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Collaborative Research Area on Developmental Toxicology

Coordinator: Thomas Burbacher, Ph.D.

Exposure to environmental chemicals and therapeutic drugs during pregnancy and during childhood can have serious consequences on normal growth and development. Infants and children are more susceptible to chemically-induced injury than adults and neurotoxicant-related injuries can range from frank birth defects to more subtle changes in learning and memory. Although there are important exceptions, the developing brain is the site most vulnerable to disruption from early chemical exposure and effects can emerge over decades and even across a lifetime. The issue of early toxicant exposure and its effects on structural and functional development is an emerging theme in contemporary pediatric health research across the globe. This CRA reflects an active research interest in this scientific area and offers a multifaceted approach that spans from molecular mechanisms of toxicity to the shaping of public health policy. Investigators within the Developmental Toxicology CRA are involved in research that reaches across species, including studies with human populations and a variety of animal models, to enhance a fundamental understanding of toxicants and their role in biological and behavioral development.

The goals of the Collaborative Research Area in Developmental Toxicology are:

• To promote research that reveals the structural and functional effects associated with exposure to environmental chemicals and therapeutic drugs during pregnancy and childhood. There is growing recognition that chemical and drug exposures during development can have long-term consequences for growth and development. Understanding the unique risks that neurotoxic compounds pose to the developing child requires focused and highly specialized studies. Investigators in the Developmental Toxicology CRA are internationally recognized in their fields of study and research programs include large human research trials like the National Children's Study and laboratory studies with murine and primate animal models. Special interests of faculty include developmental neurotoxicants such as pesticides, methylmercury, methanol, ethanol, domoic acid, and thimerosal (ethylmercury). Pre-clinical studies are currently focusing on the neuroprotective effects of erythropoietin (Epo) in neonatal models of brain injury. This work includes studies of pharmacokinetics, drug dosing, and duration of therapy as well as identifying mechanisms of Epo neuroprotection and possible synergistic treatments.

• To enhance our understanding of the mechanisms by which developmental toxicants impact the central nervous system during prenatal and postnatal growth. Neurotoxic substances may play a role in a number of developmental disorders and in psychiatric and neurodegenerative diseases. Studies of the biochemical and molecular mechanisms that define children's susceptibility to neurotoxicants are actively on-going in the laboratories of the Developmental Toxicology faculty. Investigative tools in research aimed at defining the molecular mechanisms involved in neurotoxicity include in vivo and in vitro cell culture systems, biochemical, molecular and imaging techniques and transgenic animal models. Compounds of interest include metals (methylmercury and arsenic), organophosphate insecticides, domoic acid, pesticides (organophosphates, and benomyl), N-nitroso compounds and polybrominated diphenyl ether fire retardants. Studies of neuronal apoptosis and neural stem cell proliferation and differentiation are also taking place. Abnormal apoptosis may cause or contribute to various neurodegenerative disorders, including stroke, epilepsy, Parkinson's disease, Huntington's disease, and Alzheimer's disease.

• To develop processes for evaluating the risk of developmental toxicants and promote adequate policies to protect public health. Scientific factors provide the basis for risk assessment, including information drawn from toxicology, chemistry, epidemiology, ecology, and statistics. Effectively communicating the health risks of chemical exposures is an important goal of Developmental Toxicology faculty. Group members are working with federal and local government agencies to improve risk assessment methods and the scientific foundation behind risk assessment computation. Several investigators sit on national and international review panels, helping to develop standards for exposures to developmental toxicants.

• To educate physicians, other health care providers and the general public on the teratogenic potential of drugs and chemicals in an effort to prevent birth defects and developmental disabilities. Every infant has at least a 5% risk of being born with a serious congenital anomaly. This not only includes physical malformations but also intellectual disability and other important functional deficits which may not become apparent until later in life. Our web-based TERIS teratogen information service for physicians and other health care professionals is of great value. TERIS includes data on teratogenicity, transplacental carcinogenesis, embryonic or fetal death, and fetal and perinatal pharmacologic effects of drugs and selected environmental agents. The TERIS database also provides access to Shepherd's Catalogue of Teratogenic Agents. In addition, several investigators are involved in research translation activities to health care providers and the general public.

• Thomas Burbacher, Ph.D., Professor, Environmental and Occupational Health Sciences, Coordinator
• Lucio Costa, Ph.D., Professor, Environmental and Occupational Health Sciences
• Michael Cunningham, M.D., Ph.D., Professor, Pediatrics
• Elaine Faustman, Ph.D., Professor, Environmental and Occupational Health Sciences
• Clement Furlong, Ph.D., Research Professor, Medical Genetics
• Anne Hing, M.D., Associate Professor, Pediatrics
• Sandra Juul, M.D., Ph.D., Professor, Pediatrics
• Raj Kapur, M.D., Ph.D., Professor, Pathology
• Janine Polifka, Ph.D., Clinical lecturer, Pediatrics
• Joe Rutledge, M.D., Professor, Laboratory Medicine
• Danny Shen, Professor, Pharmaceutics
• Zhengui Xia, Ph.D., Professor, Environmental and Occupational Health Sciences