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Carbon black exposure causes oxidative stress, inflammation and genotoxicity. The objective of this systematic review was to assess the contributions of primary (i.e. direct formation of DNA damage) and secondary genotoxicity (i.e., DNA lesions produced indirectly by inflammation) to the overall level of DNA damage by carbon black. The database is dominated by studies that have measured DNA damage by the comet assay. Cell culture studies indicate a genotoxic action of carbon black, which might be mediated by oxidative stress. Many in vivo studies originate from one laboratory that has investigated the genotoxic effects of Printex 90 in mice by intra-tracheal instillation. Meta-analysis and pooled analysis of these results demonstrate that Printex 90 exposure is associated with a slightly increased level of DNA strand breaks in bronchoalveolar lavage cells and lung tissue. Other types of genotoxic damage have not been investigated as thoroughly as DNA strand breaks, although there is evidence to suggest that carbon black exposure might increase the mutation frequency and cytogenetic endpoints. Stratification of studies according to concurrent inflammation and DNA damage does not indicate that carbon black exposure gives rise to secondary genotoxicity. Even substantial pulmonary inflammation is at best only associated with a weak genotoxic response in lung tissue. In conclusion, the review indicates that nanosized carbon black is a weak genotoxic agent and this effect is more likely to originate from a primary genotoxic mechanism of action, mediated by e.g., oxidative stress, than inflammation-driven (secondary) genotoxicity. [ABSTRACT FROM AUTHOR]

• Nanoclay surface modification reduces pro-inflammatory response in both cell lines. • GO and r-GO induced a pro-inflammatory response in A549 cells. • Strong in vitro-in vivo correlation of nanomaterials-induced inflammation. • Most materials induced genotoxicity in THP-1 and only one in A549 cells. • Concordant genotoxicity between THP-1a cells and BAL cells. Nanoclays and graphene oxide nanomaterials represent a class of materials sharing similar shapes constituted of high aspect ratio platelets. The increased production of these materials for various industrial applications increases the risk of occupational exposure, consequently with elevated risk of adverse reactions and development of pulmonary diseases, including lung cancer. In this study, pro-inflammatory responses and genotoxicity were assessed in alveolar epithelial cells (A549) and activated THP-1 macrophages (THP-1a) after exposure to three nanoclays; a pristine (Bentonite) and two surface modified (benzalkonium chloride-coated Nanofil9, and dialkyldimethyl-ammonium-coated NanofilSE3000); graphene oxide (GO) and reduced graphene oxide (r-GO) nanomaterials. The pro-inflammatory response in terms of IL-8 expression was strongest in cells exposed to Bentonite, whereas surface modification resulted in decreased toxicity in both cell lines when exposed to Nanofil9 and NanofilSE3000. GO and r-GO induced a pro-inflammatory response in A549 cells, while no effect was detected with the two nanomaterials on THP-1a cells. The pro-inflammatory response was strongly correlated with in vivo inflammation in mice after intra-tracheal instillation when doses were normalized against surface area. Genotoxicity was assessed as DNA strand breaks, using the alkaline comet assay. In A549 cells, an increase in DNA strand breaks was detected only in cells exposed to Bentonite, whereas Bentonite, NanofilSE3000 and GO caused an increased level of genotoxicity in THP-1a cells. Genotoxicity in THP-1a cells was concordant with the DNA damage in bronchoalveolar lavage fluid cells following 1 and 3 days after intra-tracheal instillation in mice. In conclusion, this study shows that surface modification of pristine nanoclays reduces the inflammatory and genotoxic response in A549 and THP-1a cells, and these in vitro models show comparable toxicity to what seen in previous mouse studies with the same materials. [ABSTRACT FROM AUTHOR]

Female C57BL/6J mice were fed a regular low-fat diet or high-fat diets combined with either high or low protein-to-sucrose ratios during their entire lifespan to examine the long-term effects on obesity development, gut microbiota, and survival. Intake of a high-fat diet with a low protein/sucrose ratio precipitated obesity and reduced survival relative to mice fed a low-fat diet. By contrast, intake of a high-fat diet with a high protein/sucrose ratio attenuated lifelong weight gain and adipose tissue expansion, and survival was not significantly altered relative to low-fat-fed mice. Our findings support the notion that reduced survival in response to high-fat/high-sucrose feeding is linked to obesity development. Digital gene expression analyses, further validated by qPCR, demonstrated that the protein/sucrose ratio modulated global gene expression over time in liver and adipose tissue, affecting pathways related to metabolism and inflammation. Analysis of fecal bacterial DNA using the Mouse Intestinal Tract Chip revealed significant changes in the composition of the gut microbiota in relation to host age and dietary fat content, but not the protein/sucrose ratio. Accordingly, dietary fat rather than the protein/sucrose ratio or adiposity is a major driver shaping the gut microbiota, whereas the effect of a high-fat diet on survival is dependent on the protein/sucrose ratio. [ABSTRACT FROM AUTHOR]

The gene RAI was originally described as an inhibitor of RelA/p65 subunit of nuclear factor κB (NF-κB). Here, we analyse the association between genetic variation in the genes RAI and CD3EAP and outcome of 348 myeloma patients treated with high-dose treatment (HDT), 146 patients treated with interferon-α (INF-α) as maintenance treatment, 177 patients treated with thalidomide, and 74 patients treated with bortezomib at relapse and address if the effects of polymorphisms in CD3EAP and RAI are modified by a functional polymorphism in NFКB1. By linkage disequilibrium mapping, we found that variant alleles of several polymorphisms in a sub-region of 19q13.3 spanning the regions RAI-intron1-1 to RAI intron1-3 and the region exon1 to exon3–6 in CD3EAP were associated with prolonged time-to-treatment failure (TTF; p = 0.003) and overall survival (OS; p = 0.02). Haplotype analyses revealed that none of the haplotypes were more strongly associated to TTF or OS than the two strongly linked SNPs, RAI-intron1-1 (rs4572514) and CD3EAP G-21A (rs967591). The association of RAI-intron1-1 and CD3EAP G-21A with TTF was independent of NFKB1-94 ins/del, but homozygous ins-allele carriers which were also variant allele carriers of RAI-intron1-1 or CD3EAP G-21A had the longest OS. Among patients treated with INF-α or thalidomide, no effect was seen in relation to genotype. Our results indicate that polymorphism in RAI and CD3EAP are associated with outcome of myeloma patients treated with HDT. Combination analyses with the functional polymorphism in NFKB1 suggest that a possibly functional effect of RAI or CD3EAP could be related to NF-κB availability. [ABSTRACT FROM AUTHOR]