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Michael L Cunningham

Publications and source records attributed to Michael L Cunningham.

47 records · Page 3Linked to original sources
PubMed2003

Changes in global gene and protein expression during early mouse liver carcinogenesis induced by non-genotoxic model carcinogens oxazepam and Wyeth-14,643.

We hypothesized that the mouse liver tumor response to non-genotoxic carcinogens would involve some common early gene and protein expression changes that could ultimately be used to predict chemical hepatocarcinogenesis. In order to identify a panel of genes to test, we analyzed global differences in gene and protein expression in livers from B6C3F1 mice following dietary treatment with two rodent carcinogens, the benzodiazepine anti-anxiety drug oxazepam (2500 p.p.m.) and the hypolipidemic agent Wyeth (Wy)-14,643 (500 p.p.m.) compared with livers from untreated mice. Male mice were exposed for 2 weeks and 1, 3 or 6 months to oxazepam or Wy-14,643 in an age-matched study design. By histopathological evaluation, no liver preneoplastic foci or tumors were detected at 6 months in treated or control groups. By cDNA microarray analysis [NIEHS Mouse Chip (8700 genes); n = 3 individual livers/group, four hybridizations/sample], expression of 36 genes or 220 genes were changed relative to control livers following 6 months of oxazepam or Wy-14,643 treatment, respectively. To obtain a more comprehensive picture of gene/protein expression changes, we also conducted a proteomics study by 2D-gel electrophoresis followed by matrix assisted laser desorption/ionization-mass spectrometry on cytoplasmic, nuclear, and microsomal subcellular fractions of the same liver samples utilized for the cDNA microarray analysis. Real-time PCR, western blot analysis and immunohistochemistry were utilized for validation and to expand the results to other time points. Cyp2b20, growth arrest- and damage-inducible gene beta (Gadd45beta), tumor necrosis factor alpha-induced protein 2 and insulin-like growth factor binding protein 1 (Igfbp5) genes and proteins were upregulated by oxazepam, and Cyp2b20, Cyclin D1, proliferating cell nuclear antigen, Igfbp5, Gadd45beta and cell death-inducing DNA fragmentation factor alpha subunit-like effector A exhibited higher expression after Wy-14,643 treatment. Most of these genes/proteins were also deregulated at 2 weeks. There appeared to be more distinct than common changes in the expression of carcinogenesis-related genes/proteins between the two compounds, suggesting that the major carcinogenic pathways are different for these compounds and may be distinct for different chemical classes.

Animals↗
PubMed2002

Pulmonary agenesis: expansion of the VCFS phenotype.

In this report, we describe a child with the typical craniofacial manifestations of velocardiofacial syndrome (VCFS), a 22q11.2 deletion, and unilateral pulmonary agenesis. The 22q11.2 deletion syndromes are associated with malformations presumed to be caused by a disruption of cephalic neural crest cell migration during the fourth week of embryonic development. We suggest that the pulmonary agenesis seen in this case is related to a disruption of the dorsal aortic arch development that selectively interfered with lung bud growth. We suggest that pulmonary agenesis should be considered part of the spectrum of malformations seen in 22q11.2 deletion.

Chromosome Deletion↗
PubMed2002

Effect of peroxisome proliferators on the methylation and protein level of the c-myc protooncogene in B6C3F1 mice liver.

Peroxisome proliferators in general are nongenotoxic mouse liver carcinogens for which DNA hypomethylation and altered gene expression are proposed mechanisms. Therefore, the peroxisome proliferators 2,4-dichlorophenoxyacetic acid (2,4-D), dibutyl phthalate (DBP), gemfibrozil, and Wy-14,643 were evaluated for the ability to alter the methylation and expression of the c-myc protooncogene. Male B6C3F1 mice were administered for 6 days in their diet Wy-14,643 (5-500 ppm), 2,4-D (1,680 ppm), DBP (20,000 ppm), or gemfibrozil (8,000 ppm). All four peroxisome proliferators caused hypomethylation of the c-myc gene in the liver. Wy-14,643 appeared to be the most efficacious with a threshold between 10 and 50 ppm. The level of the c-myc protein was increased by Wy-14,643, but not the other peroxisome proliferators. When female B6C3F1 mice received a two-thirds partially hepatectomy and 16 h later were administered 50 mg/kg Wy-14,643 by gavage, hypomethylation of the gene occurred 24 h later. Hypomethylation was not found in mice that received Wy-14,643 following a sham operation. Hypomethylation of the c-myc gene within 24 h of administering Wy-14,643 after a partial hepatectomy but not after a sham operation supports the hypothesis that the peroxisome proliferators prevent methylation of hemimethylated sites formed by DNA replication.

Administration, Oral↗
PubMed2002

Peroxisome proliferators do not activate the transcription factors AP-1, early growth response-1, or heat shock factors 1 and 2 in rats or hamsters.

Peroxisome proliferators (PPs) cause hepatomegaly, peroxisome proliferation, and hepatocarcinogenesis in rats and mice, whereas hamsters are less responsive to these compounds. PPs increase peroxisomal beta-oxidation and P4504A subfamily activity, which have been hypothesized to result in oxidative stress. Work in our laboratory indicated that differential modulation of the redox-sensitive transcription factor NF-kappaB may contribute to the resulting difference in species susceptibility following PP administration. Therefore, we hypothesized that other redox-sensitive transcription factors such as AP-1, early growth response gene 1 (Egr-1), and heat-shock factors 1 and 2 (HSF1/2) may also be alternatively activated in differentially susceptible species. Accordingly, we measured the activation of these transcription factors using gel mobility shift assays, with hepatic nuclear extracts derived from rats and Syrian hamsters fed two doses of three peroxisome proliferators (dibutyl-phthalate [DBP], gemfibrozil and Wy-14,643) for 6, 34, or 90 days. Although changes were observed at various time points, no consistent, dose-responsive changes were observed in the DNA binding activities of these transcription factors following PP treatment. The lack of increased binding of AP-1, Egr-1, and HSFs suggests that these factors are not involved in increased cell proliferation following PP administration, although we cannot rule out that these factors are activated at earlier time points than those examined in this study.

Animals↗
PubMed2002

Outcomes of prenatal antidepressant exposure.

OBJECTIVE: This study evaluated the effects of prenatal antidepressant exposure on perinatal outcomes, congenital malformations, and early growth and development. METHOD: Within a group-model health maintenance organization, all infants with apparent prenatal exposure to tricyclic or selective serotonin reuptake inhibitor (SSRI) antidepressants were frequency matched to an unexposed comparison group by year of birth, maternal age, and mother's lifetime use of antidepressant drugs and mental health care. A structured blind review of mothers' and infants' medical records examined perinatal outcomes, congenital malformations, and developmental delay. RESULTS: Tricyclic antidepressant exposure was not associated with any significant difference in perinatal outcomes. Exposure to SSRIs was associated with a 0.9-week decrease in mean gestational age, a 175-g decrease in mean birth weight, and a 0.29 decrease in mean Apgar score at 5 minutes, but differences in birth weights and Apgar scores were not significant after adjustment for gestational age. Differences in gestational age and birth weights were unrelated to length of exposure, but differences in Apgar scores were limited to those with third-trimester exposure. Neither tricyclic antidepressant nor SSRI exposure was significantly associated with congenital malformations or developmental delay. CONCLUSIONS: The authors found no association between tricyclic antidepressant or SSRI exposure and either congenital malformations or developmental delay. SSRI exposure during pregnancy was associated with earlier delivery and consequent lower birth weight. Third-trimester SSRI exposure was also associated with lower Apgar scores. Women considering taking SSRIs during pregnancy may balance any higher fetal risk against the risk of persistent or recurrent depression.

Adult↗
PubMedDate not supplied

Methapyrilene toxicity: anchorage of pathologic observations to gene expression alterations.

Methapyrilene (MP) exposure of animals can result in an array of adverse pathological responses including hepatotoxicity. This study investigates gene expression and histopathological alterations in response to MP treatment in order to 1) utilize computational approaches to classify samples derived from livers of MP treated rats based on severity of toxicity incurred in the corresponding tissue, 2) to phenotypically anchor gene expression pattems, and 3) to gain insight into mechanism(s) of methapyrilene hepatotoxicity. Large-scale differential gene expression levels associated with the exposure of male Sprague-Dawley rats to the rodent hepatic carcinogen MP for 1, 3, or 7 days after daily dosage with 10 or 100 mg/kg/day were monitored. Hierarchical clustering and principal component analysis were successful in classifying samples in agreement with microscopic observations and revealed low-dose effects that were not observed histopathologically. Data from cDNA microarray analysis corroborated observed histopathological alterations such as hepatocellular necrosis, bile duct hyperplasia, microvesicular vacuolization, and portal inflammation observed in the livers of MP exposed rats and provided insight into the role of specific genes in the studied toxicological processes.

Animals↗
PubMedDate not supplied

Application of toxicogenomics to toxicology: basic concepts in the analysis of microarray data.

Toxicology and the practice of pathology are rapidly evolving in the postgenomic era. Observable treatment related changes have been the hallmark of toxicology studies. Toxicogenomics is a powerful new tool that may show gene and protein changes earlier and at treatment levels below the limits of detection of traditional measures of toxicity. It may also aid in the understanding of toxic mechanisms. It is important to remember that it is only a tool and will provide meaningful results only when properly applied. As is often the case with new experimental tools, the initial utilization is driven more by the technology than application to problem solving. Toxicogenomics is interdisciplinary in nature including at a minimum, pathology, toxicology, and genomics. Most studies will require the input from the disciplines of toxicology, pathology, molecular biology, bioinformatics, biochemistry, and others depending on the types of questions being asked.

Acetaminophen↗