Environmentally induced cardiovascular malformations. (Fellowships, Grants, & Awards).

The NIEHS invites applications to study environmental agents that cause cardiovascular malformations (CVMs). This PA is intended to stimulate research to characterize environmental agents that cause alterations in the development of the cardiovascular system and thereby lead to CVMs, and to investigate the cellular and molecular mechanisms involved in the development of these CVMs. The use of mammalian and nonmammalian animal models, including transgenic and gene knockout animal models, and of state-of-the-art molecular biology techniques such as genomics and proteomics is encouraged, as well as collaborations between environmental health scientists and developmental biologists, to develop research programs to address the high rate of CVMs.

CVMs are the most common type of birth defect among live births in the United States, occurring in approximately 0.8% of live births. The most common types of CVMs include atrial or ventricular septal defects, transposition of the great vessels, persistent truncus arteriosus, teratology of Fallot, and coarctations. Despite the importance of these in malformations, in terms both of human suffering and cost to the health care system, the causes of most cases of CVMs are not known.

Etiologic factors that have been identified include genetics, maternal diseases such as diabetes, certain drugs such as phenytoin and cocaine, and dietary factors such as folic acid deficiency, vitamin A excess, and copper deficiency. In addition, certain environmental chemicals have been shown to be associated with CVMs. For instance, in the Baltimore-Washington Infant Study, a large epidemiologic study of cardiac malformations, exposure to such environmental factors as paints, solvents, degreasers, and pesticides was associated with increased CVMs.

Epidemiologic studies have also reported CVM associations with air pollutants (ozone and carbon monoxide) and trichloroethylene (TCE). In addition, environmental contaminants such as TCE, bisdiamine, and dioxin have been shown to be cardiac teratogens in animal studies.

Despite the evidence for an environmental role in CVMs, the list of environmental agents tested for teratogenic effects on the heart is limited, and relatively little research has been done on the cellular and molecular basis of the teratogenic effects of environmental agents or on the possible interactions between environmental exposures and other factors such as diet and genetics. Recent advances in genomic and molecular biology technology and in the understanding of the development of the fetal heart make this an opportune time to initiate such studies.

Specific areas of interest to the NIEHS include, but are not limited to, the following: 1) characterization of new potential environmental cardioteratogens that would include the types of CVMs induced, dose--response evaluation, identification of specific windows of vulnerability to the agent, and development of preliminary data for further mechanistic studies; 2) use of forward and reverse mutagenesis studies in model organisms to determine the genes altered by specific cardiovascular developmental toxicants and the relationship of the altered gene activity to dysmorphogenesis; 3) characterization of global gene expression profiles in the developing heart of model organisms associated with the normal range of development and after a developmentally toxic exposure (the relationship between the changes in gene expression and the developmental lesion should be assessed); 4) use of genomic and/or proteomic profiling to determine how well data on toxicant-induced malformations can be extrapolated across species; 5) identification and evaluation of specific signal transduction pathways and the associated genetic regulatory circuits that might be sites of action of developmental cardiovascular toxicants (the causal relationships between exposure and the CVMs should be developed); and 6) determination of the potential for interactions between exposures to environmental agents and genetic susceptibility that increase the risk for .cardiovascular developmental toxicity.

This PA will use the NIH R21 and R01 award mechanism(s). Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/ phs398/phs398.html in an interactive format. Applications submitted in response to this PA will be accepted at the standard application deadlines, which are indicated in the PHS 398 application kit. Complete information on this PA is available at http://grants.nih.gov/grants/guide/pa-files/ PA-02093.html.

Contact: J. Patrick Mastin, Scientific Program Administrator, Organs and Systems Toxicology Branch, Division of Extramural Research and Training, NIEHS, PO Box 12233, EC-23, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709 USA, 919-541-3289, fax: 919-54t-5064; e-mail: [e-mail]. Reference: PA No. PA-02-093