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      Global Transcriptional Analysis of Nontransformed Human Intestinal Epithelial Cells (FHs 74 Int) after Exposure to Selected Drinking Water Disinfection By-Products

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          Abstract

          Background:

          Drinking water disinfection inadvertently leads to the formation of numerous disinfection by-products (DBPs), some of which are cytotoxic, mutagenic, genotoxic, teratogenic, and potential carcinogens both in vitro and in vivo.

          Objectives:

          We investigated alterations to global gene expression (GE) in nontransformed human small intestine epithelial cells (FHs 74 Int) after exposure to six brominated and two chlorinated DBPs: bromoacetic acid (BAA), bromoacetonitrile (BAN), 2,6-dibromo- p-benzoquinone (DBBQ), bromoacetamide (BAM), tribromoacetaldehyde (TBAL), bromate ( BrO 3 − ), trichloroacetic acid (TCAA), and trichloroacetaldehyde (TCAL).

          Methods:

          Using whole-genome cDNA microarray technology (Illumina), we examined GE in nontransformed human cells after 4 h exposure to DBPs at predetermined equipotent concentrations, identified significant changes in gene expression ( p ≤ 0.01 ), and investigated the relevance of these genes to specific toxicity pathways via gene and pathway enrichment analysis.

          Results:

          Genes related to activation of oxidative stress–responsive pathways exhibited fewer alterations than expected based on prior work, whereas all DBPs induced notable effects on transcription of genes related to immunity and inflammation.

          Discussion:

          Our results suggest that alterations to genes associated with immune and inflammatory pathways play an important role in the potential adverse health effects of exposure to DBPs. The interrelationship between these pathways and the production of reactive oxygen species (ROS) may explain the common occurrence of oxidative stress in other studies exploring DBP toxicity. Finally, transcriptional changes and shared induction of toxicity pathways observed for all DBPs caution of additive effects of mixtures and suggest further assessment of adverse health effects of mixtures is warranted. https://doi.org/10.1289/EHP4945

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          Rank products: a simple, yet powerful, new method to detect differentially regulated genes in replicated microarray experiments.

          Rainer Breitling, Patrick Armengaud, Anna Amtmann … (2004)
          One of the main objectives in the analysis of microarray experiments is the identification of genes that are differentially expressed under two experimental conditions. This task is complicated by the noisiness of the data and the large number of genes that are examined simultaneously. Here, we present a novel technique for identifying differentially expressed genes that does not originate from a sophisticated statistical model but rather from an analysis of biological reasoning. The new technique, which is based on calculating rank products (RP) from replicate experiments, is fast and simple. At the same time, it provides a straightforward and statistically stringent way to determine the significance level for each gene and allows for the flexible control of the false-detection rate and familywise error rate in the multiple testing situation of a microarray experiment. We use the RP technique on three biological data sets and show that in each case it performs more reliably and consistently than the non-parametric t-test variant implemented in Tusher et al.'s significance analysis of microarrays (SAM). We also show that the RP results are reliable in highly noisy data. An analysis of the physiological function of the identified genes indicates that the RP approach is powerful for identifying biologically relevant expression changes. In addition, using RP can lead to a sharp reduction in the number of replicate experiments needed to obtain reproducible results.
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            Occurrence, genotoxicity, and carcinogenicity of regulated and emerging disinfection by-products in drinking water: a review and roadmap for research.

            S. Richardson, M. Plewa, E. Wagner … (2007)
            Disinfection by-products (DBPs) are formed when disinfectants (chlorine, ozone, chlorine dioxide, or chloramines) react with naturally occurring organic matter, anthropogenic contaminants, bromide, and iodide during the production of drinking water. Here we review 30 years of research on the occurrence, genotoxicity, and carcinogenicity of 85 DBPs, 11 of which are currently regulated by the U.S., and 74 of which are considered emerging DBPs due to their moderate occurrence levels and/or toxicological properties. These 74 include halonitromethanes, iodo-acids and other unregulated halo-acids, iodo-trihalomethanes (THMs), and other unregulated halomethanes, halofuranones (MX [3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone] and brominated MX DBPs), haloamides, haloacetonitriles, tribromopyrrole, aldehydes, and N-nitrosodimethylamine (NDMA) and other nitrosamines. Alternative disinfection practices result in drinking water from which extracted organic material is less mutagenic than extracts of chlorinated water. However, the levels of many emerging DBPs are increased by alternative disinfectants (primarily ozone or chloramines) compared to chlorination, and many emerging DBPs are more genotoxic than some of the regulated DBPs. Our analysis identified three categories of DBPs of particular interest. Category 1 contains eight DBPs with some or all of the toxicologic characteristics of human carcinogens: four regulated (bromodichloromethane, dichloroacetic acid, dibromoacetic acid, and bromate) and four unregulated DBPs (formaldehyde, acetaldehyde, MX, and NDMA). Categories 2 and 3 contain 43 emerging DBPs that are present at moderate levels (sub- to low-mug/L): category 2 contains 29 of these that are genotoxic (including chloral hydrate and chloroacetaldehyde, which are also a rodent carcinogens); category 3 contains the remaining 14 for which little or no toxicological data are available. In general, the brominated DBPs are both more genotoxic and carcinogenic than are chlorinated compounds, and iodinated DBPs were the most genotoxic of all but have not been tested for carcinogenicity. There were toxicological data gaps for even some of the 11 regulated DBPs, as well as for most of the 74 emerging DBPs. A systematic assessment of DBPs for genotoxicity has been performed for approximately 60 DBPs for DNA damage in mammalian cells and 16 for mutagenicity in Salmonella. A recent epidemiologic study found that much of the risk for bladder cancer associated with drinking water was associated with three factors: THM levels, showering/bathing/swimming (i.e., dermal/inhalation exposure), and genotype (having the GSTT1-1 gene). This finding, along with mechanistic studies, highlights the emerging importance of dermal/inhalation exposure to the THMs, or possibly other DBPs, and the role of genotype for risk for drinking-water-associated bladder cancer. More than 50% of the total organic halogen (TOX) formed by chlorination and more than 50% of the assimilable organic carbon (AOC) formed by ozonation has not been identified chemically. The potential interactions among the 600 identified DBPs in the complex mixture of drinking water to which we are exposed by various routes is not reflected in any of the toxicology studies of individual DBPs. The categories of DBPs described here, the identified data gaps, and the emerging role of dermal/inhalation exposure provide guidance for drinking water and public health research.
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              Toll-like receptors and cancer.

              Seth Rakoff-Nahoum, Ruslan Medzhitov (2009)
              Toll-like receptors (TLRs) are a family of pattern recognition receptors that are best-known for their role in host defence from infection. Emerging evidence also suggests that TLRs have an important role in maintaining tissue homeostasis by regulating the inflammatory and tissue repair responses to injury. The development of cancer has been associated with microbial infection, injury, inflammation and tissue repair. Here we discuss how the function of TLRs may relate to these processes in the context of carcinogenesis.
              Article 0 comments Cited 296 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Environ Health Perspect
                Journal ID (iso-abbrev): Environ. Health Perspect
                Journal ID (publisher-id): EHP
                Title: Environmental Health Perspectives
                Publisher: Environmental Health Perspectives
                ISSN (Print): 0091-6765
                ISSN (Electronic): 1552-9924
                Publication date (Electronic): 22 November 2019
                Publication date Collection: November 2019
                Volume: 127
                Issue: 11
                Electronic Location Identifier: 117006
                Affiliations
                [1 ]Australian Rivers Institute, School of Environment and Science, Griffith University , Gold Coast, Queensland, Australia
                [2 ]Department of Cell Toxicology, Helmholtz Centre for Environmental Research – UFZ , Leipzig, Germany
                [3 ]Environmental Toxicology, Centre for Applied Geoscience, Eberhard Karls University , Tübingen, Germany
                [4 ]Department of Crop Sciences, University of Illinois at Urbana-Champaign , Urbana, Illinois, USA
                [5 ]Safe Global Water Institute, University of Illinois at Urbana-Champaign , Urbana, Illinois, USA
                Author notes
                Address correspondence to Frederic D.L. Leusch, Australian Rivers Institute, School of Environment and Science, Griffith University, Gold Coast Campus, Parklands Dr., Southport, Queensland 4222, Australia. Telephone: +61 7 555 27832. Email: f.leusch@ 123456griffith.edu.au
                Article
                Publisher ID: EHP4945
                DOI: 10.1289/EHP4945
                PMC ID: 6927499
                PubMed ID: 31755747
                SO-VID: 5c708c26-0191-4f45-b973-d90336ffac34
                License:

                EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted.

                History
                Date received : 23 December 2018
                Date revision received : 23 October 2019
                Date accepted : 29 October 2019
                Categories
                Subject: Research

                ScienceOpen disciplines: Public health
                Data availability:
                ScienceOpen disciplines: Public health

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