Identification of potential mechanisms of toxicity after di-(2-ethylhexyl)-phthalate (DEHP) adult exposure in the liver using a systems biology approach

Phthalates are industrial additives widely used as plasticizers. In addition to deleterious effects on male genital development, population studies have documented correlations between phthalates exposure and impacts on reproductive tract development and on the metabolic syndrome in male adults. In this work we investigated potential mechanisms underlying the impact of DEHP on adult mouse liver in vivo. A parallel analysis of hepatic transcript and metabolic profiles from adult mice exposed to varying DEHP doses was performed. Hepatic genes modulated by DEHP are predominantly PPARalpha targets. However, the induction of prototypic cytochrome P450 genes strongly supports the activation of additional NR pathways, including Constitutive Androstane Receptor (CAR). Integration of transcriptomic and metabonomic profiles revealed a correlation between the impacts of DEHP on genes and metabolites related to heme synthesis and to the Rev-erbalpha pathway that senses endogenous heme level. We further confirmed the combined impact of DEHP on the hepatic expression of Alas1, a critical enzyme in heme synthesis and on the expression of Rev-erbalpha target genes involved in the cellular clock and in energy metabolism. This work shows that DEHP interferes with hepatic CAR and Rev-erbalpha pathways which are both involved in the control of metabolism. The identification of these new hepatic pathways targeted by DEHP could contribute to metabolic and endocrine disruption associated with phthalate exposure. Gene expression profiles performed on microdissected testis territories displayed a differential responsiveness to DEHP. Altogether, this suggests that impacts of DEHP on adult organs, including testis, could be documented and deserve further investigations.

Dietary quebracho tannins are not absorbed, but increase the antioxidant capacity of liver and plasma in sheep

A total of sixteen lambs were divided into two groups and fed two different diets. Of these, eight lambs were fed a control diet (C) and eight lambs were fed the C diet supplemented with quebracho tannins (C+T). The objective of the present study was to assess whether dietary quebracho tannins can improve the antioxidant capacity of lamb liver and plasma and if such improvement is due to a direct transfer of phenolic compounds or their metabolites, to the animal tissues. Feed, liver and plasma samples were purified by solid-phase extraction (SPE) and analysed by liquid chromatography–MS for phenolic compounds. Profisitinidin compounds were identified in the C+T diet. However, no phenolic compounds were found in lamb tissues. The liver and the plasma from lambs fed the C+T diet displayed a greater antioxidant capacity than tissues from lambs fed the C diet, but only when samples were not purified with SPE. Profisetinidin tannins from quebracho seem not to be degraded or absorbed in the gastrointestinal tract. However, they induced antioxidant effects in animal tissues.

Optimal estimation of sea surface temperature from split-window observations

Optimal estimation (OE) improves sea surface temperature (SST) estimated from satellite infrared imagery in the “split-window”, in comparison to SST retrieved using the usual multi-channel (MCSST) or non-linear (NLSST) estimators. This is demonstrated using three months of observations of the Advanced Very High Resolution Radiometer (AVHRR) on the first Meteorological Operational satellite (Metop-A), matched in time and space to drifter SSTs collected on the global telecommunications system. There are 32,175 matches. The prior for the OE is forecast atmospheric fields from the Météo-France global numerical weather prediction system (ARPEGE), the forward model is RTTOV8.7, and a reduced state vector comprising SST and total column water vapour (TCWV) is used. Operational NLSST coefficients give mean and standard deviation (SD) of the difference between satellite and drifter SSTs of 0.00 and 0.72 K. The “best possible” NLSST and MCSST coefficients, empirically regressed on the data themselves, give zero mean difference and SDs of 0.66 K and 0.73 K respectively. Significant contributions to the global SD arise from regional systematic errors (biases) of several tenths of kelvin in the NLSST. With no bias corrections to either prior fields or forward model, the SSTs retrieved by OE minus drifter SSTs have mean and SD of − 0.16 and 0.49 K respectively. The reduction in SD below the “best possible” regression results shows that OE deals with structural limitations of the NLSST and MCSST algorithms. Using simple empirical bias corrections to improve the OE, retrieved minus drifter SSTs are obtained with mean and SD of − 0.06 and 0.44 K respectively. Regional biases are greatly reduced, such that the absolute bias is less than 0.1 K in 61% of 10°-latitude by 30°-longitude cells. OE also allows a statistic of the agreement between modelled and measured brightness temperatures to be calculated. We show that this measure is more efficient than the current system of confidence levels at identifying reliable retrievals, and that the best 75% of satellite SSTs by this measure have negligible bias and retrieval error of order 0.25 K.

Effects of phthalic acid esters on the liver and thyroid

The effects, over periods from 3 days to 9 months of administration, of diets containing di-2-ethylhexyl phthalate are very similar to those observed in rats administered diets containing hypolipidemic drugs such as clofibrate. Changes occur in a characteristic order commencing with alterations in the distribution of lipid within the liver, quickly followed by proliferation of hepatic peroxisomes and induction of the specialized P-450 isoenzyme(s) catalyzing omega oxidation of fatty acids. There follows a phase of mild liver damage indicated by induction of glucose-6-phosphatase activity and a loss of glycogen, eventually leading to the formation of enlarged lysosomes through autophagy and the accumulation of lipofuscin. Associated changes are found in the kidney and thyroid. The renal changes are limited to the proximal convoluted tubules and are generally similar to changes found in the liver. The effects on the thyroid are more marked. Although the levels of thyroxine in plasma fail to about half normal values, serum triiodothyronine remains close to normal values while the appearance of the thyroid varies, very marked hyperactivity being noted 7 days after commencement of treatment, this is less marked at 14 days, but even after 9 months treatment there is clear cut evidence for hyperactivity with colloid changes which indicate this has persisted for some time. Straight chain analogs of di-2-ethylhexyl phthalate, di-n-hexyl phthalate and di-n-oxtyl phthalate differ entirely in their short-term effects on the liver and kidney but have similar effects on the thyroid. The short-term in vivo hepatic effects of the three phthalate esters can be reproduced in hepatocytes in tissue culture. All three phthalate esters, as well as clofibrate, have early marked effects on the metabolism of fatty acids in isolated hepatocytes. The nature of these changes is such as to increase storage of lipid in the liver. A hypothesis is presented to explain the progress from these initial metabolic effects to the final formation of liver tumors.

Antioxidant effects of ryegrass phenolics in lamb liver and plasma

Sixteen lambs were divided into two groups and fed two different diets. Eight lambs were stall-fed with a concentrate-based diet (C), and the remaining eight lambs were allowed to graze on Lolium perenne (G). The antioxidant status was measured in the liver and plasma samples before and after solid-phase extraction (SPE) to probe the antioxidant effects that grass phenolic compounds may have conferred onto the animal tissues. The liver and plasma samples from grass-fed lambs displayed a greater antioxidant capacity than the tissues from C lamb group, but only if samples had not been passed through SPE cartridges. Finally, the feed and animal tissues, which had been purified by SPE, were analysed by liquid chromatography combined with mass spectrometry (LC-MS) to identify phenolic compounds present in L. perenne and to evaluate the results from the antioxidant assays. It would appear that the improvement of the antioxidant capacity of lamb liver and plasma from lambs fed ryegrass was not related to the direct transfer of phenolic compounds from grass to the animal tissues.

Bound Variable, Split Antecedent and Ellipsis Interpretations in L2 Portuguese: Implications for L2 Acquisition Theories.

Recently, in light of minimalist assumptions, some partial UG accessibility accounts to adult second language acquisition have made a distinction between the post-critical period ability to acquire new features based on their LF-interpretability (i.e. interpretable vs. uninterpretable features) (HAWKINS, 2005; HAWKINS; HATTORI, 2006; TSIMPLI; MASTROPAVLOU, 2007; TSIMPLI; DIMITRAKOPOULOU, 2007). The Interpretability Hypothesis (TSIMPLI; MASTROPAVLOU, 2007; TSIMPLI; DIMITRAKOPOULOU, 2007) claims that only uninterpretable features suffer a post-critical period failure and, therefore, cannot be acquired. Conversely, Full Access approaches claim that L2 learners have full access to UG’s entire inventory of features, and that L1/L2 differences obtain outside the narrow syntax. The phenomenon studied herein, adult acquisition of the Overt Pronoun Constraint (OPC) (MONTALBETTI, 1984) and inflected infinitives in nonnative Portuguese, challenges the Interpretability hypothesis insofar as it makes the wrong predictions for what is observed. The present data demonstrate that advanced learners of L2 Portuguese acquire the OPC and the syntax and semantics of inflected infinitives with native-like accuracy. Since inflected infinitives require the acquisition of new uninterpretable φ-features, the present data provide evidence in contra Tsimpli and colleagues’ Interpretability Hypothesis.

Interactions between uncoupling protein 2 gene polymorphisms, obesity and alcohol intake on liver function: a large meta-analysed population-based study

BACKGROUND AND OBJECTIVE: Given the role of uncoupling protein 2 (UCP2) in the accumulation of fat in the hepatocytes and in the enhancement of protective mechanisms in acute ethanol intake, we hypothesised that UCP2 polymorphisms are likely to cause liver disease through their interactions with obesity and alcohol intake. To test this hypothesis, we investigated the interaction between tagging polymorphisms in the UCP2 gene (rs2306819, rs599277 and rs659366), alcohol intake and obesity traits such as BMI and waist circumference (WC) on alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) in a large meta-analysis of data sets from three populations (n=20 242). DESIGN AND METHODS: The study populations included the Northern Finland Birth Cohort 1966 (n=4996), Netherlands Study of Depression and Anxiety (n=1883) and LifeLines Cohort Study (n=13 363). Interactions between the polymorphisms and obesity and alcohol intake on dichotomised ALT and GGT levels were assessed using logistic regression and the likelihood ratio test. RESULTS: In the meta-analysis of the three cohorts, none of the three UCP2 polymorphisms were associated with GGT or ALT levels. There was no evidence for interaction between the polymorphisms and alcohol intake on GGT and ALT levels. In contrast, the association of WC and BMI with GGT levels varied by rs659366 genotype (Pinteraction=0.03 and 0.007, respectively; adjusted for age, gender, high alcohol intake, diabetes, hypertension and serum lipid concentrations). CONCLUSION: In conclusion, our findings in 20 242 individuals suggest that UCP2 gene polymorphisms may cause liver dysfunction through the interaction with body fat rather than alcohol intake.