TY - JOUR
T1 - Repeated allergic asthma in early versus late pregnancy differentially impacts offspring brain and behavior development
AU - Church, Jamie S.
AU - Tamayo, Juan M.
AU - Ashwood, Paul
AU - Schwartzer, Jared J.
N1 - Funding Information:
The authors would like to thank Kathleen Byrne, Maddy Berkowitz-Cerasano, Felicity Emerson, Megan Johnson, Kerry Ouimette, Rebecca Goodier, Fiona Chace-Donahue, Arina Kazakova, Ann Osborn, and Maliha Rahman for their technical expertise. Funding was provided by NIH R15HD082638, NIH R15MH119500, RO1MH118209, RO1HD090214, R21MH116383, R21ES025560 and the CTSC Pilot Translational and Clinical Studies Program, A Child/Lifespan Health Award.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/3
Y1 - 2021/3
N2 - 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, 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. 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.
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, 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. 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.
KW - Allergic asthma
KW - Autism
KW - Behavior
KW - Corticosterone
KW - Cytokines
KW - Mouse
KW - Pregnancy
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U2 - 10.1016/j.bbi.2020.12.014
DO - 10.1016/j.bbi.2020.12.014
M3 - Article
C2 - 33358979
AN - SCOPUS:85099002008
VL - 93
SP - 66
EP - 79
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
SN - 0889-1591
ER -