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1.
Arch Toxicol ; 90(9): 2215-2229, 2016 Sep.
Article in English | MEDLINE | ID: mdl-26525393

ABSTRACT

The assessment of the carcinogenic potential of chemicals with alternative, human-based in vitro systems has become a major goal of toxicogenomics. The central read-out of these assays is the transcriptome, and while many studies exist that explored the gene expression responses of such systems, reports on robustness and reproducibility, when testing them independently in different laboratories, are still uncommon. Furthermore, there is limited knowledge about variability induced by the data analysis protocols. We have conducted an inter-laboratory study for testing chemical carcinogenicity evaluating two human in vitro assays: hepatoma-derived cells and hTERT-immortalized renal proximal tubule epithelial cells, representing liver and kidney as major target organs. Cellular systems were initially challenged with thirty compounds, genome-wide gene expression was measured with microarrays, and hazard classifiers were built from this training set. Subsequently, each system was independently established in three different laboratories, and gene expression measurements were conducted using anonymized compounds. Data analysis was performed independently by two separate groups applying different protocols for the assessment of inter-laboratory reproducibility and for the prediction of carcinogenic hazard. As a result, both workflows came to very similar conclusions with respect to (1) identification of experimental outliers, (2) overall assessment of robustness and inter-laboratory reproducibility and (3) re-classification of the unknown compounds to the respective toxicity classes. In summary, the developed bioinformatics workflows deliver accurate measures for inter-laboratory comparison studies, and the study can be used as guidance for validation of future carcinogenicity assays in order to implement testing of human in vitro alternatives to animal testing.


Subject(s)
Carcinogens/toxicity , Computational Biology , Gene Expression Profiling , Kidney Tubules, Proximal/drug effects , Laboratory Proficiency Testing , Liver/drug effects , Toxicogenetics/methods , Transcriptome/drug effects , Carcinogens/classification , Cell Line, Tumor , Dose-Response Relationship, Drug , Gene Expression Regulation/drug effects , Genome-Wide Association Study , Humans , Kidney Tubules, Proximal/metabolism , Liver/metabolism , Observer Variation , Oligonucleotide Array Sequence Analysis , Reproducibility of Results , Risk Assessment , Time Factors , Workflow
2.
Reprod Toxicol ; 54: 101-9, 2015 Jul.
Article in English | MEDLINE | ID: mdl-24915137

ABSTRACT

Endocrine disruptors may play substantial roles in the high incidence of breast cancer. We previously described how early exposure to the mixture of phytoestrogen genistein (G) and the anti-androgen vinclozolin (V) affects peripubertal mammary development. This study evaluates the carcinogenic potential of exposure to V alone or associated with G from conception until weaning in Wistar rats. Dams were exposed to V, G or GV during pregnancy/lactation. At PND50 offspring were treated with DMBA[7,12-dimethylbenz(a)anthracene]. V or GV maternal exposure decreased number of DMBA-induced mammary tumors in the offspring, without significant modifications in tumor incidence, multiplicity and latency. G exposure decreased number of tumors, incidence and multiplicity. Unexpectedly, GV exposure increased tumor volume (p=0.04 vs controls) and epithelial proliferation (p=0.001 vs controls; p=0.005 vs G,V only). All tumors were in situ carcinomas. Concluding, maternal gestation/lactation exposure to a vinclozolin and genistein mixture significantly increases offspring tumor growth without changes in carcinogenesis susceptibility.


Subject(s)
Androgen Antagonists/toxicity , Breast Neoplasms/chemically induced , Carcinoma in Situ/chemically induced , Endocrine Disruptors/toxicity , Fungicides, Industrial/toxicity , Genistein/toxicity , Mammary Glands, Animal/drug effects , Maternal Exposure/adverse effects , Oxazoles/toxicity , Prenatal Education , 9,10-Dimethyl-1,2-benzanthracene , Age Factors , Animals , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/prevention & control , Carcinoma in Situ/metabolism , Carcinoma in Situ/pathology , Carcinoma in Situ/prevention & control , Cell Proliferation/drug effects , Diet , Disease Models, Animal , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Gestational Age , Mammary Glands, Animal/metabolism , Mammary Glands, Animal/pathology , Pregnancy , Rats, Wistar , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Risk Assessment , Risk Factors , Tumor Burden/drug effects
3.
Reprod Toxicol ; 32(1): 15-25, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21539910

ABSTRACT

The impact of early exposure to endocrine disruptor mixtures on mammary gland development is poorly known. Here, we identify the effects of a conception to weaning exposure of rats to the phytoestrogen genistein (G) and/or the antiandrogen vinclozolin (V) at 1mg/kg-d, alone or in association. Using several approaches, we found that G- and GV-exposed rats displayed significantly greater epithelial branching and proliferation, wider terminal end buds than controls at PND35, as well as ductal hyperplasia and periductal fibrosis. Focal branching defects were present in V-exposed rats. An increased ER and AR expression was observed in G- and GV- as compared to V-exposed rats at PND35. Surprisingly, a significant number of GV- and to a lesser extent, V-exposed animals displayed abnormal hyperplasic alveolar structures at PND50. Thus, gestational and lactational exposure to low doses of genistein plus vinclozolin may seriously affect peripubertal development of the rat mammary gland.


Subject(s)
Androgen Antagonists/toxicity , Genistein/toxicity , Lactation/drug effects , Mammary Glands, Animal/drug effects , Oxazoles/toxicity , Phytoestrogens/toxicity , Animals , Body Weight/drug effects , Drug Combinations , Female , Food Contamination , Hyperplasia/chemically induced , Hyperplasia/pathology , Mammary Glands, Animal/growth & development , Mammary Glands, Animal/pathology , Maternal Exposure/adverse effects , Rats , Rats, Wistar , Sexual Maturation/drug effects , Vagina/drug effects , Vagina/growth & development
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