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In this paper, we study the controllability of multi-agent systems by equitable partition and automorphism. For the case that cells are incompletely connected outside but completely connected inside, a necessary condition for controllability is given from the perspective of the rank of connection matrix. For the case of multiple cells being completely connected outside and incompletely connected inside, in terms of the eigenvalues and eigenvectors of L and L π , several sufficient and necessary conditions for controllability are presented. Once the quotient graph is controllable under single input or all nodes in nontrivial cells are leaders, the lower bound of controllable subspace is determined. Finally, we give the gap between the necessary condition and the sufficient condition for controllability from the aspect of equitable partition. One highlight of the results in this paper is that we show sufficient conditions to judge controllability by equitable partition and automorphism, which, for specific cases, provides one method that how to break through the defect that equitable partition can only obtain necessary conditions. [ABSTRACT FROM AUTHOR]

Abstract Polychlorinated biphenyls (PCBs) are persistent organic pollutants and hazardous to human health. Aflatoxin B1 (AFB1) is a strong carcinogen dependent on activation by cytochrome P450 (CYP) 1A2 and 3A4. Humans in some regions may be exposed to both PCBs and AFB1. Since PCBs are CYP inducers, we were interested in their combined genotoxicity. In this study, the effects of non-coplanar 2,3,3′-tri- (PCB 20), 2,2′5,5′-tetra- (PCB 52), 2,3,3′,4′-tetrachlorobiphenyl (PCB 56), and coplanar 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) on protein levels of CYP1A1, 1A2, and 3A4, and nuclear receptors AhR, CAR and PXR in a human hepatocyte (L-02) line were investigated. Moreover, the combined effects of each PCB and AFB1 for induction of micronuclei and double-strand DNA breaks (indicated by an elevation of γ-H2AX) were analyzed. The results indicated that PCBs 20, 52 and 56 reduced the expression of AhR, while elevated that of CAR and PXR, with thresholds at low micromolar concentrations. However, they were less potent than PCB 126, which was active at sub-nanomolar levels. Overexpression of human splice variant CAR 3 in the cells increased CYP1A2 and 3A4 levels, which were further enhanced by each non-coplanar PCB, suggesting a role of CAR in modulating CYPs. Pretreatment of cells with each test PCB potentiated both micronuclei formation and DNA damage induced by AFB1. This study suggests that both non-coplanar and coplanar PCBs may enhance the genotoxicity of AFB1, through acting on various nuclear receptors; the potentiation of AFB1 genotoxicity by PCBs and the potential health implications may deserve concerns and further investigation. Graphical abstract Image 1 Highlights • Both non-coplanar PCBs and PCB 126 induce CYP1A2 and 3A4 with varied potencies. • Non-coplanar PCBs and PCB 126 modulate nuclear receptors differentially. • Non-coplanar PCBs enhanced genotoxicity of AFB1 with potencies lower than PCB 126. [ABSTRACT FROM AUTHOR]

2-Ethylhexyl diphenyl phosphate (EHDPP) is a common flame retardant and environmental pollutant, exposing humans with endocrinal disrupting potentials. Its mutagenicity, especially following metabolism, remains unclear. In this study, molecular docking analysis indicated that EHDPP was a potential substrate for several human CYP enzymes except for CYP1A1. Among V79-derived cell lines genetically engineered for the expression of each CYP, EHDPP (6 h exposure/18 h recovery) did not induce micronuclei in the V79 or V79-derived cells expressing human CYP1A1, however, it was positive in V79-derived cell lines expressing human CYP2E1, 3A4, and 2B6. In a human hepatoma (HepG2) cell line, EHDPP (48 h exposure) moderately induced micronuclei, which was blocked by 1-aminobenzotriazole (ABT, 60 μM, inhibitor of CYPs); pretreating HepG2 cells with bisphenol AF, another organic pollutant as inducer of CYPs (0.1 μM for 16 h), significantly potentiated micronuclei formation by EHDPP, threshold being decreased from 10 to 1.25 μM. This effect was blocked by ABT, drastically reduced by ketoconazole (inhibiting CYP3A expression/activity), and moderately inhibited by trans-1,2-dichloroethylene (selective CYP2E1 inhibitor). Immunofluorescent centromere protein B staining indicated that EHDPP-induced micronuclei in V79-derived cell lines expressing human CYP2E1 and 3A4 were predominantly centromere-negative, and that in HepG2 cells pretreated with bisphenol AF (for inducing multiple CYPs) were purely centromere-negative. In bisphenol AF-pretreated HepG2 cells EHDPP potently induced DNA breaks, as indicated by the comet assay and Western blot analysis of γ-H2AX. In conclusion, our study suggests that EHDPP is potently clastogenic, following activation by several human CYP enzymes, CYP3A4 being a major one. [Display omitted] • 2-Ethylhexyl diphenyl phosphate (EHDPP) induces chromosome/DNA breaks. • Genotoxicity of EHDPP depends on metabolic activation by human CYP enzymes. • EHDPP is activated by multiple human CYP enzymes, CYP3A4 having major contribution. [ABSTRACT FROM AUTHOR]

Benzene is a recognized environmental leukemogen, however, the mechanisms for its carcinogenesis have not been fully elucidated. Recently, miR-221, a suggested oncogene involved in a number of malignancies, has been detected with elevated expression levels in blood cells of patients with leukemia. To explore whether benzene exposure has an effect on the expression of miR-221, a population based cross-sectional study was conducted in southern China, with 97 petrol station attendants as the exposure group and 103 general residents as the control group. Plasma benzene was analyzed by using GC∖MS. miR-221 in peripheral blood lymphocytes were measured by qRT-PCR and the ΔCt value for each sample was calculated by normalizing the Ct value for miR-221 with U6 RNA (i.e., ΔCt = Ct miR-221 − Ct U6 ). Potential confounding factors were taken into account. Pearson correlation, univariate and multivariate logistic regression were performed in statistical analysis. The results showed that the air concentrations of benzene were significantly higher in petrol stations than in control sites ( P < 0.05); The levels of benzene and miR-221 in exposure group were both significantly higher than in control group ( P < 0.05) and there was a significant positive correlation between the two indexes ( r = 0.851, P < 0.05); An association between benzene levels and the ΔCt values for miR-221 was identified by univariate and multivariate logistic analysis (OR 0.274; 95%CI 0.117, 0.396). Our investigation indicates that benzene exposure may be related to elevated miR-221 expression in human lymphocytes. [ABSTRACT FROM AUTHOR]

Abstract Polychlorinated biphenyls (PCBs) as a group of persistent organic pollutants are confirmed human carcinogens; however, their mutagenicity remains mostly unknown. We have reported the mutagenicity of some PCBs with one to four chlorines in mammalian cells expressing human CYP2E1. To further explore the structural requirements for the mutagenicity of PCBs, eight tri- and tetrachlorobiphenyls untested before were investigated for the induction of gene mutations and micronuclei in a V79-derived cell line expressing both human CYP2E1 and sulfotransferase (SULT) 1A1 (V79-hCYP2E1-hSULT1A1), with SULT1A1 activity inhibited by pentachlorophenol, a potent SULT1 inhibitor. 2,2′,6-Tri-, 2,3′,6-tri, 2,4′,6-tri-, and 2,2′,5-trichlorobiphenyls (PCBs 19, 27, 32, and 18, respectively) induced micronuclei and gene mutations in V79-hCYP2E1-hSULT1A1 cells, at potencies slightly higher than 2,6-dichlorobiphenyl, but one order of magnitude below that by 2,3,3′- and 2,3,4′-trichlorobiphenyls as reported recently; in the parental V79-Mz cells, they were nonmutagenic and weak in micronuclei induction. Among the four tetrachlorobiphenyls with varying number of ortho chlorines, 2,3,3′,4′-tetrachlorobiphenyl (PCB 56) induced both micronuclei and gene mutations in V79-hCYP2E1-hSULT1A1 cells with a potency greater than the above compounds; however, 2,2′,3,3′-tetrachlorobiphenyl was equivocal and 2,2′,3,6′-tetra- and 2,2′,6,6′-tetrachlorobiphenyls inactive in V79-hCYP2E1-hSULT1A1 cells. Immunofluorescent staining of micronuclei formed by PCBs 32 and 56 in V79-hCYP2E1-hSULT1A1 cells with centromere protein B antibodies indicated that they were predominantly whole chromosomes, implying aneugenic potentials. This study suggests that tri- and tetrachlorobiphenyls with a single ortho chlorine can be most mutagenic under activation by human CYP2E1, and greater numbers of ortho chlorines may cause a drastic decline in the activity, especially for tetrachlorobiphenyls. Highlights • Activation of tetra-Cl-PCBs by CYP2E1 is limited by the increase in ortho chlorines. • Distinct structure-mutagenicity relationships exist between tri- and tetra-Cl-PCBs. • Human CYP2E1 can activate some noncoplanar PCBs for aneugenic potentials. [ABSTRACT FROM AUTHOR]

Heavy metals, such as cadmium and lead, are ubiquitously present as single substances and compounds in the environment. These substances have various and overlapping health effects. Consumption of contaminated foods is the main pathway of the human exposure, however, estimation of their dietary exposure in combination with health risk analysis, particularly at various endpoints, has rarely been reported. In this study, we integrated relative potency factor (RPF) analysis into the margin of exposure (MOE) model to evaluate the health risk of combined heavy metal (including cadmium, arsenic, lead, chromium, and nickel) exposure in the residents in Guangzhou, China, after quantifying the heavy metals in various food samples and estimating their dietary exposure. The results indicated that rice, rice products and leafy vegetables contributed primarily to the dietary exposure of all metals except arsenic, which exposed the population largely through consumption of sea-foods. With all the five metals contributing to nephro- and neurotoxicity, the 95% confidence limits of MOE for the residents were clearly below 1.0 in the 3∼6-year group, suggesting a recognizable risk to young children. This study provides substantial evidence for the non-negligible health risk in young children due to increased heavy metal exposure,at least on some toxicity targets. [Display omitted] • Relative potency factor and margin of exposure were used for risk analysis of metals. • Rice/rice products/leafy vegetables contributed largely to Cd, Pb, Cr & Ni exposure. • Multiple toxicity endpoints were evaluated based on combined metal exposure. • Children at 3–6 years were especially prone to dietary metal-associated health risks. [ABSTRACT FROM AUTHOR]

As a new-type flame retardant and toxic substance, triphenyl phosphate (TPP) is a ubiquitous pollutant present even in human blood. TPP is transformed by human CYP enzymes to oxidized/dealkylated metabolites. The impact of TPP metabolism on its toxicity, however, remains unclear. In this study, the genotoxicity of TPP in several mammalian cell lines and its relevance to CYP/sulfortransferase (SULT) activities were investigated. The results indicated that TPP induced micronucleus formation at ≥1 μM concentrations in a human hepatoma (C3A, endogenous CYPs being substantial) cell line, which was abolished by 1-aminobenzotriazole (CYPs inhibitor). In cell line HepG2 (parental to C3A with lower CYP expression) TPP was inactive up to 10 μM, while pretreatment with ethanol (CYP2E1 inducer), PCB 126 (CYP1A inducer), or rifampicin (CYP3A inducer) led to micronucleus formation by TPP. In V79-Mz and V79-derived cells expressing human CYP1A1 TPP was inactive (up to 32 μM), and in cells expressing human CYP1B1, 2B6 and 3A4 it induced micronucleus weakly (positive only at 32 μM). However, TPP induced micronucleus potently in V79-derived cells expressing human CYP1A2, while this effect was drastically reduced by human SULT1A1 co-expression; likewise, TPP was inactive in cells expressing both human CYP2E1 and SULT1A1, but became positive with pentachlorophenol (inhibitor of SULT1) co-exposure. Moreover, in C3A cells TPP selectively induced centromere-free micronucleus (immunofluorescent assay), and TPP increased γ-H2AX (by Western blot, indicating double-strand DNA breaks). In conclusion, this study suggests that TPP is potently clastogenic, human CYP1A2 and 2E1 being major activating enzymes while SULT1A1 involved in detoxification. • Triphenyl phosphate (TPP) induced genotoxic effect in mammalian cells. • The genotoxicity of TPP depended on metabolic activation by human CYP enzymes. • Human CYP1A2 and 2E1 were the major metabolic enzymes involved in activating TPP. • The mode of TPP-induced chromosome damage appeared to be purely clastogenesis. [ABSTRACT FROM AUTHOR]

Polychlorinated biphenyls (PCBs) are a group of persistent organic pollutants with confirmed carcinogenicity to humans. Metabolic activation of lower chlorinated PCBs to genotoxic metabolites may involve hydroxylation and further oxidation, and some hydroxylated metabolites may be sulfo-conjugated. However, the genotoxicity of individual PCB compounds is largely unknown. In this study, 15 mono- and dichlorobiphenyls were investigated for genotoxicity using the micronucleus and Hprt mutagenicity assays in a Chinese hamster V79-derived cell line expressing both human cytochrome P450 (CYP) 2E1 and human sulfotransferase (SULT) 1A1 (V79-hCYP2E1-hSULT1A1). All tested compounds were inactive in both assays in V79 control cells. However, eight dichlorobiphenyls strongly induced micronuclei and other congeners were weakly positive for this endpoint in V79-hCYP2E1-hSULT1A1 cells. The effects of each PCB in V79-hCYP2E1-hSULT1A1 cells were abolished or reduced in the presence of a CYP2E1 inhibitor (1-aminobenzotriazole), or enhanced by pretreatment of the cells with (CYP2E1-inducing) ethanol, while the genotoxicity was not significantly affected by a SULT1 inhibitor (pentachlorophenol). As representative dichlorobiphenyls, PCB 5, 10, 8 and 11 (2,3-, 2,5-, 2,4ʹ- and 3,3ʹ-dichlorobiphenyl, respectively) strongly induced Hprt gene mutations in V79-hCYP2E1-hSULT1A1 cells in a concentration-dependent manner. This is the first indication that human CYP2E1 is capable of converting a series of dichlorobiphenyls to strong mutagens. [ABSTRACT FROM AUTHOR]

Polybrominated biphenyl ethers (PBDEs) are a group of persistent organic pollutants with endocrine-disrupting, neurotoxic, tumorigenic and DNA-damaging activities. They are hydroxylated by human liver microsomal CYP enzymes, however, their mutagenicity remains unknown. In this study, 2,2′,4,4′-tetrabromobiphenyl ether (BDE-47, relatively abundant in human tissues) was investigated for micronuclei induction and DNA damage in mammalian cells. The results indicated that BDE-47 up to 80 μM under a 6 h/18 h (exposure/recovery, covering 2 cell cycles) regime did not induce micronuclei in V79-Mz and V79-derived cell lines expressing human CYP1A1 or 1A2, while it was moderately positive in human CYP2B6-, 2E1-and 3A4-expressing cell lines (V79-hCYP2B6, V79-hCYP2E1-hSULT1A1 and V79-hCYP3A4-hOR, respectively). Following 24 h exposure, BDE-47 induced micronuclei in V79-hCYP2E1-hSULT1A1 and V79-hCYP3A4 cells at increased potencies. In the human hepatoma (HepG2) cells BDE-47 (48 h exposure) was inactive up to 40 μM, however, pretreatment of the cells with ethanol (0.2%, v:v, inducer of CYP2E1) or rifampicin (10 μM, inducer of CYP3A4) led to significant micronuclei formation by BDE-47; pretreatment with bisphenol AF (100 nM) also potentiated BDE-47-induced micronuclei formation (which was blocked by a CYP2E1 inhibitor trans -1,2-dichloroethylene or a CYP3A inhibitor (ketoconazole). Immunofluorescent staining of centromere protein B with the micronuclei formed by BDE-47 in HepG2 cells pretreated with ethanol or rifampicin demonstrated selective formation of centromere-containing micronuclei. The increased phosphorylation of both histones H2AX and H3 in HepG2 by BDE-47 also indicated an aneugenic potential. Therefore, this study suggests that BDE-47 is an aneugen activated by several human CYP enzymes. [Display omitted] • 2,2′,4,4′-Tetrabromobiphenyl ether (BDE-47) is aneugenic in mammalian cells. • The aneugenicity of BDE-47 depends on metabolic activation by human CYP enzymes. • Human CYP3A4 and 2E1 might be the major enzymes activating BDE-47. [ABSTRACT FROM AUTHOR]

1-Methylpyrene (1-MP) is a ubiquitous environmental pollutant and rodent carcinogen. Its mutagenic activity depends on sequential activation by various CYP and sulfotransferase (SULT) enzymes. Previously we have observed induction of micronuclei and mitotic arrest by 1-MP in a Chinese hamster (V79)-derived cell line expressing both human CYP1A2 and SULT1A1 (V79-hCYP1A2-hSULT1A1), however, the mode of chromosome damage and the involvement of mitotic tubulin structures have not been clarified. In this study, we used immunofluorescent staining of centromere protein B (CENP-B) with the formed micronuclei, and that of β- and γ-tubulin reflecting the structures of mitotic spindle and centrioles, respectively, in V79-hCYP1A2-hSULT1A1 cells. The results indicated that 1-MP induced micronuclei in V79-hCYP1A2-hSULT1A1 cells from 0.125 to 2 μM under a 24 h/0 h (exposure/recovery) regime, while in the parental V79-Mz cells micronuclei were induced by 1-MP only at concentrations ≥ 8 μM; in both cases, the micronuclei induced by 1-MP were predominantly CENP-B positive. Following 54 h of exposure, 1-MP induced mitotic spindle non-congression and centrosome amplification (multipolar mitosis) in V79-hCYP1A2-hSULT1A1 cells, and anaphase/telophase retardation, at concentrations ≥ 0.125 μM with concentration-dependence; while in V79-Mz cells it was inactive up to 8 μM. This study suggests that in mammalian cells proficient in activating enzymes 1-MP may induce chromosome loss and mitotic disturbance, probably by interfering with the mitotic spindle and centrioles. 1-Methylpyrene is potently aneugenic in metabolism-proficient mammalian cells. 1-Methylpyrene may disrupt mitotic apparatus by interfering with tubulin. 1-Methylpyrene may retard mitotic progression. [ABSTRACT FROM AUTHOR]

• Subchronic arsenic exposure via food changes the gut microbiome. • Feces might be the main excreting pathway for arsenic from food exposure. • The toxicity of arsenic in staples should be comprehensively evaluated. • Gut microbiome interaction might be disturbed by arsenic. • Arsenic exposure would disturb carbohydrates, lipid, and amino acids metabolism of gut bacteria. Arsenic, a global pollutant and a threshold-free primary carcinogen, can accumulate in rice. Previous studies have focused on arsenic poisoning in drinking water and the effects on gut microbes. The research on arseniasis through food, which involves the bio-transformation of arsenic, and the related changes in gut microbiome is insufficient. Mice were exposed from animal feed prepared with four arsenic species (iAsIII, iAsV, MMA, and DMA) at a dose of 30 mg/kg according to the arsenic species proportion in rice for 30 days and 60 days. The levels of total arsenic (tAs) and arsenic species in mice feces and urine samples were determined using ICP-MS and HPLC-ICP-MS, respectively. 16S rRNA and ITS gene sequencing were conducted on microbial DNA extracted from the feces samples. At 30 days and 60 days exposure, the tAs levels excreted from urine were 0.0092 and 0.0093 mg/day, and tAs levels in feces were 0.0441 and 0.0409 mg/day, respectively. We found significant differences in arsenic species distribution in urine and feces (p < 0.05). In urine, the predominant arsenic species were iAsIII (23% and 14%, respectively), DMA (55% and 70%, respectively), and uAs (unknown arsenic, 14% and 10%, respectively). In feces, the proportion of major arsenic species (iAsV, 26% and 21%; iAsIII, 16% and 15%; MMA, 14% and 14%; DMA, 19% and 19%; and uAs, 22% and 29%, respectively) were evenly distributed. Microbiological analysis (MRPP test, α- and β-diversities) showed that diversity of gut bacteria was significantly related to arsenic exposure through food, but diversity of gut fungi is less affected. Manhattan plot and LEfSe analysis showed that arsenic exposure significantly changes microbial taxa, which might be directly associated with arsenic metabolism and diseases mediated by arsenic exposure, such as Deltaproteobacteria , Polynucleobacter , Saccharomyces , Candida , Amanitaceae, and Fusarium. Network analysis was used to identify the changing hub taxa in feces along with arsenic exposure. Function predicting analysis indicated that arsenic exposure might also significantly increase differential metabolic pathways and would disturb carbohydrates, lipid, and amino acids metabolism of gut bacteria. The results demonstrate that subchronic arsenic exposure via food significantly changes the gut microbiome, and the toxicity of arsenic in food, especially in staples, should be comprehensively evaluated in terms of the disturbance of microbiome, and feces might be the main pathway through which arsenic from food exposure is excreted and bio-transformed, providing a new insight into the investigation of bio-detoxification for arseniasis. [ABSTRACT FROM AUTHOR]