Heather Clair

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Liver Disease in a Residential Cohort With Elevated Polychlorinated Biphenyl Exposures

Toxicological Sciences

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Efficacy of Keratin 18 (CK18) as a Biomarker of Severity of Liver Injury in Acute Alcoholic Hepatitis

Gastroenterology

The Role of Aryl Hydrocarbon Receptor in PCB-Induced Fatty Liver Disease in Mice

Gastroenterology

Murine Primary Hepatocytes Exposed to AhR, PXR, CAR or LXR Agonists Produce Differential Transcriptomes which Partially Overlap with One Another and the Transcriptome Induced by PCB Exposure

Gastroenterology

Hepatic Proteome Alterations due to PCB Exposure and Diet in the Development of NASH

Gastroenterology, 2017

Polychlorinated Biphenyls Disrupt Hepatic Epidermal Growth Factor Receptor Signaling

Xenobiotica, 2016

1. Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that disrupt hepatic ... more 1. Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that disrupt hepatic xenobiotic and intermediary metabolism, leading to metabolic syndrome and nonalcoholic steatohepatitis (NASH). 2. Since phenobarbital indirectly activates Constitutive Androstane Receptor (CAR) by antagonizing growth factor binding to the epidermal growth factor receptor (EGFR), we hypothesised that PCBs may also diminish EGFR signaling. 3. The effects of the PCB mixture Aroclor 1260 on the protein phosphorylation cascade triggered by EGFR activation were determined in murine (in vitro and in vivo) and human models (in vitro). EGFR tyrosine residue phosphorylation was decreased by PCBs in all models tested. 4. The IC50 values for Aroclor 1260 concentrations that decreased Y1173 phosphorylation of EGFR were similar in murine AML-12 and human HepG2 cells (∼2-4 μg/mL). Both dioxin and non-dioxin-like PCB congeners decreased EGFR phosphorylation in cell culture. 5. PCB treatment reduced phosphorylation of downstream EGFR effectors including Akt and mTOR, as well as other phosphoprotein targets including STAT3 and c-RAF in vivo. 6. PCBs diminish EGFR signaling in human and murine hepatocyte models and may dysregulate critical phosphoprotein regulators of energy metabolism and nutrition, providing a new mechanism of action in environmental diseases.

Nuclear receptors and nonalcoholic fatty liver disease

Biochimica et biophysica acta, Sep 4, 2016

Nuclear receptors are transcription factors which sense changing environmental or hormonal signal... more Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepat...

Abstract 3338: Inflammatory Cell-Localized Tumor Necrosis Factor Receptors 1 and 2 Have Divergent Effects on Post-Infarction Left Ventricular Remodeling

Circulation, Nov 3, 2009

The effects of tumor necrosis factor- α (TNF) in heart failure (HF) are receptor (R) specific: TN... more The effects of tumor necrosis factor- α (TNF) in heart failure (HF) are receptor (R) specific: TNFR1 exacerbates, whereas TNFR2 ameliorates, LV remodeling and inflammation. We hypothesized that TNFR-specific responses localized to inflammatory cells (macrophages) contribute to these dichotomous remodeling responses. We generated chimeric mice using bone marrow (BM)-ablated wild-type (WT) mice reconstituted with BM from TNFR1 KO mice (R1KOc, n=24), TNFR2 KO mice (R2KOc, n=22), or WT mice (WTc control, n=15). These mice, which exhibit loss of either TNFR1 or TNFR2 in inflammatory cells, underwent coronary ligation or sham operation. Compared to WTc sham, 4 weeks after surgery, WTc HF hearts exhibited significantly (p increased LV size (EDV 90±16 vs. 38±6 μ L) and dysfunction (LVEF 32±4 vs. 68±5%); greater hypertrophy (LV/tibia length [TL] 3.9±0.5 vs. 2.9±0.4, ~4-fold greater atrial natriuretic factor [ANF] mRNA; increased fibrosis (13.4±2.1% vs. 1.4±0.4%) and connective tissue growth factor (CTGF) mRNA expression, and increased (~2-fold) mRNA levels of TNF, interleukin (IL)-1 β , and IL-6. WTc HF mice also had markedly reduced survival (45% vs. 90%) and increased blood levels of activated F4/80+/CD11b+ monocytes vs. WTc sham mice. In contrast, compared to WTc HF, R1KOc HF mice exhibited significantly (p 1) improved survival (75%), 2) less LV dilatation and improved LVEF (43±11%), 3) less hypertrophy (LV/TL 3.1±0.2) and ANF mRNA, 4) less fibrosis (5.1±2.2%) and CTGF mRNA, 6) less cardiac TNF and IL-1 β mRNA expression, and 7) higher circulating levels of CD4+/CD25+ anti-inflammatory regulatory T lymphocytes. Also, compared to WTc HF, R2KOc HF mice exhibited significantly (p β mRNA expression, and greater cardiac fibrosis (26.9±13.0%). We conclude that inflammatory cell-localized TNFR1 signaling exacerbates LV remodeling, inflammation, and cardiac fibrosis in HF, whereas inflammatory cell TNFR2 signaling moderates many of these effects. Modulation of global inflammatory cell function induces profound localized alterations in LV remodeling; TNFR1/R2 signaling plays an important role in these effects. This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).

Abstract 17284: Selective Macrophage Ablation Attenuates Diet-Induced Obesity and Insulin Resistance and Reverses Diabetic Cardiomyopathy

Circulation, Nov 22, 2011

Although activated macrophages infiltrate the heart and adipose tissue in type 2 diabetes (T2D), ... more

Abstract 16202: Endoplasmic Reticulum (ER) Stress is Critical for the Development of Diabetic Cardiomyopathy

Circulation, Nov 23, 2010

Abstract 3335: Inflammatory Cell-Localized Inducible Nitric Oxide Synthase Exacerbates Post-Infarction Left Ventricular Remodeling

Circulation, Nov 3, 2009

Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Nonalcoholic-Steatohepatitis

Toxicological sciences : an official journal of the Society of Toxicology, Jan 25, 2015

Polychlorinated biphenyls (PCBs) are environmental pollutants associated with nonalcoholic-steato... more Polychlorinated biphenyls (PCBs) are environmental pollutants associated with nonalcoholic-steatohepatitis (NASH), diabetes and obesity. We previously demonstrated that the PCB mixture, Aroclor 1260, induced steatohepatitis and activated nuclear receptors in a diet-induced obesity mouse model. The current study aims to evaluate PCB interactions with the pregnane-xenobiotic receptor (Pxr: Nr1i2) and constitutive androstane receptor (Car: Nr1i3) in NASH. Wild type C57Bl/6 (WT), Pxr(-/-) and Car(-/-) mice were fed the high fat diet (HFD, 42% milk fat) and exposed to a single dose of Aroclor 1260 (20 mg/kg) in this 12-week study. Metabolic phenotyping and analysis of serum, liver and adipose was performed. Steatohepatitis was pathologically similar in all Aroclor-exposed groups, while Pxr(-/-) mice displayed higher basal pro-inflammatory cytokine levels. Pxr repressed Car expression as evident by increased basal Car/Cyp2b10 expression in Pxr(-/-) mice. Both Pxr(-/-) and Car(-/-) mice sh...

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Evaluation of Aroclor 1260 exposure in a mouse model of diet-induced obesity and non-alcoholic fatty liver disease

Toxicology and Applied Pharmacology, 2014

Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with non-alcoholic ... more Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with non-alcoholic fatty liver disease (NAFLD) in epidemiologic studies. The purpose of this study was to evaluate the hepatic effects of a PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, in a mouse model of diet-induced obesity (DIO). Male C57Bl/6J mice were fed control diet or 42% high fat diet (HFD) and exposed to Aroclor 1260 (20mg/kg or 200mg/kg in corn oil) for 12weeks. A glucose tolerance test was performed; plasma/tissues were obtained at necropsy for measurements of adipocytokine levels, histology, and gene expression. Aroclor 1260 exposure was associated with decreased body fat in HFD-fed mice but had no effect on blood glucose/lipid levels. Paradoxically, Aroclor 1260+HFD co-exposed mice demonstrated increased hepatic inflammatory foci at both doses while the degree of steatosis did not change. Serum cytokines, ALT levels and hepatic expression of IL-6 and TNFα were increased only at 20mg/kg, suggesting an inhibition of pro-inflammatory cytokine production at the 200mg/kg exposure. Aroclor 1260 induced hepatic expression of cytochrome P450s including Cyp3a11 (Pregnane-Xenobiotic Receptor target) and Cyp2b10 (constitutive androstane receptor target) but Cyp2b10 inducibility was diminished with HFD-feeding. Cyp1a2 (aryl hydrocarbon Receptor target) was induced only at 200mg/kg. In summary, Aroclor 1260 worsened hepatic and systemic inflammation in DIO. The results indicated a bimodal response of PCB-diet interactions in the context of inflammation which could potentially be explained by xenobiotic receptor activation. Thus, PCB exposure may be a relevant &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;second hit&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; in the transformation of steatosis to steatohepatitis.

Identification of Environmental Chemicals Associated with the Development of Toxicant-associated Fatty Liver Disease in Rodents

Toxicologic Pathology, 2014

Background: Toxicant-associated fatty liver disease (TAFLD) is a recently identified form of nona... more Background: Toxicant-associated fatty liver disease (TAFLD) is a recently identified form of nonalcoholic fatty liver disease (NAFLD) associated with exposure to industrial chemicals and environmental pollutants. Numerous studies have been conducted to test the association between industrial chemicals/environmental pollutants and fatty liver disease both in vivo and in vitro. Objectives: The objective of the article is to report a list of chemicals associated with TAFLD. Methods: Two federal databases of rodent toxicology studies—Toxicological Reference Database (ToxRefDB; Environmental Protection Agency) and Chemical Effects in Biological Systems (CEBS, National Toxicology Program)—were searched for liver end points. Combined, these 2 databases archive nearly 2,000 rodent studies. Toxicant-associated steatohepatitis (TASH) descriptors including fatty change, fatty necrosis, Oil red O-positive staining, steatosis, and lipid deposition were queried. Results: Using these search terms,...

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Recruitment Of Endothelial Progenitor Cells May Palliate Vascular Dysfunction In Children With OSA

A109. CARDIOVASCULAR COMPLICATIONS OF OBSTRUCTIVE SLEEP APNEA, 2010

Exploring Myostatin [electronic resource] /

Myostatin, a negative regulator of muscle cell growth, is highly conserved across species. The lo... more Myostatin, a negative regulator of muscle cell growth, is highly conserved across species. The loss of functional Myostatin is known to cause the "double-muscled" phenotype in several cattle breeds, and similar phenotypes in other species. For nearly 200 years, double-muscled animals have captured the attention of livestock breeders and researchers, boasting enlarged musculature but beset by production difficulties. With the advent of transgenic technology, researchers have created a "knockout" mouse model with which to efficiently explore the biochemical pathways and influences of Myostatin. Research involving this model has both agricultural and biomedical applications, and involves several cell growth and regulation mechanisms. Analysis of growth and development patterns in Myostatin-null mice is necessary to link these findings with past research. Developmental patterns for adult Myostatin knockout mice are well-defined, however, early patterns of growth were...

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