title: Gestational Exposure to Sidestream (Secondhand) Cigarette Smoke Promotes Transgenerational Epigenetic Transmission of Exacerbated Allergic Asthma and Bronchopulmonary Dysplasia.
abstract: Embryonic development is highly sensitive to xenobiotic toxicity and in utero exposure to environmental toxins affects physiological responses of the progeny. In the United States, the prevalence of allergic asthma (AA) is inexplicably rising and in utero exposure to cigarette smoke increases the risk of AA and bronchopulmonary dysplasia (BPD) in children and animal models. We reported that gestational exposure to sidestream cigarette smoke (SS), or secondhand smoke, promoted nicotinic acetylcholine receptor-dependent exacerbation of AA and BPD in mice. Recently, perinatal nicotine injections in rats were reported to induce peroxisome proliferator-activated receptor γ-dependent transgenerational transmission of asthma. Herein, we show that first generation and second generation progeny from gestationally SS-exposed mice exhibit exacerbated AA and BPD that is not dependent on the decrease in peroxisome proliferator-activated receptor γ levels. Lungs from these mice show strong eosinophilic infiltration, excessive Th2 polarization, marked airway hyperresponsiveness, alveolar simplification, decreased lung compliance, and decreased lung angiogenesis. At the molecular level, these changes are associated with increased RUNX3 expression, alveolar cell apoptosis, and the antiangiogenic factor GAX, and decreased expression of HIF-1α and proangiogenic factors NF-κB and VEGFR2 in the 7-d first generation and second generation lungs. Moreover, the lungs from these mice exhibit lower levels of microRNA (miR)-130a and increased levels of miR-16 and miR-221. These miRs regulate HIF-1α-regulated apoptotic, angiogenic, and immune pathways. Thus the intergenerational effects of gestational SS involve epigenetic regulation of HIF-1α through specific miRs contributing to increased incidence of AA and BPD in the progenies.
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM 87108.
authors.forename: Shashi P
authors.initials: SP
authors.lastname: Singh
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM 87108.|Florida International University, Miami, FL 33199.
authors.forename: Hitendra S
authors.identifier: 0000-0002-0574-9307
authors.initials: HS
authors.lastname: Chand
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM 87108.|University of Southern Alabama, Mobile, AL 36688.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Langley
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM 87108.
authors.forename: Neerad
authors.initials: N
authors.lastname: Mishra
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM 87108.
authors.forename: Ted
authors.identifier: 0000-0003-0521-0683
authors.initials: T
authors.lastname: Barrett
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM 87108.
authors.forename: Karin
authors.initials: K
authors.lastname: Rudolph
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM 87108.
authors.forename: Carmen
authors.identifier: 0000-0002-0097-6957
authors.initials: C
authors.lastname: Tellez
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM 87108.
authors.forename: Piotr T
authors.identifier: 0000-0003-3679-0801
authors.initials: PT
authors.lastname: Filipczak
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM 87108.
authors.forename: Steve
authors.initials: S
authors.lastname: Belinsky
authors.affiliation: Pulmonary and Critical Care Medicine, University of New Mexico Medical Center, Albuquerque, NM 87131.
authors.forename: Ali I
authors.identifier: 0000-0001-8660-9578
authors.initials: AI
authors.lastname: Saeed
authors.affiliation: Department of Pediatrics, University of New Mexico Medical Center, Albuquerque, NM 87131; and.
authors.forename: Aryaz
authors.identifier: 0000-0002-8464-086X
authors.initials: A
authors.lastname: Sheybani
authors.affiliation: Department of Pediatrics, University of New Mexico Medical Center, Albuquerque, NM 87131; and.
authors.forename: Vernat
authors.initials: V
authors.lastname: Exil
authors.affiliation: Department of Pediatrics, University of New Mexico Medical Center, Albuquerque, NM 87131; and.
authors.forename: Hemant
authors.initials: H
authors.lastname: Agarwal
authors.affiliation: Environmental Health Sciences, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: Venkataramana K
authors.identifier: 0000-0002-4506-8549
authors.initials: VK
authors.lastname: Sidhaye
authors.affiliation: Environmental Health Sciences, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: Thomas
authors.identifier: 0000-0002-5240-4299
authors.initials: T
authors.lastname: Sussan
authors.affiliation: Environmental Health Sciences, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM 87108; msopori@lrri.org.
authors.forename: Mohan
authors.initials: M
authors.lastname: Sopori
mesh_terms: D056809:Alveolar Epithelial Cells / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D001249:Asthma / Q000209:etiology* / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D001997:Bronchopulmonary Dysplasia / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D008168:Lung / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D052002:NF-kappa B p50 Subunit / Q000235:genetics; D009414:Nerve Growth Factors; D009479:Neuropeptides / Q000235:genetics; D009538:Nicotine / Q000009:adverse effects; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000276:immunology* / Q000503:physiopathology; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects; D018418:Th2 Cells / Q000276:immunology; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; C497443:Hif1a protein, mouse; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C484194:Meox2 protein, mouse; D035683:MicroRNAs; D052002:NF-kappa B p50 Subunit; D009414:Nerve Growth Factors; D009479:Neuropeptides; D047495:PPAR gamma; C493730:Runx3 protein, mouse; D012906:Smoke; D014028:Tobacco Smoke Pollution; C512697:Vgf protein, mouse; C073701:Nfkb1 protein, mouse; D009538:Nicotine