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BIOMONITORING THE TOXICOGENOMIC RESPONSE TO ENDOCRINE DISRUPTING CHEMICALS IN HUMANS, LABORATORY SPECIES AND WILDLIFE
Citation:
Dix, D J., J C. Rockett, L Folmar, M J. Hemmer, S J. Degitz, AND J E. Tietge. BIOMONITORING THE TOXICOGENOMIC RESPONSE TO ENDOCRINE DISRUPTING CHEMICALS IN HUMANS, LABORATORY SPECIES AND WILDLIFE. Presented at US-Japan International Workshop for Endocrine Disrupting Chemicals, Tsukuba, Japan, February 28-March 3, 2001.
Description:
With the advent of sequence information for entire eukaryotic genomes, it is now possible to analyze gene expression on a genomic scale. The primary tool for genomic analysis of gene expression is the gene microarray. We have used commercially available and custom cDNA microarrays to define the transcriptomes of reproductive tissues, associate gene expression with fertility status, and monitor effects of chemical exposure on gene expression. The expression of over 20,000 human and 10,000 mouse genes and ESTs was screened for in the testis using commercial filter and slide-based arrays. This identified thousands of candidate genes for placement on a testis-specific array. In order to prioritize the significance of expression of individual genes in the testis, we compared gene expression in fertile and infertile humans and mice. With mice, we were able to use both genetic and exposure-induced models of infertility. The information from these commercial arrays was used to assemble custom human and mouse microarrays designed to interrogate testicular gene expression significant to male fertility status. To extend the applicability of this toxicogenomic approach, we have begun to characterize concordant alterations in gene expression between reproductive tissues and more accessible tissues. In males, this refers to comparisons between testicular gene expression and the mRNA content of ejaculated sperm. In females, we have compared estradiol-induced changes in uterine gene expression to changes in peripheral blood cell gene expression. Continuing efforts are underway to develop and apply improved human, mouse and rat microarrays for monitoring significant alterations in gene expression linked to chemical exposure and compromised reproductive health.
Gene microarrays are also being developed to evaluate ecological effects in amphibian and fish models, and establish the relationship between gene expression patterns and adverse effects of chemical exposure. Xenopus laevis arrays will be used to characterize xenobiotic modulation of the amphibian thyroid axis, and to monitor similar effects in ranid species. A similar X. laevis array could be used to monitor or predict effects with native ranid species. Sheepshead minnow (Cyprinodon variegates) genes up-regulated by estrogen are being arrayed for analysis of gene expression following exposure to xenoestrogens. The sheepshead microarray will be field-validated using feral fish from locations known to produce estrogenic responses. The breadth and selection of gene microarrays employed holds out the possibility for identifying conserved genetic responses in human, rodent, amphibian and fish species.