Problem and Pilot Data: Environmental exposures during pregnancy can influence the future health of the developing child, but specific mechanisms are unknown. Pilot data show that offspring of mother mice exposed during pregnancy to diesel exhaust particles are more susceptible to allergy than babies of normal mothers. Remarkably, this effect is also caused by control, 'inert' titanium dioxide particles. Moreover, ''inert' particles are actually pathogenic/pro-inflammatory in pregnant mice (while causing minimal effects in non pregnant controls). Hence, pregnancy causes a heretofore unrecognized change in lung responses to environmental agents, prompting the central hypothesis: pregnancy-related hormones alter local lung innate immune responses to inhaled environmental particles, leading to systemic cytokine modulation of developing offspring immunity to a state of greater susceptibility to allergy.
Specific aim 1 : To characterize the local pulmonary and systemic response of pregnant mice to environmental particles, testing the prediction of enhanced pro-Th2 responses in BAL analysis, multiplex cytokine assays of serum and lung gene expression profiling.
Specific aim 2 : To characterize effects of pregnancy hormones on the alveolar macrophage (AM) response to particles, testing the prediction that progesterone and estrogen promote pro-Th2 AM responses to particles in vitro and in vivo.
Specific aim 3 : To test the causal role of Th2 cytokines in particle-mediated effects during pregnancy by neutralizing antibody and cytokine treatment strategies. Significance: Rigorous mentorship (aim 1) will prepare the candidate for transition to independence (Aims 2 and 3) and continue developing his research career in environmental disease at a faculty level. This research will provide novel insights into the basic question of early life origins of asthma and the applied question of how environmental agents mediate in utero effects.
