Candidate's Abstract) The adverse effects on fetal development after exposure to environmental contaminants or biological pathogens are very important health concerns. Many of the mechanisms are unclear. It is evident that the immune system can and does play a significant role in the initiation and progression of toxicity induced by chemicals or substances in adult subjects. What is unclear is whether macrophages and neutrophils of embryonic or maternal origin play a role in the initiation and/or progression of specific developmental toxicities after exposure to certain agents. There is very little published information addressing the functional capabilities of fetal immuno-effector cells in developmental toxicities. In addition, the potential mediators and mechanisms by which these cells induce fetotoxicity require further elucidation. Studies have demonstrated that polychlorinated biphenyls (PCBS; environmental contaminants), and endotoxin (LPS; biological pathogen) cause a variety of developmental toxicities, with neurological aberrations and defects in bone formation among the more serious. The mechanisms of these toxicities are not fully understood. What is known, however, is that proper development of certain skeletal structures and the formation of a functional nervous system is controlled, in part, by normal neural crest cell (NCC) migration and differentiation. If NCC activity is compromised, the abnormal development of the skeletal and nervous systems will take place. Recent studies from our laboratory suggest that conditioned medium from neural crest cells (CM-NCC) exposed to either PCB or endotoxin in vitro is chemotactic for macrophages and neutrophils, and can activate them. Accordingly, this proposal was designed to test the hypothesis that after exposure to PCBs or endotoxin macrophages and neutrophils contribute to fetotoxicity by propagating NCC injury in the rat and to understand the mechanism(s) by which these, immune cells are involved. Initially, studies in utero, using immunohistochemical techniques, will be conducted to confirm the chemotactic presence and location of macrophages and neutrophils after exposure. Studies using whole embryo cultures will help to determine if fetal or maternal effector cells are involved. Finally, co-cultures of either macrophages or neutrophils with NCC or poly-cultures containing all three cell populations will be employed to determine if and how these immune cells cause NCC cytotoxicity. Because the environmental- and pathogenic-induction of developmental abnormalities is a continuous biomedical problem, the long term goal of this project is to use the acquired information to develop more effective therapeutic interventions and to continue to raise awareness to the consequences resulting from exposure to these developmentally toxic substances.
| Reese, C T; Ntam, C; Martin, T V et al. (2007) Internalization of near-infrared fluorescent dyes within isolated macrophage populations. Cell Mol Biol (Noisy-le-grand) 53:27-33 |
| Baker, Michael; Ntam, Colette; Reese, Carroll T et al. (2006) Internalization of near-infrared fluorescent dyes within isolated leukocyte populations. Int J Environ Res Public Health 3:31-7 |
