Low concentrations of antimony impair DNA damage signaling and the repair of radiation-induced DSB in HeLa S3 cells.

Antimony is utilized in a large variety of industrial applications, leading to significant environmental and occupational exposure. Mainly based on animal experiments, the IARC and MAK Commission have classified antimony and its inorganic compounds as Group 2B or 2 carcinogens, respectively. However, the underlying mode(s) of action are still largely unknown. In the present study, we investigated the impact of non-cytotoxic up to cytotoxic concentrations of SbCl3 on DNA DSB repair and cell cycle control in HeLa S3 cells. We induced DSB by γ-irradiation and analyzed inhibitory actions of antimony on potential molecular targets of the DSB repair machinery. Antimony disturbed cell cycle control, affecting phosphorylation of Chk1. Furthermore, the repair of DSB was impaired in the presence of antimony, as monitored by pulsed-field gel electrophoresis and γH2AX foci formation of cells in G1 and G2 phase. Specifically, BRCA1 and RAD51 were identified as molecular targets. Our results point towards an interference with both non-homologous end-joining (NHEJ) and homologous recombination (HR), and inhibitory effects may be explained by interactions with critical cysteine groups; this needs to be further investigated. Altogether, the results provide further evidence for the impairment of DNA repair processes as one underlying mechanism in antimony-induced carcinogenicity.

Impact of Concomitant Endometriosis on Phenotype and Natural History of Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) and endometriosis are immune-mediated chronic inflammatory disorders affecting young women. The clinical significance of concomitant endometriosis on the course of IBD has not been previously studied. The aim of this study was to determine whether women with concomitant endometriosis and IBD have a unique phenotype and worse prognosis of IBD. METHODS: This was a case-control study performed at a tertiary referral center. Cases were women with diagnoses of both endometriosis and IBD. Two random IBD controls without endometriosis were selected for each case, frequency matched for age and IBD type, Crohn's disease (CD) or ulcerative colitis. Primary outcomes included disease phenotype; the use of immunomodulators, antiTNF agents, or combination therapy and the need for IBD-related surgery. RESULTS: We identified 51 cases with endometriosis and IBD (28 CD, 23 ulcerative colitis). There was no difference in race, age at IBD diagnosis, and mean duration of IBD between endometriosis-IBD cases and controls. Among endometriosis-CD patients whose endometriosis was surgically verified, there was a higher risk for stricturing disease compared with CD controls (odds ratio, 11.8; 95% confidence interval, 2.03-69.0). There was no difference in phenotype in endometriosis-ulcerative colitis patients. There were no significant differences in IBD-related medication use or surgeries overall or when stratified by IBD type. CONCLUSIONS: Patients with CD and endometriosis, which was surgically diagnosed, were more likely to have stricturing CD. Concomitant endometriosis did not impact the natural history of IBD.

In vitro and in vivo genotoxicity investigations of differently sized amorphous SiO2 nanomaterials.

In vitro and in vivo genotoxic effects of differently sized amorphous SiO2 nanomaterials were investigated. In the alkaline Comet assay (with V79 cells), non-cytotoxic concentrations of 300 and 100-300µg/mL 15nm-SiO2 and 55nm-SiO2, respectively, relevant (at least 2-fold relative to the negative control) DNA damage. In the Alkaline unwinding assay (with V79 cells), only 15nm-SiO2 significantly increased DNA strand breaks (and only at 100µg/mL), whereas neither nanomaterial (up to 300µg/mL) increased Fpg (Formamidopyrimidine DNA glycosylase)-sensitive sites reflecting oxidative DNA base modifications. In the Comet assay using rat precision-cut lung slices, 15nm-SiO2 and 55nm-SiO2 induced significant DNA damage at ≥100µg/mL. In the Alkaline unwinding assay (with A549 cells), 30nm-SiO2 and 55nm-SiO2 (with larger primary particle size (PPS)) induced significant increases in DNA strand breaks at ≥50µg/mL, whereas 9nm-SiO2 and 15nm-SiO2 (with smaller PPS) induced significant DNA damage at higher concentrations. These two amorphous SiO2 also increased Fpg-sensitive sites (significant at 100µg/mL). In vivo, within 3 days after single intratracheal instillation of 360µg, neither 15nm-SiO2 nor 55nm-SiO2 caused genotoxic effects in the rat lung or in the bone marrow. However, pulmonary inflammation was observed in both test groups with findings being more pronounced upon treatment with 15nm-SiO2 than with 55nm-SiO2. Taken together, the study shows that colloidal amorphous SiO2 with different particle sizes may induce genotoxic effects in lung cells in vitro at comparatively high concentrations. However, the same materials elicited no genotoxic effects in the rat lung even though pronounced pulmonary inflammation evolved. This may be explained by the fact that a considerably lower dose reached the target cells in vivo than in vitro. Additionally, the different time points of investigation may provide more time for DNA damage repair after instillation.

Detailed exposure assessment of dietary furan for infants consuming commercially jarred complementary food based on data from the DONALD study.

Furan is a possible human carcinogen regularly occurring in commercially jarred complementary foods. This paper will provide a detailed exposure assessment for babies consuming these foods considering different intake scenarios. The occurrence data on furan in complementary foods were based on our own headspace-gas chromatography/mass spectrometry (HS-GC/MS) analytical results (n = 286). The average furan content in meals and menus was between 20 and 30 µg kg(-1), which is in excellent agreement with results from other European countries. Using measured food consumption data from the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) study, the average exposures for consumers of commercially jarred foods ranged between 182 and 688 ng kg(-1) bw day(-1), with a worst case scenario for P95 consumers ranging between 351 and 1066 ng kg(-1) bw day(-1). The exposure data were then used to characterize risk using the margin of exposure method based on a benchmark dose lower confidence limit for a 10% response (BMDL10) of 1.28 mg kg(-1) bw day(-1) for hepatocellular tumours in rats. The margin of exposures (MOEs) were below the threshold of 10 000, which is often used to define public health risks, in all scenarios, ranging between 7022 and 1861 for average consumers and between 3642 and 1200 for the P95 consumers. Mitigative measures to avoid furan in complementary foods should be of high priority for risk management.