Repeated allergic asthma in early versus late pregnancy differentially impacts offspring brain and behavior development

Church, Jamie S.; Tamayo, Juan M.; Ashwood, Paul; Schwartzer, Jared J.

doi:10.1016/j.bbi.2020.12.014

Cited by 10 publications

(17 citation statements)

References 85 publications

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“…Using our mouse model of maternal allergic asthma (MAA) to initiate an immune response in pregnant mice, we have previously reported systemic elevations in interleukin-4 (IL-4) and IL-5 in dams (Schwartzer et al, 2015;Tamayo et al, 2022) that parallel clinical reports associating increased IL-4 and IL-5 in mid-pregnancy maternal serum samples of mothers with children later diagnosed with ASD (Goines et al 2011). Not only do the dams in our MAA model produce a similar allergic asthma cytokine pro le to that observed in humans, but the offspring display characteristic ASD-like behaviors, such as decreased social interaction and increased repetitive-like behaviors (Schwartzer et al, 2015;Schwartzer et al, 2017;Church et al, 2021). Moreover, MAA produces transcriptional differences in microglia gene expression and neuroin ammation in both prenatal offspring and brain regions of adult mice (Ciernia et al, 2018;Church et al, 2021;Tamayo et al, 2022).…”

Section: Introductionsupporting

confidence: 80%

Characterizing the Neuroimmune Environment of Offspring in a Novel Model of Maternal Allergic Asthma and Particulate Matter Exposure

Tamayo

Schwartzer

Pinkerton

et al. 2023

Preprint

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Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by the presence of decreased social interactions and an increase in stereotyped and repetitive behaviors. Epidemiology studies suggest that cases of ASD are on the rise. Similarly, rates of asthma are increasing, and the presence of maternal asthma during pregnancy increases the likelihood of a child being later diagnosed with ASD. Particulate matter (PM), via air pollution, is an environmental factor known to worsen the symptoms of asthma, but also, PM has been associated with increased risk of neuropsychiatric disorders including ASD. Despite the links between asthma and PM with neuropsychiatric disorders, there is a lack of laboratory models investigating combined prenatal exposure to asthma and PM on offspring neurodevelopment. Thus, we developed a novel mouse model that combines exposure to maternal allergic asthma (MAA) and ultrafine iron-soot (UIS), a common component of PM. In the current study, female BALB/c mice were primed for allergic asthma with ovalbumin (OVA) prior to pregnancy. Following mating and beginning on gestational day 2 (GD2), dams were exposed to either aerosolized OVA or phosphate buffered saline (PBS) for 1 hour. Following the 1-hour exposure, pregnant females were then exposed to UIS or clean air for 4 hours. Offspring brains were collected at postnatal days (P)15 and (P)35. Cortices and hippocampal regions were then isolated and assessed for changes in cytokines using a Luminex bead-based multiplex assay. Analyses identified changes in many cytokines across treatment groups at both timepoints in the cortex, including interleukin-1 beta (IL-1β), IL-2, IL-13, and IL-17, which remained elevated from P15 to P35 in all treatment conditions compared to controls. In the hippocampus at P15, elevations in cytokines were also identified across the treatment groups, namely interferon gamma (IFNγ) and IL-7. The combination of MAA and UIS exposure (MAA-UIS) during pregnancy resulted in an increase in microglia density in the hippocampus of offspring, as identified by IBA-1 staining. Together, these data indicate that exposure to MAA, UIS, and MAA-UIS result in changes in the neuroimmune environment of offspring that persist into adulthood.

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Section: Introductionsupporting

confidence: 80%

Characterizing the Neuroimmune Environment of Offspring in a Novel Model of Maternal Allergic Asthma and Particulate Matter Exposure

Tamayo

Schwartzer

Pinkerton

et al. 2023

Preprint

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“…This global response may translate more closely to the human exposure than single cytokine exposures in isolation. These combined cytokine signals may be the central mechanistic factors that link MAA to the behavioral deficits—and shape brain chemistry and neurocircuitry—observed in our previous studies of this model [ 20 , 22 , 24 ].…”

Section: Discussionmentioning

confidence: 96%

“…Although our fetal brain analyses also show elevations in these cytokines, we have yet to perform this analysis on whole brains from adult mice. However, we recently showed elevated IFNγ in the hypothalamus of adult animals when exposed to MAA in early fetal development [ 22 ]. Notably, IL-6, which is normally expressed at low levels in the brain, plays a role in neurogenesis, cell growth, and myelination or demyelination.…”

Section: Discussionmentioning

confidence: 99%

“…Over-connectivity is a phenomenon that has been observed in some cases of ASD and has been linked to changes in social interactions, as well as increased restricted and repetitive behaviors [ 53 , 54 , 55 ], changes that our model demonstrates [ 20 ]. The cascade of inflammatory factors, specifically IL-6, IL-1𝛼, GM-CSF, and TNF𝛼, seen in the fetal brain after MAA highlight an important set of immune markers during fetal development that have neurodevelopmental impacts in shaping the brain architecture and function that may influence the behavioral, neuroinflammatory, and epigenetic alterations observed in adult offspring [ 20 , 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, our laboratory developed a model of maternal allergic asthma (MAA) in which offspring mimic behavioral outcomes relevant to the core features of ASD, including decreased social interaction and repetitive-like behaviors [ 20 , 21 , 22 ]. Within this model, MAA exposure results in changes in gene expression in microglia of adult offspring, highlighting the lasting epigenetic impact of MAA on the offspring’s neuroimmune environment [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Maternal Allergic Asthma Induces Prenatal Neuroinflammation

et al. 2022

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Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders characterized by impaired social interactions and communication skills and repetitive or stereotyped behaviors. Rates of ASD diagnosis continue to rise, with current estimates at 1 in 44 children in the US (Maenner 2021). Epidemiological studies have suggested a link between maternal allergic asthma and an increased likelihood of having a child diagnosed with ASD. However, a lack of robust laboratory models prevents mechanistic research from being carried out. We developed a novel mouse model of maternal asthma-allergy (MAA) and previously reported that offspring from these mothers exhibit behavioral deficits compared to controls. In addition, it was shown that epigenetic regulation of gene expression in microglia was altered in these offspring, including several autism candidate genes. To further elucidate if there is neuroinflammation in the fetus following MAA, we investigated how allergic asthma impacts the maternal environment and inflammatory markers in the placenta and fetal brain during gestation. Female C57Bl/6 mice were primed with ovalbumin (OVA) prior to allergic asthma induction during pregnancy by administering aerosolized ovalbumin or PBS control to pregnant dams at gestational days (GD)9.5, 12.5, and 17.5. Four hours after the final induction, placenta and fetal brains were collected and measured for changes in cytokines using a Luminex bead-based multiplex assay. Placental MAA tissue showed a decrease in interleukin (IL)-17 in male and female offspring. There was a sex-dependent decrease in female monocyte chemoattractant protein 1 (MCP-1). In male placentas, IL-4, C–X–C motif chemokine 10 (CXCL10)—also known as interferon γ-induced protein 10 kDa (IP-10)—and chemokine (C-C motif) ligand 5 (RANTES) were decreased. In fetal brains, elevated inflammatory cytokines were found in MAA offspring when compared to controls. Specifically, interferon-gamma (IFN-γ), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 1α (IL-1α), IL-6, and tumor necrosis factor α (TNFα) were elevated in both males and females. In contrast, a decrease in the cytokine IL-9 was also observed. There were slight sex differences after OVA exposures. Male fetal brains showed elevated levels of macrophage inflammatory protein-2 (MIP-2), whereas female brains showed increased keratinocytes-derived chemokine (KC). In addition, IL-1𝛽 and IP-10 in male fetal brains were decreased. Together, these data indicate that repeated exposure to allergic asthma during pregnancy alters cytokine expression in the fetal environment in a sex-dependent way, resulting in homeostatic and neuroinflammatory alterations in the fetal brain.

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The influence of asthma on neuroinflammation and neurodevelopment: From epidemiology to basic models

Tamayo,

Osman,

Schwartzer

et al. 2024

Brain, Behavior, and Immunity

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Repeated allergic asthma in early versus late pregnancy differentially impacts offspring brain and behavior development

Cited by 10 publications

References 85 publications

Characterizing the Neuroimmune Environment of Offspring in a Novel Model of Maternal Allergic Asthma and Particulate Matter Exposure

Characterizing the Neuroimmune Environment of Offspring in a Novel Model of Maternal Allergic Asthma and Particulate Matter Exposure

Maternal Allergic Asthma Induces Prenatal Neuroinflammation

The influence of asthma on neuroinflammation and neurodevelopment: From epidemiology to basic models

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