UC Davis

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.