In vitro cytotoxicity and adaptive stress responses to selected haloacetic acid and halobenzoquinone water disinfection byproducts

Prochazka, Erik, Escher, Beate I., Plewa, Michael J. and Leusch, Frederic D. L. (2015) In vitro cytotoxicity and adaptive stress responses to selected haloacetic acid and halobenzoquinone water disinfection byproducts. Chemical Research in Toxicology, 28 10: 2059-2068. doi:10.1021/acs.chemrestox.5b00283


Author Prochazka, Erik
Escher, Beate I.
Plewa, Michael J.
Leusch, Frederic D. L.
Title In vitro cytotoxicity and adaptive stress responses to selected haloacetic acid and halobenzoquinone water disinfection byproducts
Journal name Chemical Research in Toxicology   Check publisher's open access policy
ISSN 1520-5010
0893-228X
Publication date 2015-09-01
Year available 2015
Sub-type Article (original research)
DOI 10.1021/acs.chemrestox.5b00283
Open Access Status Not yet assessed
Volume 28
Issue 10
Start page 2059
End page 2068
Total pages 10
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Abstract The process of disinfecting drinking water inadvertently leads to the formation of numerous disinfection byproducts (DBPs). Some of these are mutagenic, genotoidc, teratogenic, and cytotoxic, as well as potentially carcinogenic both in vivo and in vitro. We investigated the in vitro biological activity of five DBPs: three monohaloacetic acids (monoHAAs) [chloroacetic acid (CAA), bromoacetic acid (BAA), and iodoacetic acid (IAA)] and two novel halobenzoquinones (HBQs) [2,6-dichloro-p-benzoquinone (DCBQ) and 2,6-dibromo-p-benzoquinone]. We focused particularly on cytotoxidty and induction of two adaptive stress response pathways: the oxidative stress responsive Nrf2/ARE and DNA-damage responsive p53 pathways. All five DBPs were cytotoidc to the Caco-2 cell line after a 4 h exposure, and all DBPs induced both of the adaptive stress response pathways, Nrf2/ARE and p53, in the micromolar range, as measured by two beta-lactamase-based reporter gene assays. The decreasing order of potency for all three endpoints for the five DBPs was IAA similar to BAA > DCBQ similar to DBBQ > CAA. Induction of oxidative stress was previously proposed to be the molecular initiating event (MIE) for both classes of DBPs. However, comparing the levels of activation of the two pathways uncovered that the Nrf2/ARE pathway was the more sensitive endpoint for HAAs, whereas the p53 pathway was more sensitive in the case of HBQs. Therefore, the DNA damage-responsive p53 pathway may be an important piece of information to fill in a gap in the adverse outcome pathway framework for the assessment of HBQs. Finally, we cautiously compared the potential risk of the two novel HBQs using a benchmarking approach to that of the well-studied CAA, which suggested that their relative risk may be lower than that of BAA and IAA.
Formatted abstract
The process of disinfecting drinking water inadvertently leads to the formation of numerous disinfection byproducts (DBPs). Some of these are mutagenic, genotoxic, teratogenic, and cytotoxic, as well as potentially carcinogenic both in vivo and in vitro. We investigated the in vitro biological activity of five DBPs: three monohaloacetic acids (monoHAAs) [chloroacetic acid (CAA), bromoacetic acid (BAA), and iodoacetic acid (IAA)] and two novel halobenzoquinones (HBQs) [2,6-dichloro-p-benzoquinone (DCBQ) and 2,6-dibromo-p-benzoquinone]. We focused particularly on cytotoxicity and induction of two adaptive stress response pathways: the oxidative stress responsive Nrf2/ARE and DNA-damage responsive p53 pathways. All five DBPs were cytotoxic to the Caco-2 cell line after a 4 h exposure, and all DBPs induced both of the adaptive stress response pathways, Nrf2/ARE and p53, in the micromolar range, as measured by two β-lactamase-based reporter gene assays. The decreasing order of potency for all three endpoints for the five DBPs was IAA ∼ BAA > DCBQ ∼ DBBQ > CAA. Induction of oxidative stress was previously proposed to be the molecular initiating event (MIE) for both classes of DBPs. However, comparing the levels of activation of the two pathways uncovered that the Nrf2/ARE pathway was the more sensitive endpoint for HAAs, whereas the p53 pathway was more sensitive in the case of HBQs. Therefore, the DNA damage-responsive p53 pathway may be an important piece of information to fill in a gap in the adverse outcome pathway framework for the assessment of HBQs. Finally, we cautiously compared the potential risk of the two novel HBQs using a benchmarking approach to that of the well-studied CAA, which suggested that their relative risk may be lower than that of BAA and IAA.
Keyword Chemistry, Medicinal
Chemistry, Multidisciplinary
Toxicology
Pharmacology & Pharmacy
Chemistry
Toxicology
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: National Research Centre for Environmental Toxicology Publications
 
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