Transcript profiles elicited by developmental exposure to endocrine-mediated
toxicants
G. Daston
Miami Valley Laboratories, Procter &Gamble, Cincinnati,
OH 45253, USA
Abstract: Genomics can be applied in toxicology as a means of
identifying modes of action, for generating hypotheses on the relationships
of gene activity and toxicity, and for better characterizing the nature
of dose-response relationships at low doses. This paper provides examples
from our research on endocrine active compounds that illustrate each
of these applications. We have determined that agents that bind estrogen
receptors produce a characteristic transcript profile in estrogen-responsive
tissues of the fetal and juvenile rat. The transcript profile is diagnostic
of the mechanism of action. The transcripts that are up- or down-regulated
by estrogens belong to a number of functional groups, such as growth
factors, pro-apoptotic factors, transcription factors, and steroid metabolizing
enzymes. There are a number of testable hypotheses that can be generated
from these data regarding the relationships between changes in these
genes and developmental or physiological responses to estrogens. We
have determined that the sensitivity of gene expression changes is high,
making it possible to define the shape of the dose-response curve at
dose levels of estrogen several orders of magnitude below those that
cause a physiological response (in this case, a uterotrophic response).
The shape of the dose response is monotonic: both the number of genes
changed and the intensity of the up- or down-regulation decreases with
decreasing dose.
*Report from a SCOPE/IUPAC project: Implication of
Endocrine Active Substances for Human and Wildlife (J. Miyamoto and
J.Burger, editors). Other reports are published in this issue,
pp. 1617-2615.
Page last modified 12 February 2004.
Copyright © 2004 International Union of Pure and Applied Chemistry.
Questions or comments about IUPAC, please contact, the Secretariat.
Questions regarding the website, please contact web
manager.