Problem &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. Remaricably, this effect is also caused by control, 'inert'titanium dioxide particles. Moreover, 'inert' particles are actually pathogenic/pro-infiammatory in pregnant mice (while causing minimal effects in nonpregnant 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 eariy life origins of asthma and the applied question of how environmental agents mediate in utero effects.
The study utilizes a novel model and offers an approach to identify molecular mechanisms for environmentmatemal- fetal interaction. The long-term goal is to elucidate the specific mechanisms of altered immune response to environmental particles in the lungs of pregnant females and to delineate the consequences of such maternal exposure on offspring immunity. Ultimately, 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.
|Zhang, Yiming; Mikhaylova, Lyudmila; Kobzik, Lester et al. (2015) Estrogen-mediated impairment of macrophageal uptake of environmental TiO2 particles to explain inflammatory effect of TiO2 on airways during pregnancy. J Immunotoxicol 12:81-91|
|Gregory, David J; Zhang, Yiming; Kobzik, Lester et al. (2013) Specific transcriptional enhancement of inducible nitric oxide synthase by targeted promoter demethylation. Epigenetics 8:1205-12|
|Mikhaylova, Lyudmila; Zhang, Yiming; Kobzik, Lester et al. (2013) Link between epigenomic alterations and genome-wide aberrant transcriptional response to allergen in dendritic cells conveying maternal asthma risk. PLoS One 8:e70387|
|Gregory, David J; Mikhaylova, Lyudmila; Fedulov, Alexey V (2012) Selective DNA demethylation by fusion of TDG with a sequence-specific DNA-binding domain. Epigenetics 7:344-9|
|Lamoureux, Denise P; Kobzik, Lester; Fedulov, Alexey V (2010) Customized PCR-array analysis informed by gene-chip microarray and biological hypothesis reveals pathways involved in lung inflammatory response to titanium dioxide in pregnancy. J Toxicol Environ Health A 73:596-606|