Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis

Probert, Philip M. E.; Leitch, Alistair C.; Dunn, Michael; Meyer, Stephanie K.; Palmer, Jeremy M.; Abdelghany, Tarek M.; Lakey, Anne F.; Cooke, Martin; Talbot, Helen M.; Wills, Corinne; McFarlane, William; Blake, Lynsay I.; Rosenmai, Anna Kjerstine; Oskarsson, Agneta; Figueiredo, Rodrigo; Wilson, Colin; Kass, George E.N.; Jones, David; Blain, Peter G.; Wright, Matthew C.

doi:10.1016/j.jhep.2018.06.027

Cited by 65 publications

(65 citation statements)

References 63 publications

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“…112 Probert et al recently identified a man-made chemical present in soils around a waste sites with structural similarity to lipoic acid, which was capable of replacing lipoic acid in mitochondrial proteins. 113 Although further confirmatory studies are needed, these results identify a xenobiotic in the environment that may be an environmental trigger for PBC.…”

Section: Environmental Factorsmentioning

confidence: 89%

The Pathogenesis of Primary Biliary Cholangitis: A Comprehensive Review

et al. 2019

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Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by autoimmune destruction of small to medium size intrahepatic bile ducts. The etiology of PBC remains unknown and pathogenesis features immune-mediated biliary injury, alongside the consequences of chronic cholestasis. PBC is strongly associated with the loss of immune tolerance against mitochondrial antigens and the subsequent presence of an articulated immunologic response that involves both humoral and cellular responses. Both environmental factors and genetic variants increase PBC susceptibility. Biliary epithelial cells have often been considered a passive target of the immune attack in PBC; however, cholangiocyte dedifferentiation, senescence, stress, and deoxyribonucleic acid damage have been recognized to play an active role in the pathogenesis of PBC. This review highlights and discusses the most relevant pathogenetic mechanisms in PBC, focusing on the key factors that lead to the onset of cholestasis and immune activation.

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Section: Environmental Factorsmentioning

confidence: 89%

The Pathogenesis of Primary Biliary Cholangitis: A Comprehensive Review

et al. 2019

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“…Ten hours after administration, the authors report histopathological changes in the liver [15]. This observation has been followed by several in vitro studies in human liver cell lines showing that M8OI exposure leads to increased oxidative stress and cell death by an apoptotic mechanism(s) [16][17][18][19]. However, in our hands, the target organ for the toxic effects of M8OI after exposure by i.p.…”

Section: Introductionmentioning

confidence: 65%

“…The fate of M8OI was examined after oral administration to mice by gavage as outlined in the methods section (and illustrated in Fig 3A) using an established assay [19] and the levels of M8OI and its metabolites determined in serum, bile and urine at time of sacrifice. Fig 3B demonstrates that M8OI was absorbed from the gastrointestinal tract and systemically distributed since it appears at an increasing concentration in the urine with increasing dose.…”

Section: Oral Exposure To M8oi Results In Absorption Followed By Renamentioning

confidence: 99%

“…Biological samples (serum, bile and urine) were analysed for the presence of M8OI and its major metabolites-HO8IM and HOOC7IM-essentially as previously described [19] using non targeted data independent LC-HR-MS/MS using a TripleTOF 5600 high-resolution quadrupole time-of-flight (TOF) mass spectrometer (Sciex) equipped with a DuoSpray ion source operated in positive electrospray mode, coupled to an Eksigent Nano LC 420 system. M8OI and metabolites were quantified by standard multiple reaction monitoring (MRM) techniques using a Q-Trap 5500 hybrid linear ion trap/triple quadrupole mass spectrometer (Sciex) coupled to a Shimadzu Prominence liquid chromatograph.…”

Section: M8oi and Metabolite Determination In Biological Samplesmentioning

confidence: 99%

“…The gastrointestinal microbiota was examined given the apparent impact of the microbiota on a variety of chronic diseases [21,22]. M8OI was selected for study because the cation was recently detected at high levels in soils in close proximity to a landfill waste site [19] and is a potential hazard trigger for an autoimmune liver disease primary biliary cholangitis (PBC) [19,3]. BMI was included as this structurallyrelated ionic liquid is more widely used and is a more likely potential hazard trigger for PBC based on structural considerations [3].…”

Section: Introductionmentioning

confidence: 99%

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Changes in the gut microbiota of mice orally exposed to methylimidazolium ionic liquids

et al. 2020

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Ionic liquids are salts used in a variety of industrial processes, and being relatively non-volatile, are proposed as environmentally-friendly replacements for existing volatile liquids. Methylimidazolium ionic liquids resist complete degradation in the environment, likely because the imidazolium moiety does not exist naturally in biological systems. However, there is limited data available regarding their mammalian effects in vivo. This study aimed to examine the effects of exposing mice separately to 2 different methylimidazolium ionic liquids (BMI and M8OI) through their addition to drinking water. Potential effects on key target organs-the liver and kidney-were examined, as well as the gut microbiome. Adult male mice were exposed to drinking water containing ionic liquids at a concentration of 440 mg/L for 18 weeks prior to examination of tissues, serum, urine and the gut microbiome. Histopathology was performed on tissues and clinical chemistry on serum for biomarkers of hepatic and renal injury. Bacterial DNA was isolated from the gut contents and subjected to targeted 16S rRNA sequencing. Mild hepatic and renal effects were limited to glycogen depletion and mild degenerative changes respectively. No hepatic or renal adverse effects were observed. In contrast, ionic liquid exposure altered gut microbial composition but not overall alpha diversity. Proportional abundance of Lachnospiraceae, Clostridia and Coriobacteriaceae spp. were significantly greater in ionic liquid-exposed mice, as were predicted KEGG functional pathways associated with xenobiotic and amino acid metabolism. Exposure to ionic liquids via drinking water therefore resulted in marked changes in the gut microbiome in mice prior to any overt pathological effects in target organs. Ionic liquids may be an emerging risk to health through their potential effects on the gut microbiome, which is implicated in the causes and/or severity of an array of chronic disease in humans.

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