Developmental Nicotine Exposure & Transgenerationally Altered Lung Phenotype

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 DESCRIPTION (provided by applicant): This application is in response to NHLBI TOSI HL-131: Exposure of the developing lung to cigarette smoke is an independent risk factor for the development of chronic lung disease (CLD), including asthma in later life. Even more importantly, recently, it has been shown that by altering specific developmental signaling pathways necessary for fetal lung development, the perinatal nicotine exposure-related CLD risk is not restricted only to the nicotine exposed offspring, but is also transmitted transgenerationally to the progeny of the subsequent non-exposed offspring (Rehan et al, AJP Lung; 2013;305:L501-7). Specifically, nicotine alters the normal differentiation of mesenchymal cells in the developing lung by stimulating the Wnt pathway, inhibiting PPARɣ signaling, resulting in the myogenic phenotype of the airway smooth muscle (ASM) cells. Interestingly, these effects are sex-specific, with the molecular and functional effects on ASM cells seen exclusively in males. Importantly, PPARɣ agonists, which are potent Wnt antagonists, can inhibit and/or reverse these effects. Hypothesizing that these effects are determined by nicotine-induced epigenetic changes in the gonadal germ line, which lead to lung specific molecular and functional effects, we propose to examine the mechanistic basis for the 1) transgenerational (TG) transmission, and 2) gender-specificity of perinatal nicotine exposure-induced offspring lung hyperresponsive phenotype. In Aim 1, we will determine whether the perinatal nicotine exposure-induced lung phenotype is transmitted via the male vs. female germline (Aim 1A), whether it is affected by the genetic diversity of parents (Aim 1B), and whether the lung phenotype seen in childhood is also seen in adulthood (Aim 1C). In Aim 2, we will determine whether the more pronounced perinatal nicotine exposure-induced pulmonary phenotype seen in males is determined by the differential PKC expression and activation in ASM cells of males vs. females (Aim 2A) and whether this is abrogated by blocking the specific PKC isoform involved (Aim 2B). In Aim 3, we will determine whether perinatal nicotine exposure-induced germ line and ASM epigenetic changes are transmitted from F1 to F3 generation (Aim 3A) and whether concomitant suppression of nicotine-induced Wnt activation, using PPARɣ agonist rosiglitazone, blocks these epigenetic changes and protects against perinatal nicotine-induced TG transmission of the lung myogenic phenotype (Aim 3B). The concepts put forward in this proposal are totally novel and innovative, thus advancing the field significantly by addressing the fundamental mechanism(s) that explain the detrimental effects of maternal smoking not only on the exposed offspring, but also on the many generations that follow. Using this comprehensive cell-molecular-epigenetic approach, the proposed studies are likely to not only generate new, pivotal molecular data that could significantly impact our understanding of the pathogenesis of CLD, but also provide novel mechanistic information underlying CLD risk, paving the way for studying molecular mechanisms underlying TG effects on a host of other environmental exposures.