Project description:REACH, the EU regulation on chemicals and their safe use, stipulates that about 30,000 chemical substances are to be assessed on their possible risks. Toxicological evaluation of these compounds will at least partly be based on animal testing. Especially reproductive toxicity is one of the most complicated, time-consuming and expensive in vivo endpoints. Introducing microarray-based endpoints can potentially refine in vivo toxicity testing. If compounds from a distinct chemical class induce reproducible gene-expression responses with a recognizable overlap, these gene-expression signatures may indicate intrinsic features of certain compounds, including toxicity. In the present study, we investigated this theory for the reproductive toxicity of phthalates. Male rats were treated with a single dose of either reprotoxic or non-reprotoxic phthalates and sacrificed 24h thereafter. Subsequently, histopathological and gene-expression profiling analyses were performed. Despite ambiguous histopathological observations, we were able to distinguish the reprotoxic from the non-reprotoxic phthalates based on differential gene expression. This shows that differences in gene expression indicative for the type of exposure can be detected earlier, or at lower doses, than phenotypic tissue damage. These findings are promising for ’early warning’ biomarker analyses and for using toxicogenomics in a category approach.
Project description:REACH, the EU regulation on chemicals and their safe use, stipulates that about 30,000 chemical substances are to be assessed on their possible risks. Toxicological evaluation of these compounds will at least partly be based on animal testing. Especially reproductive toxicity is one of the most complicated, time-consuming and expensive in vivo endpoints. Introducing microarray-based endpoints can potentially refine in vivo toxicity testing. If compounds from a distinct chemical class induce reproducible gene-expression responses with a recognizable overlap, these gene-expression signatures may indicate intrinsic features of certain compounds, including toxicity. In the present study, we investigated this theory for the reproductive toxicity of phthalates. Male rats were treated with a single dose of either reprotoxic or non-reprotoxic phthalates and sacrificed 24h thereafter. Subsequently, histopathological and gene-expression profiling analyses were performed. Despite ambiguous histopathological observations, we were able to distinguish the reprotoxic from the non-reprotoxic phthalates based on differential gene expression. This shows that differences in gene expression indicative for the type of exposure can be detected earlier, or at lower doses, than phenotypic tissue damage. These findings are promising for ’early warning’ biomarker analyses and for using toxicogenomics in a category approach. Male rats were treated with a single dose of either reprotoxic (DMP, DEP, DPrP, DOP) or non-reprotoxic phthalates (DBP, DPeP, DHP, DEHP, MEHP), positive control (2-ME) or negative control (vehicle) and killed 24 h thereafter. Rat testes were preserved for RNA extraction and hybridization on Affymetrix microarrays.
Project description:Toxicogenomics profiling of bone marrow from rats treated with topotecan in combination with oxaliplatin: a mechanistic strategy to inform combination toxicity.
Project description:Inflammation is a key component of pathological angiogenesis. Here we induce cornea neovascularisation using sutures placed into the cornea, and sutures are removed to induce a regression phase. We used whole transcriptome microarray to monitor gene expression profies of several genes
