Toxicity of Drinking Water Disinfection Byproducts: Cell Cycle Alterations Induced by the Monohaloacetonitriles

Abstract

Haloacetonitriles (HANs) are a chemical class of drinking water disinfection byproducts (DBPs) that form from reactions between disinfectants and nitrogen-containing precursors, the latter more prevalent in water sources impacted by algae bloom and municipal wastewater effluent discharge. HANs, previously demonstrated to be genotoxic, were investigated for their effects on the mammalian cell cycle. Treating Chinese hamster ovary (CHO) cells with monoHANs followed by the release from the chemical treatment resulted in the accumulation of abnormally high DNA content in cells over time (hyperploid). The potency for the cell cycle alteration followed the order: iodoacetonitrile (IAN) > bromoacetonitrile (BAN) ≫ chloroacetonitrile (CAN). Exposure to 6 μM IAN, 12 μM BAN and 900 μM CAN after 26 h post-treatment incubation resulted in DNA repair; however, subsequent cell cycle alteration effects were observed. Cell proliferation of HAN-treated cells was suppressed for as long as 43 to 52 h. Enlarged cell size was observed after 52 h post-treatment incubation without the induction of cytotoxicity. The HAN-mediated cell cycle alteration was mitosis- and proliferation-dependent, which suggests that HAN treatment induced mitosis override, and that HAN-treated cells proceeded into S phase and directly into the next cell cycle. Cells with multiples genomes would result in aneuploidy (state of abnormal chromosome number and DNA content) at the next mitosis since extra centrosomes could compromise the assembly of bipolar spindles. There is accumulating evidence of a transient tetraploid state proceeding to aneuploidy in cancer progression. Biological self-defense systems to ensure genomic stability and to eliminate tetraploid cells exist in eukaryotic cells. A key tumor suppressor gene, p53, is oftentimes mutated in various types of human cancer. It is possible that HAN disruption of the normal cell cycle and the generation of aberrant cells with an abnormal number of chromosomes may contribute to cancer induction and perhaps be involved in the induction of adverse pregnancy outcomes associated with long-term consumption of disinfected water. Here we present the first observation of the induction of hyperploidy by a class of DBPs.

Disinfection by-product formation during seawater desalination: A review

“…Therefore, disinfection should be taken with great care, especially when using source waters with elevated Br À and I À levels. Increasing evidence shows that brominated and iodinated DBPs are more toxic than their chlorinated analogues (Plewa and Wagner, 2009;Plewa et al, 2004;Richrdson et al, 2007;Komaki et al, 2014). According to a comprehensive genotoxicity/cytotoxicity database of the DNA damage and cytotoxicity study with CHO cell assays, halogenated DBPs follow a toxicity order of I À > Br À > Cl À as shown in Fig.…”

Charting a New Path To Resolve the Adverse Health Effects of DBPs

“…Inhibition of GAPDH leads to pyruvate starvation and mitochondrial stress that generates ROS (58,59). New research demonstrated that the monohalonitriles, at non-cytotoxic concentrations, impact the M-phase of the cell cycle and induce hyperploidy in mammalian cells (35). These examples indicate that the molecular mechanisms of DBP toxicity involve a diversity of cellular targets and affect a host of different biological pathways.…”

“…Research into the formation, occurrence, toxicity, epidemiology and engineering processes have resulted in enhanced interest in the adverse impact of DBPs on the environment and the public health (12,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Although the last decade experienced increased interdisciplinary collaborations amongst chemists, biologists, epidemiologists and engineers, resolving the risks of DBPs follows a dated paradigm.…”

Fingerprinting the reactive toxicity pathways of 50 drinking water disinfection by-products

“…Drinking water disinfection effectively reduces waterborne diseases (Akin et al 1982) but the formation of disinfection by-products (DBPs) has raised concerns due to their potential adverse health effects (Cantor et al 2010, Komaki et al 2014, Plewa et al 2008b. Some of the 600 to 700 known DBPs have been toxicologically characterized with in vitro bioassays and a few with chronic in vivo studies demonstrating that some DBPs are potent cytotoxicants, genotoxicants, and carcinogens (Plewa et al 2010, Plewa et al 2008b, Richardson et al 2007.…”

“…Attack of proteins by soft electrophilic DBPs, for example, can lead to enzyme inhibition and depletion of glutathione, which causes a multitude of subsequent effects, such as generation of reactive oxygen species (ROS), impaired DNA repair, or disturbed DNA replication. This can indirectly result in genotoxic effects (Komaki et al 2014, Komaki et al 2009.…”