title: Association between exposures to brominated trihalomethanes, hepatic injury and type II diabetes mellitus.
abstract: Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder in the Western world, commonly diagnosed in the majority of obese patients with type 2 diabetes mellitus (T2DM). Metabolic disrupting chemicals with short half-lives, such as those of halogenated structure (trihalomethanes, THM) have been linked with hepatic insulin resistance phenomena in animal studies. However, human studies evaluating the role of THM exposure on liver pathogenesis and T2DM disease process are scarce. The objectives of this study were to: i) determine the association of urinary brominated THM (BrTHM) levels and T2DM disease status, and ii) investigate the association between urinary BrTHM levels and serum alanine aminotransferase (ALT) concentrations, often used as surrogate markers of NAFLD. A pilot case-control study was conducted in Nicosia, Cyprus (n=95). Cases were physician-diagnosed T2DM patients and controls were healthy individuals. Liver enzymes, leptin and TNF-α were measured in sera, while urinary THM levels were measured using tandem mass spectrometry. Diabetics had higher levels of serum leptin, body mass index and ALT than the controls. Among all study participants those with serum ALT levels above the median (17IU/L) had higher mean tribromomethane (TBM) concentrations compared to those with serum ALT below 17IU/L. A significant increase in the odds of having above the median serum ALT levels [OR 6.38, 95% CI: 1.11, 42.84 (p=0.044)] was observed for each unit increase in creatinine-unadjusted urinary TBM levels, along with BMI and past smoking, after adjusting for possible confounders, such as urinary creatinine, age, sex, and leptin; no other THM compound showed a significant association with serum ALT. Logistic regression models for T2DM using the urinary BrTHM as exposure variables did not reach the predetermined level of significance. The interplay between exposures to BrTHM and the initiation of key pathophysiological events relating to hepatic injury (ALT) and inflammation (leptin) was recognized via the use of selected biomarkers of effect. Our evidence that THM could act as hepatic toxins with a further initiation of diabetogenic effects call for additional studies to help us better understand the disease process of the two co-morbidities (NAFLD and T2DM).
authors.affiliation: Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus. Electronic address: konstantinos.makris@cut.ac.cy.
authors.forename: Konstantinos C
authors.initials: KC
authors.lastname: Makris
authors.affiliation: Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus.
authors.forename: Xanthi D
authors.initials: XD
authors.lastname: Andrianou
authors.affiliation: Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus.
authors.forename: Pantelis
authors.initials: P
authors.lastname: Charisiadis
authors.affiliation: South Carolina Statewide Cancer Prevention & Control Program, University of South Carolina, Columbia, SC, USA; Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA; Dorn Department of Veterans Affairs Medical Center, Columbia, SC, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Burch
authors.affiliation: Environmental Health & Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA.
authors.forename: Ratanesh K
authors.initials: RK
authors.lastname: Seth
authors.affiliation: Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus.
authors.forename: Androniki
authors.initials: A
authors.lastname: Ioannou
authors.affiliation: Endocrinology Clinic, Nicosia, Cyprus.
authors.forename: Michael
authors.initials: M
authors.lastname: Picolos
authors.affiliation: Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus.
authors.forename: Costas A
authors.initials: CA
authors.lastname: Christophi
authors.affiliation: Environmental Health & Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA. Electronic address: schatt@mailbox.sc.edu.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Chatterjee
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000652:urine; D004784:Environmental Monitoring; D005260:Female; D054879:Halogenation; D006801:Humans; D007249:Inflammation / Q000097:blood; D020738:Leptin / Q000097:blood; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000453:epidemiology* / Q000652:urine; D022882:Trihalomethanes / Q000652:urine*; D014874:Water Pollutants, Chemical / Q000652:urine*
chemical_list: D015415:Biomarkers; D020738:Leptin; D022882:Trihalomethanes; D014874:Water Pollutants, Chemical; D000410:Alanine Transaminase
keywords: Brominated trihalomethanes; Diabetes; Disinfection byproducts; Fatty liver; Inflammation; Non-alcoholic; Obesity