Pretreatment with TCDD exacerbates liver injury from Concanavalin A: critical role for NK cells.

For many liver diseases, including viral and autoimmune hepatitis, immune cells play an important role in the development and progression of liver injury. Concanavalin A (Con A) administration to rodents has been used as a model of immune-mediated liver injury resembling human autoimmune hepatitis. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to alter the development of immune-mediated diseases.

Instrumental and bioanalytical measures of dioxin-like compounds and activities in sediments of the Pohang Area, Korea.

Pohang is a mid-sized city in which Korea's largest manufacturer of steel is located. The Hyeongsan River, which runs through Pohang and empties into Yeongil Bay, is therefore expected to be affected by various municipal and industrial inputs. In order to characterize aryl hydrocarbon receptor (AhR)-mediated activities in sediments from the Pohang area, a total of eight locations along the Hyeongsan River were chosen and 16 sediment samples were collected during two sampling campaigns in 2010.

PPARα-mediated responses in human adult liver stem cells: In vivo/in vitro and cross-species comparisons.

The peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that regulates a variety of biological processes including lipid metabolism and energy homeostasis. Peroxisome proliferators (PPs) are carcinogens in rodents, while humans are resistant to peroxisome proliferation and carcinogenesis. In this study, we examined the differential gene expression elicited by clofibrate (CLO) and WY-14,643 (WY) in C57BL/6 mouse liver compared to responses in human HepG2 hepatoma and HL1-1 adult stem cells.

Hepatocyte tissue factor activates the coagulation cascade in mice.

In this study, we characterized tissue factor (TF) expression in mouse hepatocytes (HPCs) and evaluated its role in mouse models of HPC transplantation and acetaminophen (APAP) overdose. TF expression was significantly reduced in isolated HPCs and liver homogenates from TF(flox/flox)/albumin-Cre mice (HPC(ΔTF) mice) compared with TF(flox/flox) mice (control mice). Isolated mouse HPCs expressed low levels of TF that clotted factor VII-deficient human plasma.

The role of CB1 in immune modulation by cannabinoids.

There is clear evidence that CB(2), historically referred to as the peripheral cannabinoid receptor, mediates many of the immune modulatory effects of cannabinoids. However, cannabinoid receptors cannot be classified simply as central or peripheral since CB(2) has been shown to play a role in the central nervous system (CNS) and CB(1) mediates many immune system effects. Although Cnr1 mRNA and CB(1) protein expression is lower than Cnr2 mRNA or CB(2) protein expression in cells of the immune system, several studies have shown direct modulation of immune function via CB(1) by endogenous and exogenous cannabinoids in T cells, innate cells, and to a lesser extent, B cells.

Genetic variations in miR-27a gene decrease mature miR-27a level and reduce gastric cancer susceptibility.

MicroRNAs (miRNAs) are noncoding RNAs that function as post-transcriptional regulators of tumor oncogenes and suppressors. Single-nucleotide polymorphisms (SNPs) in miRNA genes are a novel class of genetic variations in the human genome that are currently being identified and investigated in human cancers. In this study, we aimed to investigate whether SNPs in the miR-27a gene affect miR-27a expression and alter susceptibility to gastric cancer.

Comparison of TCDD-elicited genome-wide hepatic gene expression in Sprague-Dawley rats and C57BL/6 mice.

Although the structure and function of the AhR are conserved, emerging evidence suggests that downstream effects are species-specific. In this study, rat hepatic gene expression data from the DrugMatrix database (National Toxicology Program) were compared to mouse hepatic whole-genome gene expression data following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). For the DrugMatrix study, male Sprague-Dawley rats were gavaged daily with 20μg/kg TCDD for 1, 3 and 5days, while female C57BL/6 ovariectomized mice were examined 1, 3 and 7days after a single oral gavage of 30μg/kg TCDD.

Cannabidiol (CBD) enhances lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice.

Cannabidiol (CBD) is a plant-derived cannabinoid that has been predominantly characterized as anti-inflammatory. However, it is clear that immune effects of cannabinoids can vary with cannabinoid concentration, or type or magnitude of immune stimulus. The present studies demonstrate that oral administration of CBD enhanced lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice.

2,3,7,8-TCDD enhances the sensitivity of mice to concanavalin A immune-mediated liver injury.

Inflammation plays a major role in immune-mediated liver injury, and exposure to environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been reported to alter the inflammatory response as well as affect immune cell activity. In this study, we tested the hypothesis that TCDD pretreatment exacerbates hepatotoxicity in a murine model of immune-mediated liver injury induced by concanavalin A (Con A) administration. Mice were pretreated with 30 μg/kg TCDD or vehicle control on day zero and then given either Con A or saline intravenously on day four.

15-Deoxy-Δ¹²,¹⁴-prostaglandin J₂-glycerol, a putative metabolite of 2-arachidonyl glycerol and a peroxisome proliferator-activated receptor γ ligand, modulates nuclear factor of activated T cells.

2-Arachidonyl glycerol (2-AG) is an endogenous arachidonic acid derivative released on demand from membrane precursors. 2-AG-mediated suppression of interleukin (IL)-2 depends on cyclooxygenase 2 (COX-2) metabolism and peroxisome proliferator-activated receptor γ (PPARγ) activation. 15-Deoxy-Δ¹²,¹⁴-prostaglandin J₂-glycerol ester (15d-PGJ₂-G), a putative COX-2 metabolite of 2-AG, acts as a PPARγ ligand and produces IL-2 suppression in activated Jurkat T cells, in part, by decreasing nuclear factor of activated T cells (NFAT) transcriptional activity.

Comparative toxicogenomic analysis of oral Cr(VI) exposure effects in rat and mouse small intestinal epithelia.

Continuous exposure to high concentrations of hexavalent chromium [Cr(VI)] in drinking water results in intestinal tumors in mice but not rats. Concentration-dependent gene expression effects were evaluated in female F344 rat duodenal and jejunal epithelia following 7 and 90 days of exposure to 0.3-520 mg/L (as sodium dichromate dihydrate, SDD) in drinking water.

Signal peptide and denaturing temperature are critical factors for efficient mammalian expression and immunoblotting of cannabinoid receptors.

Many researchers employed mammalian expression system to artificially express cannabinoid receptors, but immunoblot data that directly prove efficient protein expression can hardly be seen in related research reports. In present study, we demonstrated cannabinoid receptor protein was not able to be properly expressed with routine mammalian expression system. This inefficient expression was rescued by endowing an exogenous signal peptide ahead of cannabinoid receptor peptide.

Perfluorooctanoic acid effects on ovaries mediate its inhibition of peripubertal mammary gland development in Balb/c and C57Bl/6 mice.

Exposure to perfluorooctanoic acid (PFOA), a synthetic perfluorinated compound and an agonist of peroxisome proliferator-activated receptor α (PPARα), causes stunted mouse mammary gland development in various developmental stages. However, the underlying mechanisms remain poorly understood. We found that peripubertal PFOA exposure significantly inhibited mammary gland growth in both Balb/c and C57Bl/6 wild type mice, but not in C57Bl/6 PPARα knockout mice, and Balb/c mice were more sensitive to PFOA inhibition.

Dietary- and tissue-based exposure of belted kingfisher to PCDFs and PCDDs in the Tittabawassee River floodplain, Midland, MI, USA.

Concentrations of polychlorinated dibenzofurans (PCDFs) and other dioxin-like compounds in soils and sediments of the Tittabawassee River and associated floodplains downstream of Midland, Michigan, USA, are greater than upstream sites. As a result of these concentrations, which are some of the greatest ever reported, a site-specific exposure assessment of belted kingfisher breeding in the assessment area was conducted. To reduce the uncertainty associated with predicting exposure from abiotic matrices, concentrations of residues were quantified in site-specific prey items and in eggs and nestlings of belted kingfisher.

Complement activation in acetaminophen-induced liver injury in mice.

Overdose with acetaminophen (APAP) results in acute liver failure in humans and experimental animals. Complement comprises more than 30 proteins that can participate in tissue injury and/or repair, but the role of complement activation in APAP-induced hepatotoxicity has not been evaluated. Treatment of male, C57BL6J mice with APAP (200-400 mg/kg) resulted in liver injury as evidenced by increased activity of alanine aminotransferase (ALT) in plasma and hepatocellular necrosis.

Genome-wide gene expression effects in B6C3F1 mouse intestinal epithelia following 7 and 90days of exposure to hexavalent chromium in drinking water.

Chronic administration of high doses of hexavalent chromium [Cr(VI)] as sodium dichromate dihydrate (SDD) elicits alimentary cancers in mice. To further elucidate key events underlying tumor formation, a 90-day drinking water study was conducted in B6C3F1 mice. Differential gene expression was examined in duodenal and jejunal epithelial samples following 7 or 90days of exposure to 0, 0.

Comparative metabolomic and genomic analyses of TCDD-elicited metabolic disruption in mouse and rat liver.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) elicits a broad spectrum of species-specific effects that have not yet been fully characterized. This study compares the temporal effects of TCDD on hepatic aqueous and lipid metabolite extracts from immature ovariectomized C57BL/6 mice and Sprague-Dawley rats using gas chromatography-mass spectrometry and nuclear magnetic resonance-based metabolomic approaches and integrates published gene expression data to identify species-specific pathways affected by treatment. TCDD elicited metabolite and gene expression changes associated with lipid metabolism and transport, choline metabolism, bile acid metabolism, glycolysis, and glycerophospholipid metabolism.

Deletion of cannabinoid receptors 1 and 2 exacerbates APC function to increase inflammation and cellular immunity during influenza infection.

We and others have reported that simultaneous targeted deletion of CB(1) and CB(2) resulted in exacerbation of immune reactivity, suggesting a role of endocannabinoids in down-regulating immune function. In this study, we demonstrate that APC function is enhanced specifically in the absence of CB(1) and CB(2) signaling, resulting in an exacerbated immune response phenotype. After influenza infection, CB(1)(-/-)CB(2)(-/-) mice showed more pronounced pulmonary damage, increased inflammatory cell infiltrate, inflammation, and a greater cellular immune responses compared with WT mice, as evidenced by transcriptome analysis, more robust T cell activation, and effector cell cytokine production.

2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated disruption of the CD40 ligand-induced activation of primary human B cells.

Suppression of the primary antibody response is particularly sensitive to suppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice; however, surprisingly little is known concerning the effects of TCDD on humoral immunity or B cell function in humans. Results from a limited number of previous studies, primarily employing in vitro activation models, suggested that human B cell effector function is suppressed by TCDD. The present study sought to extend these findings by investigating, in primary human B cells, the effects of TCDD on several critical stages leading to antibody secretion including activation and plasmacytic differentiation using an in vitro CD40 ligand activation model.

Animal models of idiosyncratic drug-induced liver injury--current status.

The infrequent occurrence of idiosyncratic reactions and their dependence on individual sensitivity factors allow them to go undetected in current preclinical safety evaluation using conventional animal tests. Better predictive models for idiosyncratic, drug-induced liver injury (IDILI) would enable the preclinical elimination of drug candidates with idiosyncrasy liability and could provide evidence for a mode of action for these responses, suggest early biomarkers of IDILI, and lead to the development of mechanism-based, in vitro screens. Desirable characteristics of an animal model include the production of liver injury in a large fraction of animals of relatively inexpensive species/strains and the ability to distinguish drugs that cause IDILI in humans from ones that do not.

15-Deoxy-delta12,14-prostaglandin J2-glycerol ester, a putative metabolite of 2-arachidonyl glycerol, activates peroxisome proliferator activated receptor gamma.

2-Arachidonyl glycerol (2-AG) is an endogenous arachidonic acid derivative capable of suppressing interleukin (IL)-2 production by activated T cells. 2-AG-mediated IL-2 suppression is dependent on cyclooxygenase-2 (COX-2) metabolism and peroxisome proliferator activated receptor γ (PPARγ) activation. The objective of the present studies was to examine whether 15-deoxy-Δ(12,14)-PGJ(2)-glycerol ester (15d-PGJ(2)-G), a putative metabolite of 2-AG, can mimic the actions of 2-AG on IL-2 regulation through PPARγ activation.

Effects of deoxynivalenol consumption on body weight and adiposity in the diet-induced obese mouse.

The potential for the obese state to alter sensitivity to toxic chemicals is poorly understood. In this study, dose-response effects of the trichothecene deoxynivalenol (DON), a common food-borne mycotoxin, were determined on body weight of diet-induced obese mice. In study 1, the effects of feeding adult female B6C3F1 mice a high-fat diet (HFD; 60% kcal from fat) containing 0, 2, 5, or 10 ppm DON for 10 wk on body weight and adiposity were compared.

TCDD adsorbed on silica as a model for TCDD contaminated soils: Evidence for suppression of humoral immunity in mice.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the prototypical aryl hydrocarbon receptor (AhR) ligand, exhibits immune suppression in vivo and in vitro. Suppression of primary humoral immune responses in particular has been well characterized as one of the most sensitive functional immune endpoints in animals treated with TCDD. Previous studies have used purified TCDD to elucidate the mechanisms by which TCDD and dioxin-like compounds (DLC) impair IgM production by B cells, but did not represent the route by which animals and humans are likely to be exposed environmentally.

Dietary exposure of great blue heron (Ardea herodias) to PCDD/DFs in the Tittabawassee River floodplain, MI, USA.

Concentrations of dioxin-like compounds, primarily polychlorinated dibenzofurans (PCDFs), in soils and sediments of the Tittabawassee River (TR) and associated floodplains downstream of Midland, Michigan (USA) were greater than upstream sites and prompted a site-specific risk assessment of great blue herons (GBH). Dietary exposure of GBH to PCDFs and polychlorinated dibenzo-p-dioxins (PCDDs) was evaluated based on site-specific concentrations of residues in prey items. Concentrations of ∑PCDD/DFs and 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEQ(WHO-Avian)) in prey items collected from the TR were consistently greater than those collected from associated reference areas (RAs) and further downstream in the Saginaw River (SR).

Tissue-based risk assessment of great blue heron (Ardea herodias) exposed to PCDD/DF in the Tittabawassee River floodplain, Michigan, USA.

Concentrations of dioxin-like compounds, primarily polychlorinated dibenzofurans (PCDFs), in soils and sediments of the Tittabawassee River (TR) and associated floodplains downstream of Midland, Michigan, USA, were greater than upstream sites and prompted a site-specific risk assessment of great blue herons (GBH). Tissue exposure of PCDF and polychlorinated dibenzo-p-dioxins (PCDDs) was assessed in multiple GBH tissue types, including blood plasma of adults and eggs, as well as blood plasma, adipose, liver, and muscle of nestlings. Adult GBH exposure was associated with foraging area and age class, with concentrations of PCDD/DF being greater in blood plasma of adult GBH foraging in the TR compared with those foraging in upstream reference areas and in older birds as compared with their younger cohorts.