Responses to Transition Metals
Jonathan H. Freedman, Ph.D.
Tel (919) 541-7899
Fax (919) 541-5737
P.O. Box 12233
Mail Drop E1-05
Research Triangle Park, North Carolina 27709
The overall research program in the Comparative Genomics Group involves understanding the regulatory processes controlling an organism's response to environmental stress. In particular, the group is interested in how organisms respond when they are exposed to toxic concentrations of 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, prooxidants and chemical carcinogens. To investigate these processes a variety of model systems are used: the nematode C. elegans, zebrafish, yeast, mice, and mammalian cell culture. Ultimately, using classic genetic and reverse-genetic approaches, molecular biology, image analysis and visualization, 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.
The Comparative Genomics Group also seeks to understand the contribution of environmental toxicants to the etiology of human diseases. Specifically, the group is interested in understanding how organisms respond on the molecular level when they are exposed to transition metals. Research has focused on understanding the metal-responsive regulatory processes controlling gene expression. Ultimately, disruption of these regulatory processes or the inability of an organism to effectively respond to metal exposure may lead to the development of pathologies. The group is concerned with the role of metals in the etiology of cancer; in addition, recent research efforts have focused on understanding how environmental agents disrupt neuronal development to affect nerve structure and the cognitive ability of an organism (e.g., neural tube defects and autism).
To address these problems, the group’s research interests are 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 mechanism associated with cadmium, copper and mercury exposure, the mechanism of global metal responsiveness is also being investigated by examining silver, zinc, arsenic and chromium toxicity. To investigate these mechanisms, a variety of model systems are used, each with characteristics that make it applicable to this research.
The Comparative Genomics Group applies research techniques that include classic genetic and reverse-genetic approaches, RNA interference, molecular biology, protein biochemistry, traditional toxicology, cell biology, image analysis and visualization, and transcriptomics. 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:
Jonathan H. Freedman, Ph.D., heads the Comparative Genomics Group within the Laboratory of Molecular Toxicology. 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.