Doctor of Philosophy (PhD)


Biomedical and Veterinary Medical Sciences - Comparative Biomedical Sciences

Document Type



In utero exposure to second-hand smoke (SHS) has modulatory effects on adult lung responses to various irritants. To further elucidate diverse responses with different inhaled irritants and to understand how long the effects persist, we have focused on two environmentally-relevant and asthma-associated irritants--SHS and ovalbumin (OVA)--for adult mice that had been exposed in utero to SHS. We hypothesized that in utero SHS exposure aggravates lung responses to various inhaled irritants, including SHS and OVA, in adult mice beyond the age of 15 weeks; and that the responses will likely exhibit a sex bias. Pregnant BALB/c mice were exposed (days 6-19 of pregnancy) to SHS (10 mg/m3) or HEPA-filtered air (AIR). The lung responses of 15-week-old male offspring were examined after daily exposure from 11-15 weeks of age to either SHS or AIR. Another set of lung responses were assessed on 23-week-old mice, both females and males, after OVA sensitization and challenge from 19-23 weeks of age. The assessments focused on pulmonary function, bronchoalveolar lavage fluid (BALF), histopathology, and lung transcriptome screening (mRNAs and miRNAs). In utero SHS exposure significantly aggravates lung responses in synergy with recurring SHS to 15-week-old male mice, shown by increased airway hyper-responsiveness (AHR) and BALF pro-inflammatory cytokines. Additional morphometric analysis and transcriptome screening indicated that in utero exposure resulted in enlarged air spaces and arteries in adult mice regardless of adult irritants. In the case of recurring (adult) SHS exposure, pro-fibrotic genes were activated. This also was evident by increased collagen deposition in the lungs. On the other hand, in utero SHS exposure also aggravated lung responses to OVA in 23-week-old mice, as indicated by further increased lung inflammation, AHR, BALF Th2 cytokines, and pro-asthmatic gene expression changes, with the majority of responses being more pronounced in males than in females. Furthermore, the additional miRNA expression screening identified overexpressed miRNAs that are oncogenic; 16 tumor suppressor genes, as targets of these miRNAs, were found to be down-regulated. In conclusion, in utero SHS exposure elicits deleterious effects on adult mice challenged with inhaled irritants, and may promote and predispose affected individuals to certain respiratory diseases.



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Committee Chair

Penn, Arthur.