Repeated allergic asthma in early versus late pregnancy differentially impacts offspring brain and behavior development |
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| Institution: | 1. Program in Neuroscience and Behavior, Department of Psychology and Education, Mount Holyoke College, 50 College Street, South Hadley, MA 01075, USA;2. Department of Medical Microbiology and Immunology, and the M.I.N.D. Institute, University of California at Davis, CA 95817, USA;1. Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610, USA;2. Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610, USA;1. Institute of Global Health, University of North Carolina-Chapel Hill, Chapel Hill, NC, United States;2. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, United States;3. Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, United States;4. Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, United States;5. Division of Biostatistics and Bioinformatics at The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States;6. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States;7. Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, United States;8. Johns Hopkins University School of Arts and Sciences, Baltimore, United States;9. Department of Psychiatry, Makerere University, Kampala, Uganda;10. Rakai Health Sciences Program, Kalisizo, Uganda;11. Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, United States;12. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States;13. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States;14. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States;1. Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan;2. Department of Psychiatry, Cathay General Hospital, Taipei, Taiwan;3. School of Medicine, Fu Jen Catholic University, Taipei 24205, Taiwan;4. College of Medicine, China Medical University, Taichung, Taiwan;5. Tainan Municipal An-Nan Hospital-China Medical University, Tainan, Taiwan;1. Department of Neurology of University Hospital Würzburg, Josef-Schneider-Straße 2, 97080 Würzburg, Germany;2. Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;3. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA;4. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;5. Department of Neurology of University Hospital Essen, Hufelandstraße 55, 45147 Essen, Germany;1. Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, United States;2. The Center for Neuroscience, University of Colorado, Boulder, CO, United States;3. Xalud Therapeutics, Berkeley, CA, United States;4. Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States;5. Department of Anatomy and Neuroscience, Amsterdam UMC, Vrije Universiteit, Amsterdam, Netherlands |
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| Abstract: | BackgroundStress during pregnancy and maternal inflammation are two common prenatal factors that impact offspring development. Asthma is the leading chronic condition complicating pregnancy and a common source of prenatal stress and inflammation.ObjectiveThe goal of this study was to characterize the developmental impact of repeated allergic asthma inflammation during pregnancy on offspring behavioral outcomes and brain inflammation.MethodsPregnant female C57BL/6 mice were sensitized with ovalbumin (OVA) or PBS vehicle control and then randomly assigned to receive daily aerosol exposures to the same OVA or PBS treatment during early, gestational days (GD) 2-GD9, or late pregnancy, GD10-GD17. Maternal sera were collected after the first and last aerosol induction regimen and measured for concentrations of corticosterone, anti-OVA IgE, and cytokine profiles. Juvenile male and female offspring were assessed for locomotor and social behaviors and later as adults assessed for anxiety-like, and marble burying behaviors using a series of behavioral tasks. Offspring brains were evaluated for region-specific differences in cytokine concentrations.ResultsIn early gestation, both PBS and OVA-exposed dams had similar serum corticosterone concentration at the start (GD2) and end (GD9) of daily aerosol inductions. Only OVA-exposed dams showed elevations in cytokines that imply a diverse and robust T helper cell-mediated immune response. Male offspring of early OVA-exposed dams showed decreases in open-arm exploration in the elevated plus maze and increased marble burying without concomitant changes in locomotor activity or social interactions. These behavioral deficits in early OVA-exposed male offspring were associated with lower concentrations of G-CSF, IL-4, IL-7, IFNγ, and TNFα in the hypothalamus. In late gestation, both PBS and OVA-exposed dams had increased corticosterone levels at the end of daily aerosol inductions (GD17) compared to at the start of inductions (GD10). Male offspring from both PBS and OVA-exposed dams in late gestation showed similar decreases in open arm exploration on the elevated plus maze compared to OVA male offspring exposed in early gestation. No behavioral differences were present in female offspring across all treatment groups. However, females of dams exposed to OVA during early gestation displayed similar reductions as males in hypothalamic G-CSF, IL-7, IL-4, and IFNγ.DiscussionThe inflammatory responses from maternal allergic asthma in early gestation and resulting increases in anxiety-like behavior in males support a link between the timing of prenatal insults and sex-specific developmental outcomes. Moreover, the heightened stress responses in late gestation and concomitant dampened inflammatory response to allergic asthma suggest that interactions between the maternal immune and stress-response systems shape early life fetal programming. |
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| Keywords: | Pregnancy Allergic asthma Autism Cytokines Corticosterone Mouse Behavior |
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