Unknown,Transcriptomics,Genomics,Proteomics

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A molecular and phenotypic integrative approach to identify a no effect dose level for anti-androgen induced testicular toxicity

ABSTRACT: With the advent of high information content technologies, especially microarrays, it is pertinent to determine the impact of molecular data on the NOAELs. Consequently, we conducted an integrative study to identify a no transcriptomic effect dose using microarray analyses coupled with qPCR and determined how this correlated with the NOAEL. We assessed the testicular effects of the antiandrogen, flutamide (FM), in a rat 28-day toxicity study using doses of 0.2-30 mg/kg/day. Concerning molecular data, we observed differential gene expression starting from 1 mg/kg/day and a deregulation of more than 1500 genes at 30 mg/kg/day. Dose-related changes were identified for the major pathways associated with the testicular lesion (eg fatty acid metabolism), that were confirmed by qPCR. These data, along with standard measurements supported the no effect dose of 0.2 mg/kg/day. Flutamide was administered in suspension to rats (7 weeks old at start of treatment, 10 per group) by oral gavage at a daily dose of 0 (control), 0.2, 1, 6 and 30 mg/kg body weight, for 28 consecutive days. Dose-related changes in gene expression were determined in the testes using whole genome oligonucleotide microarrays.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Sophie Ludwig

PROVIDER: E-GEOD-28202 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A molecular and phenotypic integrative approach to identify a no-effect dose level for antiandrogen-induced testicular toxicity.

Ludwig Sophie S Tinwell Helen H Schorsch Frédéric F Cavaillé Christel C Pallardy Marc M Rouquié David D Bars Rémi R

Toxicological sciences : an official journal of the Society of Toxicology 20110427 1

The safety assessment of chemicals for humans relies on identifying no-observed adverse effect levels (NOAELs) in animal toxicity studies using standard methods. With the advent of high information content technologies, especially microarrays, it is pertinent to determine the impact of molecular data on the NOAELs. Consequently, we conducted an integrative study to identify a no-transcriptomic effect dose using microarray analyses coupled with quantitative reverse transcriptase PCR (RT-qPCR) and ...[more]

PMID: 21525395

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Project description:17alpha-ethinylestradiol (EE2) is one of the most potent estrogens that have the ability to interfere with the endocrine system of fish. The objective was to investigate the effects and mechanisms of action caused by 60 days of dietary exposure to 0.2 mg EE2/kg and 0.07 mg EE2/kg feed in female largemouth bass (LMB) during the reproductive season. Microarrays and pathway analyses were performed on hepatic tissues to identify genes and biological processes altered in female LMB by EE2 exposure. The hypothesis was that the two concentrations of EE2 would produce dose-response changes in sensitive genes. Body and ovary weights were measured and blood was collected for measurement of plasma steroid hormones (17beta-estradiol (E2), testosterone (T)) and vitellogenin (VTG) using ELISA. The 0.2 mg EE2/kg feed exposure reduced the gonadosomatic index (GSI) by 75%, and plasma levels of E2 and T were reduced by over 90%. Plasma VTG was increased by approximately 100% (from 4 to 8mg/ml) by the 0.2 mg/kg treatment. T levels, from the 0.07 mg EE2/kg feed, reduced GSI by approximately 30% and circulating E2 and T by ~80% but did not affect VTG concentrations. We found 1,594 and 1,165 genes were significantly affected (p<0.05) by the 0.07 mg EE2/kg feed and 0.2 mg EE2/kg feed, respectively. Gene ontology (GO) analysis revealed that there were different biological processes regulated by the two concentrations of EE2. Pathway analysis showed that the 0.07 mg EE2/kg feed exposure caused differential regulation of genes associated with fatty acid biosynthesis and glycolysis, indicating some metabolic effects. In contrast, the 0.2 mg EE2/kg feed exposure altered transcription of genes involved in immune response and apoptosis, suggesting a toxic response at this concentration. These results suggest that the two concentrations demonstrated distinct physiological responses, with the higher concentration inducing complete endocrine disruption in LMB. These findings demonstrate the usefulness of microarrays to identify possible biomarkers and modes of toxic action to dietary exposure in LMB. Two concentrations of EE2 would produce dose-response changes in sensitive genes. Female LMB were fed 5 days per week for 60 days with floating pellets that contained 0.07 or 0.2 mg/kg of EE2.

Dataset Information

A molecular and phenotypic integrative approach to identify a no effect dose level for anti-androgen induced testicular toxicity

Publications

A molecular and phenotypic integrative approach to identify a no-effect dose level for antiandrogen-induced testicular toxicity.

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