Unknown,Transcriptomics,Genomics,Proteomics

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Comparison of Bzrp ligands

ABSTRACT: This series compares the effects that two pharmacologically distinct ligands at the mitochondrial peripheral-type benzodiazepine receptor (Bzrp). PK11195 (4.0 mg/kg, a presumed antagonist) has no observable adverse effects in pregnant mice on either 8 days post-coitus (d.p.c.) or 9 d.p.c. Furthermore, PK11195 is shown to rescue mouse fetuses from microphthalmia or microphthalmia-microcephaly induced with 2CdA or MeHg, respectively; effects of PK11195 on EtOH-induced craniofacial malformations are not yet unkown. Ro5-4864 (4.0 mg/kg, a presumed agonist) is weakly teratogenic on 8 d.p.c. (effects on 9 d.p.c. unknown) and this Bzrp ligand does not rescue fetuses from malformations induced with either 2CdA or MeHg; effects of Ro5-4864 on EtOH-induced craniofacial malformations is unknown for either sensitive (C57BL/6J) or insensitive (C57BL/6N) strains. The 4.0 mg/kg dose of Bzrp ligands is consistent with pharmacological activity in several studies. Pregnant mice were exposed to these agents on 8 d.p.c. (2CdA, EtOH) or 9 d.p.c. (MeHg). The test dose of 2.5 mg/kg 2CdA was modeled for a 5% increased risk of microphthalmia in term fetuses. Full remediation with PK11195 anticipated. The test dose of 5.0 mg/kg MeHg gives an estimated 20% increased risk of microphthalmia-microcephaly (encephalopathy) in term fetuses. Partial remediation with PK11195 is anticipated to <10% malformations. Again the effects of PK11195 on EtOH teratogenicity is not yet known. The sampling time was chosen as the time of p53 protein induction (3.0h to 4.5h post-treatment). Whereas co-treatment with PK11195 suppresses embryonic p53 protein induction Ro5-4864 does not block this reaction. All measurements were on RNA from the embryonic headfold (8 d.p.c.) or prosencephalon (9 d.p.c.). Keywords = peripheral benzodiazepine receptor Keywords = Bzrp ligands Keywords = PK11195 Keywords = Ro5-4864 Keywords = embryo Keywords = p53 protein induction

ORGANISM(S): Mus musculus

SUBMITTER: Amar Singh

PROVIDER: E-GEOD-1072 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:EXPERIMENT: Microarray expression profiles derived from the cranial neural folds (headfold) of neurulation-stage mouse embryos 3.0h after maternal alcohol exposure on 8 d.p.c. ANIMAL MODEL: Pregnancies from 2 substrains of C57BL/6 mice that differ in relative risk of Fetal Alcohol Syndrome (FAS): C57BL/6J (B6J) high-risk condition, and C57BL/6NCrl (B6N) low-risk condition. EXPOSURE: Dams dosed with ethanol (EtOH) by intraperitoneal injection at 2.9 g EtOH per kg body weight. Controls received vehicle (saline) alone. A third group of dams received EtOH + 4.0 mg/kg PK11195, a specific high-affinity ligand to the 18 KDa mitochondrial peripheral benzodiazepine receptor site. INTERVAL: High blood alcohol content must be sustained in dams for several hours to invoke FAS and is traditionally accomplished by a double injection of EtOH 4.0h apart. Since these embryos were harvested for genetic analysis 1h before dams would have gotten the second alcohol injection, the interval represents a snapshot of the critical response, prior to the second maternal injection that invokes greater risk. Counter-exposure to PK11195 significantly lowers the adverse response of B6J embryos to EtOH. PLATFORM: Two independent assays run. The first dataset (PE), run April 2002 â January 2003, used samples pooled from 2 litters (PE) and the platform was a two-channel MPS621 array (http://www.lifesciences.perkinelmer.com/). This platform has 4800 sequence-verified gene elements derived from over 50 different human cDNA libraries reflecting a variety of well-annotated cellular processes and disease pathways. The second dataset (AF), run between May 2005 â November 2005, used samples pooled from 1 litter and the platform was Affymetrix GeneChipÂ® Mouse Genome 430A 2.0 Array (http://www.affymetrix.com/). The MG430A 2.0 platform has 45,102 oligonucleotide probe cells representing approximately 14,000 well-characterized genes in the draft mouse genome assembly. The corresponding GEO samples are GSM12218 - GSM12227 for the two-channel PE arrays, and GSM136067 - GSM136078 for the one-channel AF arrays. Keywords = fetal alcohol syndrome Keywords = alcohol-related birth defects Keywords = EtOH Keywords = PK11195 Keywords = embryo Keywords = strain differences Keywords: Ordered Assay of early mouse embryos during pathogenesis of Fetal Alcohol Syndrome (FAS). Replicate RNA samples were arrayed by one-channel oligonucleotide (Affymetrix) or two-channel cDNA (Perkin-Elmer) platforms.

Project description:Methylmercury (MeHg) is a potent neurotoxin and endocrine disruptor that accumulates in aquatic systems. Previous studies have shown suppression of hormone levels in both male and female fish, suggesting effects on gonadotropin regulation in the brain. We investigated the gene expression profile in adult female zebrafish whole brain induced by acute (96 hr) MeHg exposure. Fish were exposed by injection to 0 or 0.5 M-BM-5g MeHg/g. Gene expression changes in the brain were examined using a two-color 22,000 feature zebrafish microarray. At a significance level of p<0.01, 79 genes were up-regulated and 76 genes were down-regulated in response to MeHg exposure. Individual genes exhibiting altered expression in response to MeHg exposure implicate effects on glutathione metabolism and GABA-A receptors in the mechanism of MeHg neurotoxicity. Gene ontology (GO) terms significantly enriched among altered genes included protein folding, cell redox homeostasis, and steroid biosynthetic process. The most affected biological functions were related to the nervous system development and function, as well as lipid metabolism and molecular transport. These results support the involvement of oxidative stress and effects on protein structure in the mechanism of action of MeHg in the female brain. Future studies will compare the gene expression profile induced in response to MeHg with that induced by other toxins and investigate responsive genes as potential biomarkers of MeHg exposure. Wild-type strain AB-1 zebrafish (Zebrafish International Resource Center, University of Oregon, Eugene, OR) were cultured at the Columbia Environmental Research Center (CERC), USGS, for MeHg exposures. Adult female zebrafish were injected with 0 M-NM-<g/g or 0.5 M-NM-<g/g MeHg in 2 M-BM-5L Na2CO3 (pH 6.98)/g body weight. After 96 hr, fish were anesthetized using ethyl 3-aminobenzoate methanesulfonate (MS-222, Sigma, St. Louis, MO). Whole brains were removed, flash frozen with liquid nitrogen and stored at 80M-BM-0C. For the microarray experiment, two zebrafish brains were pooled per sample. Four pooled samples were taken from fish treated with 0.5 M-NM-<g/g of MeHg, and the other five were taken from control fish treated with sodium carbonate. Array hybridizations were performed using a reference design, where each sample was compared to a reference sample. The reference sample consisted of equal amounts of RNA from control and treated female brains. Five replicates for the control and four replicates for the treated were analyzed. cDNA synthesis, cRNA labeling, amplification and hybridization were performed following the manufacturerM-bM-^@M-^Ys kits and protocols (Agilent Low RNA Input Fluorescent Linear Amplification Kit and Agilent 60-mer oligo microarray processing protocol; Agilent, Palo Alto, CA).

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Comparison of Bzrp ligands

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