PMID- 33358979 OWN - NLM STAT- MEDLINE DCOM- 20210527 LR - 20220302 IS - 1090-2139 (Electronic) IS - 0889-1591 (Print) IS - 0889-1591 (Linking) VI - 93 DP - 2021 Mar TI - Repeated allergic asthma in early versus late pregnancy differentially impacts offspring brain and behavior development. PG - 66-79 LID - S0889-1591(20)32457-0 [pii] LID - 10.1016/j.bbi.2020.12.014 [doi] AB - BACKGROUND: Stress 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. OBJECTIVE: The goal of this study was to characterize the developmental impact of repeated allergic asthma inflammation during pregnancy on offspring behavioral outcomes and brain inflammation. METHODS: Pregnant 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. RESULTS: In 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, IFNgamma, and TNFalpha 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 IFNgamma. DISCUSSION: The 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. CI - Copyright (c) 2020 Elsevier Inc. All rights reserved. FAU - Church, Jamie S AU - Church JS AD - Program in Neuroscience and Behavior, Department of Psychology and Education, Mount Holyoke College, 50 College Street, South Hadley, MA 01075, USA. FAU - Tamayo, Juan M AU - Tamayo JM AD - Department of Medical Microbiology and Immunology, and the M.I.N.D. Institute, University of California at Davis, CA 95817, USA. FAU - Ashwood, Paul AU - Ashwood P AD - Department of Medical Microbiology and Immunology, and the M.I.N.D. Institute, University of California at Davis, CA 95817, USA. FAU - Schwartzer, Jared J AU - Schwartzer JJ AD - Program in Neuroscience and Behavior, Department of Psychology and Education, Mount Holyoke College, 50 College Street, South Hadley, MA 01075, USA. Electronic address: jjschwar@mtholyoke.edu. LA - eng GR - R15 MH119500/MH/NIMH NIH HHS/United States GR - R01 HD090214/HD/NICHD NIH HHS/United States GR - R21 ES025560/ES/NIEHS NIH HHS/United States GR - R01 MH118209/MH/NIMH NIH HHS/United States GR - R21 MH116383/MH/NIMH NIH HHS/United States GR - R15 HD082638/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20201221 PL - Netherlands TA - Brain Behav Immun JT - Brain, behavior, and immunity JID - 8800478 SB - IM MH - Adult MH - Animals MH - *Asthma/chemically induced MH - Brain MH - Female MH - Humans MH - Male MH - Maternal Exposure MH - Mice MH - Mice, Inbred C57BL MH - Pregnancy MH - *Prenatal Exposure Delayed Effects PMC - PMC7979463 MID - NIHMS1659064 OTO - NOTNLM OT - Allergic asthma OT - Autism OT - Behavior OT - Corticosterone OT - Cytokines OT - Mouse OT - Pregnancy EDAT- 2020/12/29 06:00 MHDA- 2021/05/28 06:00 PMCR- 2022/03/01 CRDT- 2020/12/28 10:42 PHST- 2020/09/28 00:00 [received] PHST- 2020/11/24 00:00 [revised] PHST- 2020/12/16 00:00 [accepted] PHST- 2020/12/29 06:00 [pubmed] PHST- 2021/05/28 06:00 [medline] PHST- 2020/12/28 10:42 [entrez] PHST- 2022/03/01 00:00 [pmc-release] AID - S0889-1591(20)32457-0 [pii] AID - 10.1016/j.bbi.2020.12.014 [doi] PST - ppublish SO - Brain Behav Immun. 2021 Mar;93:66-79. doi: 10.1016/j.bbi.2020.12.014. Epub 2020 Dec 21.