In Vitro Cytotoxicity and Adaptive Stress Responses to Selected Haloacetic Acid and Halobenzoquinone Water Disinfection Byproducts.
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.
Smart Water Research Centre, Australian Rivers Institute, School of Environment, Griffith University , Gold Coast, Queensland 4222, Australia.
Erik
E
Procházka
Smart Water Research Centre, Australian Rivers Institute, School of Environment, Griffith University , Gold Coast, Queensland 4222, Australia.|Cell Toxicology, Helmholtz Centre for Environmental Research-UFZ , 04318 Leipzig, Germany.|Environmental Toxicology, Center for Applied Geosciences, Eberhard Karls University Tübingen , 72074 Tübingen, Germany.
Beate I
BI
Escher
Michael J
MJ
Plewa
Smart Water Research Centre, Australian Rivers Institute, School of Environment, Griffith University , Gold Coast, Queensland 4222, Australia.
Frederic D L
FD
Leusch
D000085:Acetates / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D019342:Acetic Acid / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D016227:Benzoquinones / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D004202:Disinfectants / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D060766:Drinking Water / Q000032:analysis*; D017930:Genes, Reporter; D054879:Halogenation; D006801:Humans; D019807:Iodoacetic Acid / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000085:Acetates; D016227:Benzoquinones; D004202:Disinfectants; D060766:Drinking Water; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C004532:quinone; C006972:chloroacetic acid; C016274:bromoacetate; D019342:Acetic Acid; D019807:Iodoacetic Acid