Impact/Purpose:

This project addresses the long-term consequences of perturbations during the in utero period and various diseases later in life. Its objectives are to develop animal models to evaluate effects of developmental perturbation on adverse health outcomes during adulthood; assess key health outcomes during adulthood following developmental perturbation; investigate mechanism(s) of adverse health effects in adults following developmental perturbation; and provide input into interpretation of low birth weight data from EPA testing guideline studies.

This project has the potential to change the basic study designs for assessing developmental toxicity and to reveal latent toxic effects not seen before. If the results demonstrate long-term morbidity associated with prenatal and/or postnatal exposures, it may be necessary to extend existing study designs or create new designs to test for such effects. Perhaps some types of morbidity associated with developmental exposures are general in nature, while others are chemical-specific. We may find that no increase in disease is associated with exposures that also affect fetal or early postnatal growth, in which case we may not need additional tests, but such results would clearly raise the significance of affects on fetal weight or postnatal growth seen using current study designs. These studies thus have the potential to bring significant improvements to the risk assessment process.

Description:

Clinical and epidemiological studies have shown significant correlations between conditions during development and various diseases later in life. In humans, low birth weight has been used as a surrogate for adverse developmental conditions, but the specific conditions affecting birth weight are usually unknown. The most common adverse effect seen in standard rodent developmental toxicology studies is reduced fetal weight at term. Current EPA guidelines for interpretation of develop-mental toxicity studies state that fetal weight is an adverse outcome on par with death and malformation, the other adverse outcomes detectable in fetuses at term. However, the interpretation of reduced fetal weight is a contentious subject, especially when fetal weight is affected only at maternally toxic exposures. Current study designs do not examine the long term health of offspring exposed during development (in utero and/or postnatally). The utilization of animal models will help define the causal factors and identify long-term effects under controlled experimental conditions that are impossible to duplicate in epidemiology studies. Current developmental toxicity tests do not address this important issue and may be missing important adverse effects highly relevant to the human condition. This project will examine the long-term health effects of toxic exposures during development. The overall goal is to determine the conditions under which developmental perturbations will lead to adverse health outcomes at adulthood. There is evidence that some environmental contaminants may alter developmental programming in a manner that does not necessarily result in malformations but affects function later in life. The best-studied examples of this are environmental agents with endocrine activity, and these agents typically affect the reproductive tract or reproductive function. Effects of these agents may not become apparent until puberty, or in some cases, may only hasten the onset of reproductive senescence much later in life. Latent health effects due to developmental exposures to other classes of agents have received scant attention, but there are examples of neurological and neurodegenerative effects of developmental exposures. There is evidence that in utero exposure to polychlorinated biphenyls leads to altered thyroid function and learning disabilities later in life. The mechanisms underlying these effects are poorly understood, but well-designed studies and new technologies such as gene expression profiling should begin to reveal clues to the developmental pathways involved. Studies using this technology will be designed and incorporated into this program project as results emerge from the more descriptive animal studies. Our studies will look at the effects of developmental toxicant exposure or undernutrition on adult physiology, long-term immune function deficits following immune system perturbation during development, placental tissue as a potential source of biomarkers associated with intrauterine growth retardation (IUGR) and long-term health effects, the effects of high use herbicides on breast and prostate development and life-time disease risk in humans and rodents following gestational or lactational exposures, long-term metabolic system perturbations after developmental exposures, intergenerational effects on female reproduction, gene expression profiling for the elucidation of developmental pathways involved in embryo/fetal programming, and the effects of low birth weight on the development of allergy.

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