Gene expression changes related to growth and differentiation in the fetal and juvenile reproductive system of the female rat: evaluation of microarray results

Microarrays make it possible to evaluate the responses of a major fraction of the genome in response to physiological perturbation or exogenous insult. This represents a huge advance in our ability to detect changes in gene expression that may be responsible for physiological or toxicological responses. Our laboratory is interested in the effects of estrogens on female reproductive system development and function. We have evaluated the changes in gene expression in response to estrogens in the female reproductive tract of rats during embryo/fetal development and in the juvenile rat (which is capable of mounting a uterotrophic response). The results of these experiments indicate that a number of genes (dozens to hundreds) are changed in a reproducible, dose-related manner in response to estrogens. These results have been published elsewhere; the purpose of this review is to evaluate, based on information from the literature, the potential role of selected genes on processes of cell proliferation and differentiation, and to suggest plausible relationships among these genes in eliciting responses at the tissue or organ level. We also discuss the utility of gene-expression experiments in elucidating the shape of the dose-response curve at low doses. In particular, we show that the dose-response for gene expression in the juvenile rat uterus is monotonic down to levels a few orders of magnitude below the NOEL for a uterotrophic response, suggesting that gene expression (and by inference higher order responses) do not follow patterns that are unpredictable based on response at higher dosages.