAS , a naphthenic acid. Both acute and chronic toxicity, including hepatotoxicity to fish and other organisms, has been reported for naphthenic acids mixtures.

Timely and mechanistic toxicity screening and assessment of 4-MCHM and its metabolites, as pointed out by the recent report of Whelton et al. This study reports timely results of mechanistic toxicity assessment of 4-MCHM and its metabolites via a newly developed quantitative toxicogenomics approach, employing proteomics analysis in yeast cells and transcriptional analysis in human cells. Yeast has been commonly used for toxicity assessment because it shares a lot of functional homologues with mammalian cells.

Specific toxicity and stress response-based studies have been used by both our group 28 , 31 and others, with specific focus on oxidative damage, 32 , 33 DNA damage, 34 and inflammation and apoptosis, 35 , 36 to provide important insights into the toxicological potential elicited by chemicals. These in vitro high throughput molecular assays provide fast yet informative results for initial toxicity screening and risk identification to guide further extensive toxicity evaluation, as needed for the case of the 4-MCHM chemical spill.

The results provide useful information for guiding further 4-MCHM toxicity study, public health protection strategy, and regulation formation. For yeast cells, cytotoxicity was evaluated by growth inhibition in yeast for 24 h in triplicates. A library of in-frame GFP fusion proteins involved in known cellular stress response pathways of S.

The plates were then placed in a Micro plate Reader Synergy H1Multi-Mode, Biotech, Winooski, VT for absorbance OD for cell growth and GFP signal filters with nm excitation and nm emission for protein expression measurements every 5 min for 2 h after a fast shake for 1 min. All experiments were performed in triplicate.

A detailed description of data processing for the yeast reporters library assay was provided in our previous report. Then, the P level was further normalized among replicate plates based on mean P PGK1 of medium control on each plate.

To quantifiy the chemical-induced protein expression level effect, the real-time protein expression profile was then integrated into the Protein Effect Level Index PELI in a similar manner as the Transcriptional Effect Level Index TELI proposed for transcriptomics analysis in our previous studies. For protein ORF i , the protein effect level was quantified as the accumulative protein expression changes averaged over a 2 h exposure time as follows:.

An assay noise cutoff treshold was determined as 1. The analysis was conducted on the basis of protein expression levels of each chemical ln I , average of triplicates during a 2 h exposure by software suite MeV MutiExperiment Viewer v4. The proteins in each stress category from Table S1 , Supporting Information , were used to define the stress response gene sets.

Gene ontology GO analysis was performed with novel Network Ontology Analysis method NOA for enrichment analysis to determine the significantly represented GO biological categories and to analyze functions of gene network, as it allows enrichment analysis with a user defined reference set. A p -value threshold of 0. The potential acute toxicity of 4-MCHM and its metabolites with rat liver extract S9 fraction was evaluated by a 24 h cytotoxicity assay quantifying the survival percentage of yeast S.

Human cells were more sensitive to the toxicity of 4-MCHM and its metabolites than yeast cells with much lower IC50 and IC5 values than those for yeast cells. The real-time differential protein expression profiles of proteins in yeast indicative of cellular stress pathway activities were distinctive for 4-MCHM and its metabolites Figure 2 , suggesting compound s -specific cellular responses as results of their different toxicity mechanisms.

The temporal protein expression profiles were dose dependent, and protein activation shift in response to dose concentrations has been reported previously. The mean natural log of induction factor ln I indicates the magnitude of altered protein expression represented by a green—black—red color scale at the bottom. Red spectrum colors indicate up-regulation; green spectrum colors indicate down-regulation.

X -axis top: concentrations for each chemical; X -axis bottom: testing time in minutes; the first data point shown is at 20 min after exposure due to data smoothing with a moving average of every five data points. Y -axis left: clusters of proteins by stress response pathways; Y -axis right: list of proteins ORFs tested, with details in Table S1 , Supporting Information. The chemical-specific and concentration-dependent real time protein expression profiles of 4-MCHM and its metabolites may serve as fingerprints to allow chemicals clustering based on their specific toxicity mechanisms.

The principle component analysis PCA Figure 3 also showed the clear separation of 4-MCHM and its metabolites based on their altered stress response protein expression profiles, suggesting that 4-MCHM was likely transformed by S9 into other metabolites with different toxicity mechanisms from those exhibited by 4-MCHM, as discussed in more depth in the later section.

PCA graphical representations of the three major components of protein expression change profiles for 4-MCHM red square and 4-MCHM with S9 green sphere , based on induction factor ln I during a 2 h exposure across six-log concentrations. Samples are color coded according to chemicals. Each square or sphere represents one treatment a chemical at a given concentration with symbol size indicating the relative level of concentration. This suggested that the toxicity mechanism of 4-MCHM is likely related to chemical transport, membrane damage, and protein stress.

The 4-MCHM metabolites resulting from S9 transformation likely contained oxidizing chemicals that induce oxidative stress. In summary, the two independent gene enrichment analysis of yeast cell assays suggested that 4-MCHM mainly induced chemical stress related to transmembrane transport and transporter activity, while 4-MCHM metabolites of S9 mainly induced oxidative stress and DNA stress.

Gene expression analysis of 12 selected toxicity and stress-response related genes in human lung epithelial cells A was performed to investigate the potential adverse effect of 4-MCHM and its metabolites in human cells. The mean natural log of induction factor ln I indicates the magnitude of altered gene expression represented by a green—black—red color scale at the bottom. X -axis top: concentrations tested; Y -axis left: clusters of genes by stress categories; Y -axis right: list of genes tested, with details of gene descriptions in Table 1.

The 4-MCHM metabolites of S9 affected biomarkers indicative of oxidative damage and inflammation at lower concentrations and affected apoptosis biomarkers at higher concentration. This study reports the first investigation of cytotoxicity, molecular toxicity potential, and mechanisms of 4-MCHM and its metabolites by rat liver extraction.

Previous toxicity reports of 4-MCHM focused on conventional in vivo endpoints, with limited mechanistic information reported. There has been no toxicity report about its metabolites. This study investigated cytotoxicity and molecular mechanistic toxicity profiles of the 4-MCHM and its metabolites using a toxicogenomics approach in two cell lines with yeast and a human epithelial cell line A relevant to respiratory exposures in humans , respectively. This study shows that 4-MCHM metabolites were more toxic than 4-MCHM in both yeast and human cells, with different toxicity profiles and potential mechanisms.

With human A cells, 4-MCHM mainly induced DNA damage-related biomarkers, suggesting potential chronic effects that warrant further genotoxicity evaluation. This study also pointed out the need to consider metabolism for further 4-MCHM toxicity assessment. On the basis of previous toxicology studies of alicyclic primary alcohols, to which 4-MCHM belongs, 4-MCHM was likely transformed by S9 into the corresponding aldehyde and carboxylic acid: 4-methylcyclohexanecarboxylic acid.

This study suggested that 4-methylcyclohexanecarboxylic acid or further metabolite s may have the potential to be more toxic and need further investigation. The oxidative transformation pathways of organic contaminants are rather complex and dynamic, and the degradation intermediate mixtures can be even more toxic than the original contaminant s. The crude MCHM contains other chemicals, which may lead to various toxicity responses.

In conclusion, this study revealed different toxicity and potential mechanisms of 4-MCHM and its metabolites by S9 in yeast and human cells A These results suggested that, although 4-MCHM is considered only moderately toxic based on previous limited acute toxicity evaluation, its metabolites may be more toxic than 4-MCHM and are more relevant to human exposure.

Our study at the molecular level revealed some subcytotoxic molecular mechanisms such as DNA damage potential, which indicates that 4-MCHM is related to carcinogenesis and reproductive toxicity due to its DNA damage effect on human cells. Our results suggested that longterm medical monitoring should be considered for the population. It may also provide insights into potential longterm aquatic toxicity issues.

The toxicogenomics-based molecular toxicity screening assay employed in this study provides timely information regarding the underlying mechanisms of toxic action of 4-MCHM and its metabolites, especially related to low-dose and chronic exposures, which makes it a useful tool for public health protection and health monitoring needs. List of proteins in stress response pathways ensemble yeast cell library; primers used for measuring gene expression by RT q-PCR in A cells.

National Center for Biotechnology Information , U. Environ Sci Technol. Author manuscript; available in PMC Nov Author information Copyright and License information Disclaimer. Copyright notice. The publisher's final edited version of this article is available at Environ Sci Technol.

See other articles in PMC that cite the published article. Abstract The large-scale chemical spill on January 9, from coal processing and cleaning storage tanks of Freedom Industries in Charleston affected the drinking water supply to , people in Charleston, West Virginia metropolitan, while the short-term and long-term health impacts remain largely unknown and need to be assessed and monitored.

Graphical Abstract. Table 2. Open in a separate window. Data Processing. Molecular Endpoint Derivation. PCA Analysis. Gene Set Enrichment Analysis. Gene Ontology. Figure 1. Table 1. Figure 2. Figure 3. Table 3. Table 4. Figure 4. Figure 5.

Supplementary Material SI Click here to view. Footnotes Supporting Information List of proteins in stress response pathways ensemble yeast cell library; primers used for measuring gene expression by RT q-PCR in A cells. Notes The authors declare no competing financial interest.

DUBLINESCA ENRIQUE VILA MATAS PDF

Federal study of MCHM concludes

Classified as a saturated higher alicyclic primary alcohol. Both cis and trans isomers exist, depending on the relative positions of the methyl CH 3 and hydroxymethyl CH 2 OH groups on the cyclohexane ring. Commercial samples of MCHM consists of a mixture of these isomers as well as other components that vary with the supplier. It is a colourless oil with a faint mint-like alcohol odor. The solubility of 1-octanol in water is 2. It was first prepared in by Bouveault—Blanc reduction of a methylcyclohexanecarboxylate ester. It is also produced as a byproduct ca.

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4-Methylcyclohexanemethanol

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