The immunology of primary biliary cirrhosis: the end of the beginning?

The chronic liver disease primary biliary cirrhosis (PBC) is characterised by autoreactive B‐cell and T‐cell responses directed against mitochondrial antigens. In recent years these responses have been extensively characterised and the principal PBC associated autoantigen identified as pyruvate dehydrogenase complex (PDC). The identification of anti‐PDC responses (present in over 95% of PDC patients) has given rise to important questions pertinent to our understanding of the pathogenesis of PBC. What specific role to anti‐PDC responses play in target cell damage? How and why does immune tolerance break down to as highly conserved and ubiquitously expressed self‐antigen as PDC? Why does breakdown in tolerance to an antigen present in all nucleated cells result in damage restricted to the intra‐hepatic bile ducts? In attempting to answer these key questions we have, in this review, proposed a unifying hypothesis for the pathogenesis of PBC.     

毒物基因组学展望

本文介绍了毒物基因组学定义，并阐述了毒物基因组学对特异毒性、实验病理、混合物危险性评价、免疫毒理、神经毒理、生态毒理、预测毒理学等研究的突破性作用，是毒理学一次革命.     

High order interactions of xenobiotic metabolizing genes and P53 codon 72 polymorphisms in acute leukemia

Polymorphisms in xenobiotic metabolizing genes are associated with altered metabolism of carcinogens in acute leukemia (AL). This study applied two data mining approaches to explore potential interactions among P53 and xenobiotic metabolizing genes in 230 AL patients [131 acute myeloid leukemia (AML) and 99 acute lymphoblastic leukemia (ALL)] and 199 controls. Individually, none of the genotypes showed significant associations with AML risk. However, in ALL the CYP1A12A TC genotype was associated with increased risk (OR = 2.02; 95% CI = 1.14–3.58; P = 0.01), whereas the GSTM1 null genotype imparted reduced risk (OR = 0.55; 95% CI = 0.31–0.96; P = 0.03). In classification and regression tree analysis, combinations of GSTM1 present, CYP1A12C AA or GG, EPHX1 exon3 TC, and EPHX1 exon4 AA or GG genotype strongly enhanced the risk of AML (OR = 5.89; 95% CI = 1.40–26.62; P = 0.01). In ALL, combinations of CYP1A12A TT, P53 GG or CC and GSTP1 AG genotypes conferred the highest risk (OR = 4.19; 95% CI = 1.45–12.25; P = 0.004). In multifactor dimensionality reduction analysis, a four locus model (GSTP1, P53, EPHX1 exon3, and CYP1A12A) was the best predictor model for ALL risk. The association between this model and ALL risk remained true even at low prior probabilities of 0.01% (false positive report probability = 0.05). Interaction entropy interpretations of the best model of ALL revealed that two‐way interactions were mostly synergistic. These results suggest that high order gene–gene interactions play an important role in AL risk. Environ. Mol. Mutagen., 2012. © 2012 Wiley Periodicals, Inc.     

Variations in Digestive Physiology of Rats After Short Duration Flights Aboard the US Space Shuttle

The purpose of this work was to assess the influence of microgravity on several endogenous and microbial parameters of digestive physiology. On the occasion of two Spacelab Life Sciences missions, SLS-1 (a 9-day space flight) and SLS-2 (a 14-day space flight), Sprague-Dawley rats flown aboard the US space shuttle were compared to age-matched ground-based controls. In both flights, exposure to microgravity modified cecal fermentation: concentration and profile of short-chain fatty acids were altered, whereas urea and ammonia remained unchanged. Only in SLS-1 was there an induction of intestinal glutathione-S-transferase. Additional analyses in SLS-2 showed a decrease of hepatic CYP450 and of colonic goblet cells containing neutral mucin. After a postflight recovery period equal to the mission length, only modifications of the hepatic and intestinal xenobiotic metabolizing enzymes still persisted. These findings should help to predict the alterations of digestive physiology and detoxification potential likely to occur in astronauts. Their possible influence on health is discussed.     

Irreversible effects of trichloroethylene on the gut microbial community and gut‐associated immune responses in autoimmune‐prone mice

The developing immune system is particularly sensitive to immunotoxicants. This study assessed trichloroethylene (TCE)‐induced effects on the gut microbiome and cytokine production during the development in mice. Mice were exposed to TCE (0.05 or 500 μg/mL) at the levels that approximate to environmental or occupational exposure, respectively. Mice were subjected to a continuous developmental exposure to these doses encompassing gestation, lactation and continuing directly in the drinking water postnatally for 154 days (PND154) or PND259. To observe persistence of the effect TCE was removed from the drinking water in a subset of mice on PND154 and were provided regular drinking water until the study terminus (PND259). Abundance of total tissue‐associated bacteria reduced only in mice exposed to TCE until PND259. The ratio of Firmicutes/Bacteroidetes did not alter during this continuos exposure; however, cessation of high‐dose TCE at PND154 resulted in the increased abundance Bacteroidetes at PND259. Furthermore, high‐dose TCE exposure until PND259 resulted in a lower abundance of the genera Bacteroides and Lactobaccilus and increased abundance of genus Bifidobactrium and bacterial family Enterobacteriaceae. TCE exposure until PND154 showed significant changes in the production of interleukin‐33; that might play a dual role in maintaining the balance and homeostasis between commensal microbiota and mucosal health. At PND259, interleukin‐3, granulocyte‐macrophage colony‐stimulating factor and Eotaxin were altered in both, the continuous exposure and cessation groups, whereas only a cessation group had a higher level of KC that may facilitate infiltration of neutrophils. The irreversible effects of TCE after a period of exposure cessation suggested a unique programming and potential toxicity of TCE even at the environmental level exposure.     

Induction of autoimmune cholangitis in non‐obese diabetic (NOD).1101 mice following a chemical xenobiotic immunization

Our laboratory has suggested that loss of tolerance to pyruvate dehydrogenase (PDC‐E2) leads to an anti‐mitochondrial antibody response and autoimmune cholangitis, similar to human primary biliary cirrhosis (PBC). We have suggested that this loss of tolerance can be induced either via chemical xenobiotic immunization or exposure to select bacteria. Our work has also highlighted the importance of genetic susceptibility. Using the non‐obese diabetic (NOD) congenic strain 1101 (hereafter referred to as NOD.1101 mice), which has chromosome 3 regions from B6 introgressed onto a NOD background, we exposed animals to 2‐octynoic acid (2OA) coupled to bovine serum albumin (BSA). 2OA has been demonstrated previously by a quantitative structural activity relationship to react as well as or better than lipoic acid to anti‐mitochondrial antibodies. We demonstrate herein that NOD.1101 mice immunized with 2OA‐BSA, but not with BSA alone, develop high titre anti‐mitochondrial antibodies and histological features, including portal infiltrates enriched in CD8⁺ cells and liver granulomas, similar to human PBC. We believe this model will allow the rigorous dissection of early immunogenetic cause of biliary damage.     

PXR-dependent induction of human CYP3A4 gene expression by organochlorine pesticides

OCP are xenobiotics which display various toxic effects on animal and human health. One of their effects is to bind and activate estrogen receptor alpha (ERalpha). We have previously studied the down-regulation of induced CYP1A1 (cytochrome P450) expression by this class of molecules in mammary carcinoma cells and shown the importance of ERalpha in this process. However, an alternative mechanism was suggested by those experiments in hepatoma cells. In this study, we have performed Northern blot and transient transfection assays in various cell lines and shown that OCP activate human pregnane X receptor (PXR) and subsequent CYP3A4 mRNA expression. This effect is mediated by the distal xenobiotic responsive element modulator of the promoter. The induction of CYP3A4 by OCP was dose-dependent within the 1-10 microM range. The data suggest that chronic exposure to OCP could alter a major metabolite pathway in human liver and putatively modify the pharmacokinetics of drugs and pollutants.