Citation:

Chorley, B., G. Nelson, U. Kodavanti, H. Tong, C. Wood, M. Angrish, AND S. Snow. MicroRNA biomarker identification in serum for fish oil-induced fatty liver development in Wistar Kyoto rats. Toxicoepigenetics: The Interface of Epigenetics and Risk Assessment, Tysons Corner, VA, November 02 - 04, 2016.

Impact/Purpose:

This research addresses Goal 4 of the FY2014-2018 EPA Strategic Plan (to ensure the safety of chemicals) and a recent amendment to the Toxic Substances Control Act (TSCA) which mandates considerations of greater risk for adverse health effects because of exposure due to susceptible subpopulations. Specifically, we are evaluating epigenetic-based biomarkers in rodent diet models that can demark the initiation and progression of fatty liver disease and help determine susceptibility to environmental chemicals. Fatty liver is estimated to affect 25-30% of the US population making it one of the most prevalent liver diseases. It is a characteristic of obesity, type II diabetes and metabolic syndrome, conditions which cross demographic lines but are frequently associated with socially and economically disadvantaged populations. While it has been recognized that diet and some therapeutic drugs cause fatty liver, the contribution of environmental chemicals has received little attention. By developing biomarkers to fatty liver, we can better understand how environmental chemicals cause fatty liver disease and identify subpopulations that may be susceptible to chemical exposure.

Description:

Hepatic steatosis (also known as fatty liver) is present in 25-30% of the US population and can increase susceptibility to the toxic effects of chemical exposures. There is need to develop biomarkers of hepatic steatosis that can be used in screening, experimental models, and human subjects. As a case study, we measured serum-based microRNA in Wistar Kyoto rats with diet-induced hepatic steatosis (60 g/kg fish oil for 8 weeks; n=6/group). Body weight (average ± SD; 288.9g ± 16.1g vs 319.6g ± 8.0g in control vs. fish oil diet) and lean body mass % (average ± SD; 79.95% ± 1.07% vs 83.83% ± 0.74% in control vs. fish oil diet) did increase with diet, but body fluid % and fat % did not change. Oil Red O staining of liver sections indicated significantly increased neutral triglycerides/lipids (% positive pixel counts of the stain average ± SD; 3.54% ± 2.81% vs. 8.37% ± 4.09% in control vs. fish oil diet), establishing mild hepatic steatosis. Serum microRNA was measured with small RNA-sequencing, averaging 6.1 million reads per sample with 1.65% of the reads aligning to microRNA sequence (Bowtie v0.12.8). 75 microRNA were statistically altered with fish oil diet (DESeq2; q-value < 0.05 and > 10 mean normalized reads counts across samples). 13 of 75 matched canonical, mature microRNA sequence, where 5 miRNA have been previously recognized as altered with liver toxicity/fatty liver (miRs-92a-3p, 30a-5p, 192-5p, 128-3p, and 122-5p). Interestingly, only 2 microRNA were significantly higher with fish-oil diet, indicating most of the alterations were due to source tissue downregulation and not passive release from toxicity. Taken together, significant serum-based microRNA changes occurred in rats that exhibited mild hepatic steatosis and may be useful, accessible biomarkers of hepatic steatosis. The abstract does not necessarily reflect the views and the policies of the Agency.

Record Details: