The disinfection of drinking water generates hundreds of disinfection byproducts (DBPs), including haloaromatic DBPs. These haloaromatic DBPs are suspected to be more toxic than haloaliphatic ones, and they are currently not regulated. This work investigates their toxicity and ability to interfere with estrogen synthesis in human placental JEG-3 cells, and their genotoxic potential in human alveolar A549 cells. Among the haloaromatic DBPs studied, halobenzoquinones (2,6-dichloro-1,4-benzoquinone (DCBQ) and 2,6-dibromo-1,4-benzoquinone (DBBQ)) showed the highest cytotoxicity (EC₅₀: 18-26 μg/mL). They induced the generation of very high levels of reactive oxygen species (ROS) and up-regulated the expression of genes involved in estrogen synthesis (cyp19a1, hsd17b1). Increased ROS was linked to significant depletion of polyunsaturated lipid species from inner cell membranes. The other DBPs tested showed low or no significant cytotoxicity (EC₅₀ ≥ 100 μg/mL), while 2,4,6-trichloro-phenol (TCP), 2,4,6-tribromo-phenol (TBP) and 3,5-dibromo-4-hydroxybenzaldehyde (DCHB) induced the formation of micronuclei at concentrations much higher than those typically found in water (100 μg/mL). This study reveals the different modes of action of haloaromatic DBPs, and highlights the toxic potential of halobenzoquinones, which had a significant impact on the expression of placenta steroid metabolism related genes and induce oxidative stress, implying potential adverse health effects.

01 Jan 2022·ChemosphereQ2 · ENVIRONMENTAL SCIENCE & ECOLOGY

Synergistic cytotoxicity of bromoacetic acid and three emerging bromophenolic disinfection byproducts against human intestinal and neuronal cells

Q2 · ENVIRONMENTAL SCIENCE & ECOLOGY

Article

Author: Liu, Jiaqi ; Sayes, Christie M ; Gibb, Matthew ; Pradhan, Sahar H

Halogenated disinfection byproducts (halo-DBPs) are drinking water contaminants of great public health concern. Nine haloaliphatic DBPs have been regulated by the U.S. Environmental Protection Agency and various halophenolic compounds have been identified as emerging DBPs. In this study, we evaluated the cytotoxic interactions of the regulated bromoacetic acid and three emerging bromophenolic DBPs, i.e., 2,4,6-tribromophenol, 3,5-dibromo-4-hydroxybenzoic acid, and 3,5-dibromo-4-hydroxybenzaldehyde. Cytotoxicity was measured for each DBP individually as well as each of their mixtures using in vitro human epithelial colorectal adenocarcinoma (Caco-2) and neuroblastoma (SH-SY5Y) cells. Concentration addition (CA) model and isobolographic analysis were employed to characterize the interactions among the DBPs. Our results show that the cytotoxicity of four bromo-DBPs against both cell-types followed the descending rank order of bromoacetic acid > 2,4,6-tribromophenol > 3,5-dibromo-4-hydroxybenzaldehyde > 3,5-dibromo-4-hydroxybenzoic acid. Compared with the toxicity data in literature, our finding that bromoacetic acid showed higher cytotoxicity than bromophenolic DBPs was consistent with the results from Chinese hamster ovary cells (a commonly used in vitro model of DBP toxicological studies); but different from the results obtained from in vivo biological models. Significantly, with CA model prediction, we found that mixtures of four bromo-DBPs exhibited synergistic cytotoxic effects on both human cell types. Isobolographic analysis of binary DBP mixtures revealed that, for Caco-2 cells, bromoacetic acid, 2,4,6-tribromophenol, and 3,5-dibromo-4-hydroxybenzoic acid induced synergism; for SH-SY5Y cells, bromoacetic acid induced synergism with all three bromophenolic DBPs. The production of reactive oxidative species (ROS) induced by DBP mixtures could be an important reason for the synergistic cytotoxicity.

01 Nov 2019·Plant and Cell PhysiologyQ2 · BIOLOGY

3,4-Dibromo-7-Azaindole Modulates Arabidopsis Circadian Clock by Inhibiting Casein Kinase 1 Activity

Q2 · BIOLOGY

Article

Author: Yanai, Takeshi ; Matsuo, Hiromi ; Nakamichi, Norihito ; Ono, Azusa ; Kinoshita, Toshinori ; Fujimoto, Kazuhiro J ; Sato, Ayato

AbstractThe circadian clock is a timekeeping system for regulation of numerous biological daily rhythms. One characteristic of the circadian clock is that period length remains relatively constant in spite of environmental fluctuations, such as temperature change. Here, using the curated collection of in-house small molecule chemical library (ITbM chemical library), we show that small molecule 3,4-dibromo-7-azaindole (B-AZ) lengthened the circadian period of Arabidopsis thaliana (Arabidopsis). B-AZ has not previously been reported to have any biological and biochemical activities. Target identification can elucidate the mode of action of small molecules, but we were unable to make a molecular probe of B-AZ for target identification. Instead, we performed other analysis, gene expression profiling that potentially reveals mode of action of molecules. Short-term treatment of B-AZ decreased the expression of four dawn- and morning-phased clock-associated genes, CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1), LATE ELONGATED HYPOCOTYL (LHY), PSEUDO-RESPONSE REGULATOR 9 (PRR9) and PRR7. Consistently, amounts of PRR5 and TIMING OF CAB EXPRESSION 1 (TOC1) proteins, transcriptional repressors of CCA1, LHY, PRR9 and PRR7 were increased upon B-AZ treatment. B-AZ inhibited Casein Kinase 1 family (CK1) that phosphorylates PRR5 and TOC1 for targeted degradation. A docking study and molecular dynamics simulation suggested that B-AZ interacts with the ATP-binding pocket of human CK1 delta, whose amino acid sequences are highly similar to those of Arabidopsis CK1. B-AZ-induced period-lengthening effect was attenuated in prr5 toc1 mutants. Collectively, this study provides a novel and simple structure CK1 inhibitor that modulates circadian clock via accumulation of PRR5 and TOC1.

100 Deals associated with Dibromotyrosine

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KEGG	Wiki	ATC	Drug Bank
D08659	Dibromotyrosine	H03BX02	DB07637

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