Cross-species comparison of estrogenic endocrine disruptor-induced, uterotrophic gene expression in the rodent

Estrogenic endocrine disrupting chemicals (EEDCs) are a growing matter of concern in the etiology of several developmental, reproductive and general health related adverse health effects. These include breast cancer, decreasing fertility rates, and birth defects. These chemicals are structurally diverse and arise from a broad range of sources including natural products, pesticides, food processing and packaging materials, and pharmaceuticals. These chemicals mediate most of their effects through estrogen receptors (ERs) which are ligand-dependant transcription factors. Thus the main mechanism of estrogen signaling involves the regulation of expression of target genes. A major consideration in ER signaling is selective estrogen receptor modulator (SERM) activity, which consists of differential activation of the ER depending upon ligand-specific conformational changes and subsequent transcriptional activities of the activated ER. Thus understanding the activity of SERMs is an essential part of our assessment of EEDCs.;A fundamental aspect of toxicology and pharmacology are cross-species comparisons of data between surrogate models and humans. Thus understanding how different surrogates respond to the same stimulus is essential in resolving uncertainties in assessing safety and efficacy information between models as well as extrapolating information from surrogates to humans. Two prevalent rodent models common to toxicology and basic research are the rat and mouse. Furthermore, the enhanced rodent Joshua C. Kwekel uterotrophic assay is a classic measure of estrogen activity in vivo and was thus utilized to characterize the estrogenicity of three estrogen ligands. Dose response and time course studies were conducted to examine the global gene expression profiles accompanying the uterotrophic response. Ethynylestradiol, a potent orally active and positive control estrogen; tamoxifen, a breast cancer drug and classic SERM; and o,p'-DDT, the estrogenic isomer of the legacy pesticide DDT and well known EEDC were evaluated in the mouse and rat during uterotrophy. Comparative analysis of the temporal gene expression of these three ER ligands was performed and results reveal a high degree of overlap in differentially expressed genes between ligand and species. Furthermore, ligand- and species-specific responses were also characterized and phenotypically linked. Carbonic anhydrase 2, a gene with multiple endocrine-related effecter roles was identified as a notable candidate biomarker gene exhibiting divergent regulation between species and ligand.