Effects of paternal nutritional experiences on offspring metabolism, if confirmed, would be novel and could have far-reaching implications in the context of transgenerational effects on chronic diseases.

Administration of 500 mg/kg acetaminophen (APAP) to female B6C3F1 mice resulted in well-documented pathophysiological changes in the liver manifested as increased serum concentration of liver enzymes (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and serum sorbitol dehydrogenase), centrilobular congestion, and hepatocellular degeneration and necrosis. The role of proinflammatory cytokines, including tumor necrosis factor a (TNF-α) and interleukin 1α (IL-1α), on the hepatotoxicity of APAP was examined at 4,8, 12, and 24 hr following APAP administration. Neutralization of TNF-α or IL-1α with specific antibodies partially prevented the hepatotoxic effects of APAP at the 4-and 8-hr time points. In addition, prior administration of anti-TNF-α antibodies shortened the recovery time following APAP treatment. While IL-1 receptor antagonist (IL-1ra) had only a modest protective effect against APAP-induced liver damage, as determined by serum enzyme release, IL-1ra had no effect on the degree of hepatic congestion or necrosis at any of the time points examined. On the other hand, administration of antibodies against IL-1ra exacerbated APAP-induced liver toxicity. These results suggest that TNF-α and IL-1α play an important role in the degree of damage and recovery that the liver undergoes following APAP intoxication.

Background Perfluorinated compounds are ubiquitous pollutants; epidemiologic data suggest they may be associated with adverse health outcomes, including subfecundity. We examined subfecundity in relation to two perfluorinated compounds, perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). Methods This case-control analysis included 910 women enrolled in the Norwegian Mother and Child Cohort Study in 2003 and 2004. Around gestational week 17, women reported their time to pregnancy and provided blood samples. Cases consisted of 416 women with a time to pregnancy greater than 12 months, considered subfecund. Plasma concentrations of perfluorinated compounds were analyzed using liquid chromatography-mass spectrometry. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for each pollutant quartile using logistic regression. Estimates were further stratified by parity. Results The median plasma concentration of PFOS was 13.0 ng/ml (interquartile range [IQR]=10.3-16.6 ng/ml) and of PFOA was 2.2 ng/ml (IQR=1.7-3.0 ng/ml). The relative odds of subfecundity among parous women was 2.1 (95% CI=1.2-3.8) for the highest PFOS quartile and 2.1 (1.0-4.0) for the highest PFOA quartile. Among nulliparous women, the respective relative odds were 0.7 (0.4-1.3) and 0.5 (0.2-1.2). Conclusion Previous studies suggest that the body burden of perfluorinated compounds decreases during pregnancy and lactation through transfer to the fetus and to breast milk. Afterwards, the body burden may rise again. Among parous women, increased body burden may be due to a long interpregnancy interval rather than the cause of a long time to pregnancy. Therefore, data from nulliparous women may be more informative regarding toxic effects of perfluorinated compounds. Our results among nulliparous women did not support an association with subfecundity.

To respond to potential adverse exposures properly, health care providers need accurate indicators of exposure levels. The indicators are particularly important in the case of acetaminophen (APAP) intoxication, the leading cause of liver failure in the U.S. We hypothesized that gene expression patterns derived from blood cells would provide useful indicators of acute exposure levels. To test this hypothesis, we used a blood gene expression data set from rats exposed to APAP to train classifiers in two prediction algorithms and to extract patterns for prediction using a profiling algorithm. Prediction accuracy was tested on a blinded, independent rat blood test data set and ranged from 88.9% to 95.8%. Genomic markers outperformed predictions based on traditional clinical parameters. The expression profiles of the predictor genes from the patterns extracted from the blood exhibited remarkable (97% accuracy) transtissue APAP exposure prediction when liver gene expression data were used as a test set. Analysis of human samples revealed separation of APAP-intoxicated patients from control individuals based on blood expression levels of human orthologs of the rat discriminatory genes. The major biological signal in the discriminating genes was activation of an inflammatory response after exposure to toxic doses of APAP. These results support the hypothesis that gene expression data from peripheral blood cells can provide valuable information about exposure levels, well before liver damage is detected by classical parameters. It also supports the potential use of genomic markers in the blood as surrogates for clinical markers of potential acute liver damage.acetaminophen ͉ hepatotoxicity ͉ microarray ͉ prediction ͉ genomics