Molecular responses to xenoestrogens: mechanistic insights from toxicogenomics

The xenoestrogen group of endocrine disruptors has the potential to cause reproductive and developmental effects through stimulation or disruption of sex steroid nuclear receptor signalling pathways. A more detailed understanding of the ways in which xenoestrogens interact with biological systems at the molecular level will provide a mechanistic basis for improved safety assessment. The recent sequencing of mammalian genomes has driven the development of toxicogenomic technologies, including microarray based gene expression profiling, which allow the expression levels of thousands of genes to be measured simultaneously. Since the cellular responses to xenoestrogens are predominantly mediated by estrogen receptors, which function as ligand-activated transcription factors to regulate gene expression, the application of toxicogenomics has great potential for providing insights into the molecular mechanisms of xenoestrogen action. A major challenge in applying toxicogenomics to the field of endocrine disruption is the need to define how xenoestrogen-induced changes in gene expression relate to conventional physiological and toxicological endpoints. Gene Ontology Mapping, Pathway Mapping and Phenotypic Anchoring of xenoestrogen-induced gene expression changes to cellular pathways and processes represent key steps in defining these relationships. Mechanistic insights into how xenoestrogens target specific genes and into the functional significance of xenoestrogen-induced alterations in gene expression can be further enhanced by combining transcript profiling with transgenic animal models or cell-based systems in which the estrogen receptor signalling pathways have been modified experimentally. This review illustrates how these toxicogenomic approaches are providing an unprecedented amount of mechanistic information on the molecular responses to xenoestrogens and how they are likely to impact on hazard and risk assessment.