Interplay of Obesity, Ethanol, and Contaminant Mixture on Clinical Profiles of Cardiovascular and Metabolic Diseases: Evidence from an Animal Study.

Obesity, ethanol, and contaminants are known risk factors of cardiovascular and metabolic diseases (CMD). However, their interplay on clinical profiles of these diseases remains unclear, and thus were investigated in this study. Male lean or obese JCR rats were given water or 10% ethanol and orally treated with or without a contaminant mixture (CM) dissolved in corn oil and loaded on two cookies at 0, 1.6, or 16 mg/kg BW/day dose levels for 4 weeks. The CM consisted 22 environmental contaminants found in human blood or serum of Northern populations. Over 60 parameters related to CMD were examined. The results revealed that obesity in JCR rats resembles the clinical profiles of non-alcoholic fatty liver disease in humans. Obesity was also associated with increased serum and organ retention of mercury, one of the chemical components of CM. Exposure to ethanol lightened hyperlipidemia, increased liver retention of mercury, and increased risk for hypertension in the obese rats. CM lessened hyperlipidemia and hyperenzymemia, worsened systemic inflammation and increased the risk for hypertension in the obese rats. CM markedly increased serum ethanol levels with or without ethanol exposure. Tissue total mercury contents significantly correlated with clinical parameters with altered profiles by both ethanol and obesity. These results suggest that obese individuals may be more prone to contaminant accumulation. Ethanol and CM exposure can alter clinical profiles associated with obesity, which may lead to misdiagnosis of CMD associated with obesity. CM can alter endogenous production and/or metabolism of ethanol, further complicating disease progression, diagnosis, and treatment.

Paleotoxicity of petrogenic and pyrogenic hydrocarbon mixtures in sediment cores from the Athabasca oil sands region, Alberta (Canada).

Despite the economic benefits of the oil and gas industry in Northern Alberta, significant concerns exist regarding the impacts of increased oil production on the environment and human health. Several studies have highlighted increases in the concentrations of polycyclic aromatic compounds (PACs) and other hydrocarbons in the atmosphere, water, soil and sediments, plants, wildlife and fish in the Athabasca Oil Sands Region (AOSR) as a result of oil sands industrial activity. Sediment cores can provide information on the temporal trends of contaminants to the environment and provide important baseline information when monitoring data are absent. Here we combined analytical chemistry and a mammalian cell-based bioassay in dated lake sediment cores to assess paleotoxicity in freshwater systems in the AOSR. Sediment intervals were radiometrically dated and subsequently analysed for PACs. PAC extracts from select dated intervals were used in cell-based bioassays to evaluate their endocrine disrupting properties. We demonstrated spatial and temporal variability in the PAC composition of sediment cores around the AOSR with some of the highest concentrations of PACs detected near oil sands industrial activity north of Fort McMurray (AB) in La Saline Natural Area. Recent sediment had positive enrichment factors across most PAC analytes at this site with heavier pyrogenic compounds such as benz(a)anthracene/chrysene and benzofluoranthene/benzopyrene dominating. Our study is the first to link chemical analysis of sediment cores with biological effect assessments of endocrine activity showing feasibility of extending the usefulness of sediment cores in monitoring programs interested in complex mixture assessments. While we observed no spatial or temporal differences in ERα mediated signaling, AhR CALUX results mirrored those of the chemical analysis, demonstrating the utility of coupling biological effects assessments to historical reconstructions of contaminant inputs to the natural environment.

Circulating Selenium Concentration Is Inversely Associated With the Prevalence of Stroke: Results From the Canadian Health Measures Survey and the National Health and Nutrition Examination Survey.

Background Observational studies have suggested that selenium (Se) may have beneficial effects against certain cardiovascular outcomes, with a possible U-shaped association. We assessed the hypothesis that blood Se concentration might be inversely associated with the prevalence of stroke and the relationship would be nonlinear. Methods and Results Data collected from adult participants (aged ≥20 years) in the Canadian Health Measures Survey ( CHMS 2007-2011, n=7065) and the US National Health and Nutrition Examination Survey ( NHANES 2011-2012, n=5030) were analyzed. A total of 82 (1.16%) and 202 (4.02%) stroke cases were identified in CHMS and NHANES . Respondents with stroke had lower Se levels than those without stroke, with a mean difference of 16 µg/L and 12 µg/L for CHMS and NHANES , respectively. Respondents with high blood Se concentration (tertile 3) had a lower prevalence of stroke compared with those with low Se concentration (tertile 1). The adjusted odds ratios were 0.38 (95% CI : 0.15, 0.92) and 0.57 (95% CI : 0.31, 1.03) for CHMS and NHANES , respectively. A continuous decreasing trend of stroke with whole blood selenium was observed in CHMS , whereas the curve plateaued starting at 190 µg/L for NHANES , based on the cubic restricted spline regression. Sensitivity analysis using the serum and urinary Se concentrations demonstrates that our results were consistent across different selenium biomarkers. Conclusions We observed inverse cross-sectional associations between whole blood Se and the prevalence of stroke in representative samples of the Canadian and the US population.

Genetic polymorphisms are associated with exposure biomarkers for metals and persistent organic pollutants among Inuit from the Inuvialuit Settlement Region, Canada.

BACKGROUND: Inuit are exposed to some of the highest levels of contaminants worldwide. Studies suggest that several genes that mediate the metabolism of these contaminants are polymorphic. We hypothesize that single nucleotide polymorphisms (SNPs) in such genes may underline differences in biomarker concentrations and/or modify exposure-biomarker associations. METHODS: Members from the Inuvialuit Settlement Region (Canada) were recruited. Blood concentrations of mercury (Hg), cadmium (Cd), lead (Pb), dichlorodiphenyldichloroethylene (DDE), and polychlorinated biphenyl (PCB-153) were measured. SNPs from pathways such as glutathione, metallothionein, oxidative stress, and xenobiotic transport were genotyped in 281 participants, and data from 112 SNPs were included in the analyses. Surveys were administered to obtain information on demographics, and key sources of Hg (diet) and Cd (smoking) exposure. ANOVA and linear regressions were used for data analyses. RESULTS: Geometric mean concentrations of metals were 4.6µg/L for Hg, 1.3µg/L for Cd, and 32.2µg/L for Pb. Concentrations of organic pollutants were 2.0µg/L for DDE and 0.6µg/L for PCB-153. Biomarker levels for Hg, Cd, Pb, DDE, and PCB-153 differed (p<0.05) by genotype for 4, 3, 4, 3, and 3 SNPs, respectively. In multivariable analyses (for Pb, DDE, PCB-153) adjusting age, sex and body mass index (BMI), only 2 associations (one for Pb and one for DDE) remained significant. In multivariable analyses accounting for sources of Hg or Cd exposure, 24 SNPs (9 for Hg, 15 for Cd with 4 overlapping) had significant (p<0.05) main effects on biomarker levels and/or modified exposure-biomarker associations. CONCLUSION: The findings suggest that polymorphisms in key environmentally responsive genes can influence biomarker levels and/or modify exposure-biomarker associations for contaminants of concern to Arctic populations. Consideration of such gene-environment results may help improve the ability to conduct exposure (and ultimately risk) assessments of country foods and Inuit health.

The reduction of birth weight by fine particulate matter and its modification by maternal and neighbourhood-level factors: a multilevel analysis in British Columbia, Canada.

BACKGROUND: The purpose of this research was to determine the relationship between modeled particulate matter (PM2.5) exposure and birth weight, including the potential modification by maternal risk factors and indicators of socioeconomic status (SES). METHODS: Birth records from 2001 to 2006 (N = 231,929) were linked to modeled PM2.5 data from a national land-use regression model along with neighbourhood-level SES and socio-demographic data using 6-digit residential postal codes. Multilevel random coefficient models were used to estimate the effects of PM2.5, SES and other individual and neighbourhood-level covariates on continuous birth weight and test interactions. Gestational age was modeled with a random slope to assess potential neighbourhood-level differences of its effect on birth weight and whether any between-neighbourhood variability can be explained by cross-level interactions. RESULTS: Models adjusted for individual and neighbourhood-level covariates showed a significant non-linear negative association between PM2.5 and birth weight explaining 8.5 % of the between-neighbourhood differences in mean birth weight. A significant interaction between SES and PM2.5 was observed, revealing a more pronounced negative effect of PM2.5 on birth weight in lower SES neighbourhoods. Further positive and negative modification of the PM2.5 effect was observed with maternal smoking, maternal age, gestational diabetes, and suspected maternal drug or alcohol use. The random intercept variance indicating between-neighbourhood birth weight differences was reduced by 75 % in the final model, while the random slope variance for between-neighbourhood gestational age effects remained virtually unchanged. CONCLUSION: We provide evidence that neighbourhood-level SES variables and PM2.5 have both independent and interacting associations with birth weight, and together account for 49 % of the between-neighbourhood differences in birth weight. Evidence of effect modification of PM2.5 on birth weight across various maternal and neighbourhood-level factors suggests that certain sub-populations may be more or less vulnerable to relatively low doses PM2.5 exposure.

In vitro and whole animal evidence that methylmercury disrupts GABAergic systems in discrete brain regions in captive mink.

The effects of mercury (Hg) on key components of the GABAergic system were evaluated in discrete brain regions of captive juvenile male American mink (Neovison vison) using in vitro and in vivo (whole animal) experimental approaches. In vitro studies on cortical brain tissues revealed that inorganic Hg (HgCl(2); IC50=0.5+/-0.2microM) and methyl Hg (MeHgCl; IC50=1.6+/-0.2microM) inhibited glutamic acid decarboxylase (GAD; EC 4.1.1.15) activity. There were no Hg-related effects on [(3)H]-muscimol binding to GABA(A) receptors (IC50s>100microM). HgCl(2) (IC50=0.8+/-0.3microM) but not MeHgCl (IC50>100microM) inhibited GABA-transaminase (GABA-T; EC 2.6.1.19) activity. In a whole animal study, neurochemical indicators of GABAergic function were measured in brain regions (occipital cortex, cerebellum, brain stem, and basal ganglia) of captive mink fed relevant levels of MeHgCl (0 to 2microg/g feed, ppm) daily for 89d. No effects on GAD activity were measured. Concentration-dependent decreases in [(3)H]-muscimol binding to GABA(A) receptors and GABA-T activity were found in several brain regions, with reductions as great as 94% (for GABA(A) receptor levels) and 71% (for GABA-T activity) measured in the brain stem and basal ganglia. These results show that chronic exposure to environmentally relevant levels of MeHg disrupts GABAergic signaling. Given that GABA is the main inhibitory neurotransmitter in the mammalian nervous system, prolonged disruptions of its function may underlie the sub-clinical impacts of MeHg at relevant levels to animal health.

The effects of mercury on muscarinic cholinergic receptor subtypes (M1 and M2) in captive mink.

A combination of in vitro (competitive binding assays) and in vivo (tissues from animals exposed to dietary methyl mercury, MeHg) experimental procedures was employed to assess the effects of mercury (MeHg, HgCl(2)) on the two-key muscarinic cholinergic (mACh) receptor subtypes (M1, M2) in two brain regions (occipital cortex, brain stem) of captive mink (Mustela vison). In vitro, HgCl(2) and MeHg were equipotent in inhibiting [(3)H]-pirenzipine binding to the M1 receptor in the occipital cortex, but in the brain stem, MeHg was about 65x more potent than HgCl(2). For the M2 receptor, both HgCl(2) and MeHg were more potent at inhibiting [(3)H]-AFDX-384 binding in the occipital cortex than in the brain stem. Within each brain region, HgCl(2) was more potent at inhibiting [(3)H]-AFDX-384 binding than MeHg. In vivo exposure of captive mink to MeHg (0.5, 1, and 2ppm MeHg in the diet for 89 days) resulted in greater binding of radioligands to the M1 and M2 receptor in the occipital cortex, but not in the brain stem, when compared to control animals. Based on the in vitro results, we could not conclude which mACh receptor subtype or brain region was most sensitive to Hg, but the in vivo findings suggest that Hg preferentially affects mACh receptor subtype (M1 and M2) levels in the occipital cortex. By studying distinct mACh receptors, these results extend upon previous studies in laboratory rodents and wildlife that showed Hg to affect the global population of mACh receptors.