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Scholarly Works (7 results)

  • Thesis
  • Peer Reviewed
UC Davis Electronic Theses and Dissertations (2023)

Autism Spectrum Disorders are neurodevelopmental disorders most commonly characterized by social deficits, such as decreased social interactions and/or communications, as well as stereotyped and/or repetitive behaviors. While the etiology of ASD is not known, environmental factors have been widely studied for their potential contributions to ASD development. Importantly, many of these environmental factors are also suspected contributors to other neuropsychiatric disorders, such as attention deficit/hyperactive disorder (ADHD) and schizophrenia. Several environmental factors have been linked to ASD incidence, including obesity, pollution, infection, and allergy/asthma during pregnancy, with inflammation of the maternal immune system being the common thread. Among these, asthma represents a serious concern due to its prevalence, but also, asthma symptoms become worse during pregnancy. Importantly, ASD risk, and the severity of symptoms, appears to increase with an increase in asthma severity. Here, the current work investigates the impact that maternal allergic asthma (MAA) during pregnancy can have on offspring neurodevelopment.

In the second chapter of this work, we will examine the consequences that maternal allergic asthma (MAA) has on the cytokine concentration of the placenta during gestation as well as the fetal brain. This work expands on our initial studies done in a mouse model of MAA where we demonstrated behavioral changes in offspring consistent with the core behaviors of ASD due to MAA during pregnancy. Specifically, we observed a decrease in social interaction and increased repetitive behaviors in offspring. Using this model of MAA, we collected placenta and fetal brains at gestational day (GD)17.5 and performed Luminex multiplex bead assay on the tissue homogenates. Our findings demonstrate a decrease in inflammatory cytokine concentrations in the placenta of offspring, but also an increase in many inflammatory cytokines in the offspring fetal brains. The presence of cytokine disruptions in this study provide evidence that MAA disrupts the maternal/fetal compartment which impacts offspring neurodevelopment. These neurodevelopmental changes in offspring suggest a potential driving force behind behaviors previously identified in this model.

In the third chapter of this work, we continue our studies on MAA and investigate whether the previously identified cytokine elevations in fetal offspring persist into adolescence and early adulthood. Additionally, we expand on the MAA model by including particulate matter (PM) exposure following allergic asthma challenge. PM has not only been associated with asthma development and asthma severity, but it has also been identified as a factor with the potential to increase likelihood of ASD in offspring of mothers exposed to PM during pregnancy. Despite the links between allergic asthma during pregnancy with ASD, and the link between PM exposure in pregnancy and ASD incidence, there are no studies investigating the neuroimmune outcome on offspring of these environmental factors in in combination. Here, we provide evidence from this novel model of MAA and PM exposure (using ultrafine-iron soot), that dual exposure results in altered neuroimmunity in both adolescent and young adult offspring. We also show that MAA and PM exposure alters microglial density in the hippocampus, which suggests a deviation from normal functioning of microglia in these offspring.

In the fourth and final chapter of this work, we explore MAA using a human relevant allergen and the impact this has on offspring neurodevelopment. This preliminary study used house dust mite (HDM), a common allergen in human allergic asthma, to explore whether the previously identified changes in our OVA MAA model are mirrored in this more human relevant investigation. Additionally, from human studies, it has been shown that PM exposure during allergen sensitization can increase asthma severity. Here, we investigate how PM exposure during allergen sensitization in preconception might increase asthma severity during pregnancy, and subsequently, how this impacts offspring neuroimmunity. We demonstrate in this novel model, a synergistic impact of PM exposure and allergen sensitization that may worsen neurodevelopmental outcomes in offspring.

Taken together, this body of work begins to uncover the neurobiological changes in offspring that can occur as a result of maternal allergy during pregnancy. We also show, in a first of its kind model, that exposure to asthma and PM during pregnancy increase cytokine concentration in the brains of offspring and impacts microglia function. In addition to this, we show that PM exposure with allergen sensitization, during preconception, can have a synergistic impact on offspring neurodevelopment. The findings from these studies demonstrate a need for further investigation into the links between mothers with asthma during pregnancy and the increased likelihood of birthing a child with ASD.

    Cover page: Maternal Allergic Asthma and the Impacts on Offspring Neurodevelopment
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2021)

    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.
      Cover page: Repeated allergic asthma in early versus late pregnancy differentially impacts offspring brain and behavior development
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2022)
      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.
        Cover page: Maternal Allergic Asthma Induces Prenatal Neuroinflammation
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2023)
        Inflammation during pregnancy is associated with an increased risk for neurodevelopmental disorders (NDD). Increased gestational inflammation can be a result of an immune condition/disease, exposure to infection, and/or environmental factors. Epidemiology studies suggest that cases of NDD 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 NDD such as autism spectrum disorders (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. 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 sensitized 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 to induce allergic asthma or phosphate buffered saline (PBS) for 1 h. Following the 1-h exposure, pregnant females were then exposed to UIS with a size distribution of 55 to 169 nm at an average concentration of 176 ± 45 μg/m3) (SD), or clean air for 4 h, over 8 exposure sessions. 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), and IL-17, which remained elevated from P15 to P35 in all treatment conditions compared to controls. There was a suppressive effect of the combined MAA plus UIS on the anti-inflammatory cytokine IL-10. Potentially shifting the cytokine balance towards more neuroinflammation. In the hippocampus at P15, elevations in cytokines were also identified across the treatment groups, namely 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.
          Cover page: Characterizing the neuroimmune environment of offspring in a novel model of maternal allergic asthma and particulate matter exposure
          • Article
          • Peer Reviewed
          UC Berkeley Previously Published Works (2018)
          A negative shift in the calcium isotopic composition of marine carbonate rocks spanning the end-Permian extinction horizon in South China has been used to argue for an ocean acidification event coincident with mass extinction. This interpretation has proven controversial, both because the excursion has not been demonstrated across multiple, widely separated localities, and because modeling results of coupled carbon and calcium isotope records illustrate that calcium cycle imbalances alone cannot account for the full magnitude of the isotope excursion. Here, we further test potential controls on the Permian-Triassic calcium isotope record by measuring calcium isotope ratios from shallow-marine carbonate successions spanning the Permian-Triassic boundary in Turkey, Italy, and Oman. All measured sections display negative shifts in δ44/40Ca of up to 0.6‰. Consistency in the direction, magnitude, and timing of the calcium isotope excursion across these widely separated localities implies a primary and global δ44/40Ca signature. Based on the results of a coupled box model of the geological carbon and calcium cycles, we interpret the excursion to reflect a series of consequences arising from volcanic CO2 release, including a temporary decrease in seawater δ44/40Ca due to short-lived ocean acidification and a more protracted increase in calcium isotope fractionation associated with a shift toward more primary aragonite in the sediment and, potentially, subsequently elevated carbonate saturation states caused by the persistence of elevated CO2 delivery from volcanism. Locally, changing balances between aragonite and calcite production are sufficient to account for the calcium isotope excursions, but this effect alone does not explain the globally observed negative excursion in the δ13C values of carbonate sediments and organic matter as well. Only a carbon release event and related geochemical consequences are consistent both with calcium and carbon isotope data. The carbon release scenario can also account for oxygen isotope evidence for dramatic and protracted global warming as well as paleontological evidence for the preferential extinction of marine animals most susceptible to acidification, warming, and anoxia.
            Cover page: Global perturbation of the marine calcium cycle during the Permian-Triassic transition
            • Article
            • Peer Reviewed
            UC Berkeley Previously Published Works (2017)
            The geological calcium cycle is linked to the geological carbon cycle through the weathering and burial of carbonate rocks. As a result, calcium (Ca) isotope ratios (44Ca/40Ca, expressed as δ44/40Ca) can help to constrain ancient carbon cycle dynamics if Ca cycle behavior can be reconstructed. However, the δ44/40Ca of carbonate rocks is influenced not only by the δ44/40Ca of seawater but also by diagenetic processes and fractionation associated with carbonate precipitation. In this study, we investigate the dominant controls on carbonate δ44/40Ca in Upper Permian to Middle Triassic limestones (ca. 253 to 244 Ma) from south China and Turkey. This time interval is ideal for assessing controls on Ca isotope ratios in carbonate rocks because fluctuations in seawater δ44/40Ca may be expected based on several large carbon isotope (δ13C) excursions ranging from − 2 to + 8‰. Parallel negative δ13C and δ44/40Ca excursions were previously identified across the end-Permian extinction horizon. Here, we find a second negative excursion in δ44/40Ca of ~ 0.2‰ within Lower Triassic strata in both south China and Turkey; however, this excursion is not synchronous between regions and thus cannot be interpreted to reflect secular change in the δ44/40Ca of global seawater. Additionally, δ44/40Ca values from Turkey are consistently 0.3‰ lower than contemporaneous samples from south China, providing further support for local or regional influences. By measuring δ44/40Ca and Sr concentrations ([Sr]) in two stratigraphic sections located at opposite margins of the Paleo-Tethys Ocean, we can determine whether the data represent global conditions (e.g., secular variations in the δ44/40Ca of seawater) versus local controls (e.g., original mineralogy or diagenetic alteration). The [Sr] and δ44/40Ca data from this study are best described statistically by a log-linear correlation that also exists in many previously published datasets of various geological ages. Using a model of early marine diagenetic water-rock interaction, we illustrate that this general correlation can be explained by the chemical evolution of bulk carbonate sediment samples with different initial mineralogical compositions that subsequently underwent recrystallization. Although early diagenetic resetting and carbonate mineralogy strongly influence the carbonate δ44/40Ca values, the relationship between [Sr] and δ44/40Ca holds potential for reconstructing first-order secular changes in seawater δ44/40Ca composition.
              Cover page: The influence of seawater carbonate chemistry, mineralogy, and diagenesis on calcium isotope variations in Lower-Middle Triassic carbonate rocks
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2016)

              Objective:

              To examine different health outcomes that are associated with specific lifestyle and genetic factors.

              Materials and methods:

              From March 2004 to April 2006, a sample of employees from three different health and academic institutions, as well as their family members, were enrolled in the study after providing informed consent. At baseline and follow-up (2010-2013), participants completed a self-administered questionnaire, a physical examination, and provided blood samples.

              Results:

              A total of 10 729 participants aged 6 to 94 years were recruited at baseline. Of these, 70% were females, and 50% were from the Mexican Social Security Institute. Nearly 42% of the adults in the sample were overweight, while 20% were obese.

              Conclusion:

              Our study can offer new insights into disease mechanisms and prevention through the analysis of risk factor information in a large sample of Mexicans.
                Cover page: Health workers cohort study: methods and study design.
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