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Comparative Genomics Group

Responses to Transition Metals

Jonathan H. Freedman, Ph.D.
Jonathan H. Freedman, Ph.D.
Principal Investigator and Head, WormTox Group
Tel (919) 541-7899
Fax (301) 451-5362
freedma1@niehs.nih.gov
P.O. Box 12233
Mail Drop E1-05
Research Triangle Park, North Carolina 27709
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Research Summary

The overall research program in the Comparative Genomics Group involves understanding contribution of environmental toxicants to the etiology of human diseases. Specifically, how organisms respond on the molecular level when they are exposed to transition metals (cadmium, copper, zinc, mercury). The cellular responses elicited by metals are similar to those observed following exposure to ultraviolet or ionizing radiation, heat shock, organic chemicals, pro-oxidants and chemical carcinogens. This group has focused on understanding the metal-responsive regulatory processes controlling the gene expression. Ultimately, disruption of these regulatory processes or the inability of an organism to affectively respond to metal exposure may lead to the development of pathologies.

 

To address these problems, the research is directed toward understanding the mechanisms by which metals affect the transcription of specific genes and entire genomes, activate signal transduction cascades, induce post-translational modification of metal-responsive transcription factors, and disrupt normal development. Although the major focus is on the response mechanisms associated with cadmium, copper and mercury exposure, the mechanism of global metal responsiveness is also being investigating by examining silver, zinc, arsenic, and chromium toxicity. To investigate these mechanisms, a variety of model systems, each with characteristics that make in applicable to this research: yeast (rapid growth, genetics), C. elegans (multicellular, genetics, defined cell biology), and mammalian cell culture (more applicable to human conditions) are being used. In addition, through collaborate efforts, zebrafish (multicellular, vertebrate) and mice (genetics, vertebrate) are also being utilized.

micrograph of the nematode C. elegans
This micrograph of the nematode C. elegans displays fluorescence proteins linked to the intestinal gene numr-1 (green) and hsf-1 (red) after a 24-hour exposure to 100 mM cadmium. Yellow fluorescence indicates coincident expression of NUMR-1 and HSF-1.  The inset is a higher magnification of intestinal cell nuclei.

 

Using classic genetic and reverse-genetic approaches, molecular biology, and genomics, the regulatory pathways that respond to metals and subsequently activate transcription are being identified and characterized. Results from this research will be used to help elucidate the fundamental mechanisms of transition metal-induced disease, developmental abnormalities and carcinogenesis, and how organisms adapt to increasingly toxic environments.

 

Major areas of research:

  • Regulatory processes controlling an organism’s response to environmental stress
  • Molecular level response to transition metal exposures
  • Disruption of development by environmental agents

 

Current projects:

  • Mechanism by which cadmium in affects intracellular signal transduction pathways
  • Genetics of metal-activated transcription
  • Characterization of novel metal-responsive genes in C. elegans and their homologs in higher eukaryotes
  • Linkage between cadmium exposure and diabetes
  • Genomic screens to identify cadmium hyper- and hypo-sensitive strains of C. elegans
  • Interspecies comparative genomic response to environmental toxicants

 

Jonathan H. Freedman, Ph.D., heads the Comparative Genomics Group in the Laboratory of Toxicology and Pharmacology and heads the WormTox Group as an adjunct in the Biomolecular Screening Branch. He received his Ph.D. in molecular pharmacology from the Albert Einstein College of Medicine in 1986. He has published 60 peer-reviewed articles in leading biomedical journals, as well as several book chapters. He served as Associate Professor of Molecular Toxicology at Duke University before joining NIEHS in 2005.

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