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.

Biodistribution and Systemic Effects in Mice Following Intravenous Administration of Cadmium Telluride Quantum Dot Nanoparticles.

Quantum dots (QDs) are engineered nanoparticles (NPs) of semiconductor structure that possess unique optical and electronic properties and are widely used in biomedical applications; however, their risks are not entirely understood. This study investigated the tissue distribution and toxic effects of cadmium telluride quantum dots (CdTe-QDs) in male BALB/c mice for up to 1 week after single-dose intravenous injections. CdTe-QDs were detected in the blood, lung, heart, liver, spleen, kidney, testis and brain. Most CdTe-QDs accumulated in the liver, followed by the spleen and kidney. At high doses, exposure to CdTe-QDs resulted in mild dehydration, lethargy, ruffled fur, hunched posture, and body weight loss. Histological analysis of the tissues, upon highest dose exposures, revealed hepatic hemorrhage and necrotic areas in the spleen. The sera of mice treated with high doses of CdTe-QDs showed significant increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin levels, as well as a reduction in albumin. CdTe-QD exposure also led to a reduced number of platelets and elevated total white blood cell counts, including monocytes and neutrophils, serum amyloid A, and several pro-inflammatory cytokines. These results demonstrated that the liver is the main target of CdTe-QDs and that exposure to CdTe-QDs leads to hepatic and splenic injury, as well as systemic effects, in mice. By contrast, cadmium chloride (CdCl2), at an equivalent concentration of cadmium, appeared to have a different pharmacokinetic pattern from that of CdTe-QDs, having minimal effects on the aforementioned parameters, suggesting that cadmium alone cannot fully explain the toxicity of CdTe-QDs.

Lack of adverse health effects following 30-weeks of dietary exposure to acrylamide at low doses in male F344 rats.

Understanding the health hazards following exposure to food-borne acrylamide, especially at low levels typified by human diets, is an ongoing food safety issue. We recently published results from a study that aimed to understand the effects of acrylamide short-term exposure at doses known to cause tumors in rodents, demonstrating that a number of key toxicological end points were altered by acrylamide exposure. Additionally, we reported that at much lower doses for 30 weeks of exposure, dietary acrylamide was 'not a complete carcinogen' to the colon in an organ-specific rodent carcinogenesis study but acted as a co-carcinogen along with azoxymethane (AOM, a colon-specific carcinogen). Here, we present toxicological data from a sub-set of this long-term exposure study from animals that received saline (instead of AOM). Briefly, male F344 rats were randomized to receive acrylamide at 0.5, 1.0 and 2.0 mg/kg diet (∼0.02, 0.04, and 0.09 mg/kg BW/day, respectively) or no acrylamide (control), for 30 weeks; all rats were then euthanized and their tissues harvested and processed for toxicological evaluation. We report that at the doses tested, acrylamide did not cause any changes in general well-being, body weight or food intake. Similarly, acrylamide did not cause any biologically relevant change in parameters associated with immunophenotyping, serum biochemistry or hematology. Histopathology assessment of tissues showed no changes except in the testis, where non-specific mild lesions were observed in all the groups, inclusive of the controls. No neuropathological effects of acrylamide were observed in the brain and nerve tissues. Together, these results suggest that acrylamide administered to rats through the diet at low doses for 30 weeks did not cause any toxicologically relevant changes. Given that the doses of acrylamide in the current study are low and are comparable to human dietary exposure, this null-effect study provides data that contribute to the body of scientific evidence relevant to understanding the health effects of acrylamide.

A Northern contaminant mixture impairs pancreas function in obese and lean JCR rats and inhibits insulin secretion in MIN6 cells.

Rates of obesity and diabetes mellitus of Arctic populations are increasing due to multiple reasons including a departure from traditional lifestyles and alcohol consumption patterns. These populations are also exposed to a variety of anthropogenic contaminants through consumption of contaminated country foods. We have previously shown that a Northern contaminant mixture (NCM), containing 22 organic and inorganic contaminants found in the blood of Canadian Arctic populations, induces endothelial cell dysfunction and exacerbates development of non-alcoholic fatty liver disease in experimental models. In order to determine if these contaminants affect pancreas function and physiology and if obesity and alcohol can influence contaminant toxicity and the development of diabetes, lean and obese JCR rats were orally treated with NCM at 0 (vehicle), 1.6 or 16mg/kg BW for four weeks in the presence or absence of 10% (v/v) alcohol. NCM treatment altered islet morphology, increased iron deposit in pancreas, and reduced circulating and pancreatic insulin levels and circulating glucagon levels as a result of direct islet injury with ß and α cell loss with or without exposure to alcohol. Studies conducted with cultured mouse insulin-secreting (MIN6) ß cells further demonstrated that NCM inhibited insulin release and induced cell death through oxidative stress and mitochondrial dysfunction. 2,3,4,6-Tetrabromophenol, a minor component of the NCM, alone also inhibited insulin release from MIN6 cells after 10min of exposure. These results suggest that Northern contaminants may contribute to pancreatic dysfunction, and possibly development of diabetes, in some of the highly exposed Arctic populations. The implications and relevance of these findings to Northern populations remains to be confirmed through epidemiological studies.

Toxicological effects of short-term dietary acrylamide exposure in male F344 rats.

We recently reported that acrylamide, a known rodent and probable human carcinogen, does not increase the risk of azoxymethane (AOM)-induced rat colon precancerous lesions when administered through the diet. Here, we present toxicological data from non-AOM-injected rats. Briefly, male F344 rats were randomized into four dietary groups and received experimental diets based on AIN-93G formulation and containing acrylamide at 0 (control), 5, 10 or 50mg/kg diet (wt/wt) ad libitum for 10 weeks, after which they were killed and their blood collected for hematological and biochemical markers. Acrylamide at the higher doses (10 and 50mg/kg diet) significantly lowered (p<0.05) serum total high density lipoprotein and total testosterone and increased serum lipase in comparison to the control. Blood hematocrit values and lymphocyte counts were significantly lower (p<0.05) in the high dose acrylamide (50mg/kg diet) group compared to control, with a concomitant decrease in hemoglobin level, mean corpuscular volume and mean corpuscular hemoglobin. These results provide additional hazard characterization data and strengthen the notion that at high doses, acrylamide may involve systemic toxicity potentiating tumorigenesis in experimental animals. Further studies are required to understand the health effects of food-borne acrylamide, especially at the lower exposures typified by human diets.

Exposure to a northern contaminant mixture (NCM) alters hepatic energy and lipid metabolism exacerbating hepatic steatosis in obese JCR rats.

Non-alcoholic fatty liver disease (NAFLD), defined by the American Liver Society as the buildup of extra fat in liver cells that is not caused by alcohol, is the most common liver disease in North America. Obesity and type 2 diabetes are viewed as the major causes of NAFLD. Environmental contaminants have also been implicated in the development of NAFLD. Northern populations are exposed to a myriad of persistent organic pollutants including polychlorinated biphenyls, organochlorine pesticides, flame retardants, and toxic metals, while also affected by higher rates of obesity and alcohol abuse compared to the rest of Canada. In this study, we examined the impact of a mixture of 22 contaminants detected in Inuit blood on the development and progression of NAFLD in obese JCR rats with or without co-exposure to 10% ethanol. Hepatosteatosis was found in obese rat liver, which was worsened by exposure to 10% ethanol. NCM treatment increased the number of macrovesicular lipid droplets, total lipid contents, portion of mono- and polyunsaturated fatty acids in the liver. This was complemented by an increase in hepatic total cholesterol and cholesterol ester levels which was associated with changes in the expression of genes and proteins involved in lipid metabolism and transport. In addition, NCM treatment increased cytochrome P450 2E1 protein expression and decreased ubiquinone pool, and mitochondrial ATP synthase subunit ATP5A and Complex IV activity. Despite the changes in mitochondrial physiology, hepatic ATP levels were maintained high in NCM-treated versus control rats. This was due to a decrease in ATP utilization and an increase in creatine kinase activity. Collectively, our results suggest that NCM treatment decreases hepatic cholesterol export, possibly also increases cholesterol uptake from circulation, and promotes lipid accumulation and alters ATP homeostasis which exacerbates the existing hepatic steatosis in genetically obese JCR rats with or without co-exposure to ethanol.