Search

2,6-Dibromo-1,4-benzoquinone (2,6-DBBQ) and 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), two emerging halobenzoquinones (HBQs), have the highest detection frequencies and levels in drinking water among all HBQs. They are more toxic than the regulated disinfection byproducts. Quantitative structure toxicity relationship analysis predicted that HBQs are a class of potential bladder carcinogens. However, direct experimental evidence for the carcinogenicity of 2,6-DBBQ and 2,6-DCBQ is lacking and the associated toxicity mechanisms remain unclear. In this study, we confirmed the potential carcinogenicity of 2,6-DBBQ and 2,6-DCBQ using an in vitro malignant transformation assay, evaluated their cytotoxicity and genotoxicity, and investigated their toxicity mechanisms. The results showed that 2,6-DBBQ and 2,6-DCBQ significantly decreased the viability of human uroepithelial SV-HUC-1 cells and induced DNA damage in SV-HUC-1 cells, and chromosomal damage in HepG2 cells, and malignant transformation of SV-HUC-1 cells. Moreover, transcriptome sequencing revealed that 2,6-DBBQ and 2,6-DCBQ activated the p53-mediated cell cycle pathway in bladder cancer. In the p53-mediated cell cycle pathway, 2,6-DBBQ and 2,6-DCBQ induced cell cycle arrest at the S phase by downregulating p53 and upregulating p21. Additionally, 2,6-DBBQ and 2,6-DCBQ may have produced excessive reactive oxygen species, damaging DNA and chromosomes. These results not only first confirm the potential carcinogenicity of 2,6-DBBQ and 2,6-DCBQ but also provide an important reference for exploring the cytotoxicity and genotoxicity mechanisms of these HBQs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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 (EC 50 : 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 (EC 50  ≥ 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Numerous toxic substances are directly and indirectly discharged by humans into water bodies, causing distress to the organisms living on it. 6PPD, an amino antioxidant from tires reacts with ozone to form 6PPD-Q, which has garnered global attention due to its lethal nature to various organisms. This review aims to provide an understanding of the sources, transformation, and fate of 6PPD-Q in water and the current knowledge on its effects on aquatic organisms. Furthermore, we discuss research gaps pertaining to the mechanisms by which 6PPD-Q acts within fish bodies. Previous studies have demonstrated the ubiquitous presence of 6PPD-Q in the environment, including air, water, and soil. Moreover, this compound has shown high lethality to certain fish species while not affecting others. Toxicological studies have revealed its impact on the nervous system, intestinal barrier function, cardiac function, equilibrium loss, and oxidative stress in various fish species. Additionally, exposure to 6PPD-Q has led to organ injury, lipid accumulation, and cytokine production in C. elegans and mice. Despite studies elucidating the lethal dose and effects of 6PPD-Q in fish species, the underlying mechanisms behind these symptoms remain unclear. Future studies should prioritize investigating the mechanisms underlying the lethality of 6PPD-Q in fish species to gain a better understanding of its potential effects on different organisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Caenorhabditis elegans is a useful model for examining metabolic processes and related mechanisms. We here examined the effect of exposure to N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ) on dopamine metabolism and underling molecular basis in nematodes. The dopamine content was reduced by 6-PPDQ (1 and 10 μg/L). Meanwhile, dopamine related behaviors (basal slowing response and area restricted searching) were changed by 6-PPDQ (1 and 10 μg/L). Exposure to 6-PPDQ (1 and 10 μg/L) decreased expressions of genes (cat-2 and bas-1) encoding enzymes governing dopamine synthesis and cat-1 encoding dopamine transporter. Development of dopaminergic neurons was also affected by 10 μg/L 6-PPDQ as reflected by decrease in fluorescence intensity, neuronal loss, and defect in dendrite development. Exposure to 6-PPDQ (1 and 10 μg/L) altered expressions of ast-1 and rcat-1 encoding upregulators of cat-2 and bas-1. The dopamine content and expressions of cat-2 and bas-1 were inhibited by RNAi of ast-1 and increased by RNAi of rcat-1 in 6-PPDQ exposed nematodes. Using endpoints of locomotion behavior and brood size, in 6-PPDQ exposed nematodes, the susceptibility to toxicity was caused by RNAi of ast-1, cat-2, bas-1, and cat-1, and the resistance to toxicity was induced by RNAi of rcat-1. Therefore, 6-PPDQ exposure disrupted dopamine metabolism and the altered molecular basis for dopamine metabolism was associated with 6-PPDQ toxicity induction. Moreover, the defects in dopamine related behaviors and toxicity on locomotion and reproduction could be rescued by treatment with 0.1 mM dopamine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The antioxidant N-(1,3-Dimethylbutyl)-N'-phenyl-p- phenylenediamine (6PPD) is used to protect the rubber in tires from oxidation, which extends the life of the tire. When oxidized, 6PPD is transformed into 6PPD-quinone (6PPDQ). 6PPDQ, along with other tire ingredients, can enter aquatic ecosystems through the transport of tire wear particles in runoff during a precipitation event. The mass mortality of coho salmon following precipitation events in urban areas lead to the discovery that 6PPDQ is the likely cause due to coho salmon's relatively high sensitivity to 6PPDQ. The assessment of 6PPDQ toxicity to other aquatic species has expanded, but it has focused on fish. This study investigated the toxicity of 6PPDQ to four freshwater invertebrate species, larval burrowing mayfly (Hexagenia spp.), juvenile cladoceran (Daphnia magna), file ramshorn snail embryo (Planorbella pilsbryi), and adult washboard mussel (Megalonaias nervosa). For all four species, the highest concentration of 6PPDQ tested did not result in significant mortality. This translated into the determination of the highest concentration that did not cause significant mortality (NOEC) for Hexagenia spp., D. magna, P. pilsbryi, and M. nervosa of 232.0, 42.0, 11.7, and 17.9 μg/L, respectively. The data from this study indicate that freshwater invertebrates are not as sensitive to 6PPDQ as some salmonid species (e.g., coho salmon Oncorhynchus kisutch). This study also analyzed 6PPDQ in road runoff from around the city of Guelph in Ontario, Canada. 6PPQ was detected in all samples but the concentration was two orders of magnitude lower than the NOECs for the four tested species of freshwater invertebrate., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Ryan Prosser reports financial support was provided by a Natural Sciences and Engineering Research Council of Canada Discovery Grant., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Although it has been shown that exposure to 6-PPDQ can cause toxicity on environmental organisms, its possible effects on metabolic state remain largely unclear. We here determined the effect of 6-PPDQ exposure on lipid accumulation in Caenorhabditis elegans. We observed increase in triglyceride content, enhancement in lipid accumulation, and increase in size of lipid droplets in 6-PPDQ (1-10 μg/L) exposed nematodes. This detected lipid accumulation was associated with both increase in fatty acid synthesis reflected by increased expressions of fasn-1 and pod-2 and inhibition in mitochondrial and peroxisomal fatty acid β-oxidation indicated by decreased expressions of acs-2, ech-2, acs-1, and ech-3. The observed lipid accumulation in 6-PPDQ (1-10 μg/L) exposed nematodes was also related to the increase in synthesis of monounsaturated fatty acylCoAs reflected by altered expressions of fat-5, fat-6, and fat-7. Exposure to 6-PPDQ (1-10 μg/L) further increased expressions of sbp-1 and mdt-15 encoding two metabolic sensors to initiate the lipid accumulation and to regulate the lipid metabolism. Moreover, the observed increase in triglyceride content, enhancement in lipid accumulation, and alterations in fasn-1, pod-2, acs-2, and fat-5 expressions in 6-PPDQ exposed nematodes were obviously inhibited by sbp-1 and mdt-15 RNAi. Our observations demonstrated the risk of 6-PPDQ at environmentally relevant concentration in affecting lipid metabolic state in organisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Polychlorinated biphenyls (PCBs) are notorious environmental pollutants. For their hydrophobic and lipophilic capability, they are wildly spread to environment to threat human health thus attracts more attention. In this study, we observed increasing numbers of CD163 positive (CD163 + ) macrophages in aortic valve of ApoE -/- mice after 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ) treatment, the metabolite of polychlorinated biphenyl. In addition, in vitro studies identified that PCB29-pQ exposure significantly provoked the shifting of RAW264.7 macrophages and bone marrow derived monocytes (BMDMs) to CD163 + macrophages. Upon PCB29-pQ administration, CD163 and CD206 levels were enhanced in RAW264.7 cells as well as in BMDMs. However, the concentration of iron and total cholesterol (TC) were reduced due to the boosting of ferroportin (Fpn) and ATP binding cassette transporter, subfamily A, member 1 (ABCA1) which are efflux transporters of iron and cholesterol individually. Further investigation on mechanism indicated that PCB29-pQ exposure induced reactive oxygen species (ROS), which may result in activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a protein responsible for macrophage polarization. After that, we blocked Nrf2 through Nrf2 shRNA and ROS scavenger NAC, which significantly reversed the shifting of macrophage to CD163 + sub-population. These results confirmed the importance of Nrf2 in inducing macrophage polarization. In short, our study uncovered that PCB29-pQ could promote macrophage/monocyte polarization to CD163 + macrophage which would be a potential incentive to accelerate atherosclerosis through Nrf2 signaling pathway., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

2,6-dichlorobenzoquinone (2,6-DCBQ), an emerging disinfection by-production, frequently occurs in reclaimed water and drinking water. However, limited information was available regarding its toxicity. To evaluate its impact, zebrafish at early life stage were exposed to 0, 10, 30, 60, 90, or 120 μg L -1 2,6-BDCQ for 72 h. Our results indicated that 2,6-BDCQ decreased zebrafish's survival rate to 65% and 44% at 90 and 120 μg L -1 treatments and increased its aberration rate to 11% and 26% at 90 μg L -1 and 120 μg L -1 treatments. Besides, 2,6-BDCQ had adverse effect on its oxidative stress (elevated superoxide dismutase activity), lipid peroxidation (increased malondialdehyde levels), DNA damage (increased 8-hydroxydeoxyguanosine contents) and apoptosis (increased caspase-3 activity). Although lower concentrations (≤60 μg L -1 ) of 2,6-BDCQ didn't exhibit significant effect on its survival development or lipid peroxidation of zebrafish, they induced obvious DNA damage and apoptosis occurrence. These results revealed 2,6-BDCQ caused genotoxicity and cytotoxicity to zebrafish. This study provides novel insight into 2,6-DCBQ-induced toxicity in zebrafish., (Copyright © 2018. Published by Elsevier Ltd.)

Benzene is widely employed in the field of production, and its toxicity on biological systems has received increasing attention. Cell proliferation is a major life characteristic of living organisms. KLF15 and NOTCH1 are mature and classical genes in cell proliferation studies, particularly in the area of tumor investigation. The aim of this study was to investigate the effect and mechanism of VNN3 on cell proliferation induced by 1,4-benzoquinone (1,4-BQ), an important metabolite of benzene, and obtain a sensitive biomarker for the hazard screening and health care of benzene exposure. Normally growing AHH-1 cells were cultured in vitro and were incubated with different concentrations of 1,4-BQ (0, 10, 20, and 40 μM) for 24 h. A CCK-8 assay was used to assess the cell viability, whereas EdU was used to detect the cell proliferation of AHH-1 cells. The expression of VNN3, KLF15 and NOTCH1 was detected by real-time PCR. Moreover, a lentiviral model was constructed in AHH-1 cells to interfere with VNN3 expression. The results showed that 1,4-BQ clearly increased the expression of VNN3. Moreover, 1,4-BQ dose-dependently inhibited cell proliferation and caused increased KLF15 expression; in contrast, the NOTCH1 expression decreased in AHH-1 cells. Furthermore, following interference with the VNN3 expression, the cell proliferation inhibition and the expression of KLF15 and NOTCH1 were rescued. To further investigate the action of VNN3 in benzene hematotoxicity, we assessed it in benzene-exposed workers. The results showed that there was a remarkable correlation between the VNN3 expression and hemogram, which included RBC, NEUT and HGB. In addition, analysis of the KLF15 and NOTCH1 expression showed that the VNN3 expression was related to cell proliferation, which was consistent with the in vitro results. In conclusion, VNN3 influences cell proliferation induced by 1,4-BQ by regulating the expression of KLF15 and NOTCH1. VNN3 may represent a potential biomarker of benzene toxicity., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Exposure to benzene is inevitable, and concerns regarding the adverse health effects of benzene have been raised. Most investigators found that benzene exposure induced hematotoxicity. In this regard, Our study aimed to explore a novel potential biomarker of adverse health effects following benzene exposure and the toxic mechanisms of benzene metabolites in vitro. This study consisted of 314 benzene-exposed workers and 288 control workers, an air benzene concentration of who were 2.64 ± 1.60 mg/m 3 and 0.05 ± 0.01 mg/m 3 , respectively. In this population-based study, miR-34a expression was elevated in benzene-exposed workers. The correlation of miR-34a with the airborne benzene concentration, S-phenylmercapturic acid (S-PMA) and trans, trans-muconic acid (t, t-MA), all of which reflect benzene exposure, was found. Correlation analysis indicated that miR-34a was associated with peripheral blood count, alanine transaminase (ALT) and oxidative stress. Furthermore, multivariate analysis demonstrated that miR-34a expression was strongly associated with white blood cell count (structure loadings = 0.952). In population-based study, miR-34a had the largest contribution to altered peripheral blood counts, which reflect benzene-induced hematotoxicity. The role of miR-34a in benzene toxicity was assessed using lentiviral vector transfection. Results revealed that 1,4-benzoquinone induced abnormal cell apoptosis and simultaneously upregulated miR-34a accompanied with decreased Bcl-2. Finally, inhibition of miR-34a elevated Bcl-2 and decreased 1,4-benzoquinone-induced apoptosis. In conclusion, miR-34a was observed to be involved in benzene-induced hematotoxicity by targeting Bcl-2 and could be regarded as a potential novel biomarker for benzene toxicity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Multiple-drug combination therapy is becoming more common in the treatment of advanced cancers because this approach can decrease side effects and delay or prevent drug resistance. In the present study, we developed hyaluronic acid (HA)-decorated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (HA-PLGA NPs) for co-delivery of docetaxel (DTX) and tanespimycin (17-AAG). DTX and 17-AAG were simultaneously loaded into HA-PLGA NPs using an oil-in-water emulsification/solvent evaporation method. Several formulations were tested. HA-PLGA NPs loaded with DTX and 17-AAG at a molar ratio of 2:1 produced the smallest particle size (173.3±2.2nm), polydispersity index (0.151±0.026), and zeta potential (-12.4±0.4mV). Approximately 60% and 40% of DTX and 17-AAG, respectively, were released over 168h in vitro. Cytotoxicity assays performed in vitro using MCF-7, MDA-MB-231, and SCC-7 cells showed that dual drug-loaded HA-PLGA NPs at a DTX:17-AAG molar ratio of 2:1 exhibited the highest synergistic effect, with combination index values of 0.051, 0.036, and 0.032, respectively, at the median effective dose. Furthermore, synergistic antitumor activity was demonstrated in vivo in a CD44 and RHAMM (CD168) - overexpressing squamous cell carcinoma (SCC-7) xenograft in nude mice. These findings indicated that nanosystem-based co-delivery of DTX and 17-AAG could provide a promising combined therapeutic strategy for enhanced antitumor therapy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)