Autism spectrum disorders (ASD) are a set of pervasive, highly prevalent lifelong disorders for which pharmacological interventions are not readily available. While genetic factors are likely contributors to these disorders, heritability estimates indicate strong environmental contributions. Of particular interest is the link between fetal neurodevelopment and the activation of the maternal immune system during gestation. Epidemiological reports suggest a strong association between periods of maternal immune activation and an increased risk of having a child with ASD, including immune conditions such as allergies and asthma. Unique immune cascades representative of asthma and allergy responses have been detected in amniotic fluid, newborn bloodspots and maternal mid-gestation serum samples of mothers whose child was later diagnosed with ASD. Acute exacerbations are common in pregnant asthmatic women with as many 35% suffering attacks during pregnancy. In addition, air pollution, a major exacerbating factor in allergic asthma, has been separately linked with an increased risk for ASD. However, little is known about the consequences of maternal allergic asthma (MAA) responses, air pollution, or their combined effects on fetal development. In this exploratory proposal, we will create a novel model in which to test the innovative hypothesis that the particulate matter (PM) fraction of air pollution and MAA are causally linked, and in combination lead to exacerbated ASD-relevant behaviors in offspring of PM + MAA exposed dams. The proposed studies will examine the priming effects of PM sampled from the Sacramento region in combination with MAA on ASD-relevant behaviors (Aim #1). We will test the hypothesis that the combined effects of PM + MAA exposures during gestation lead to changes in immune function and microglia activation in the fetus that disrupt neurodevelopment. The proposed studies will examine whether behavioral outcomes of PM + MAA exposures are IL-4 dependent (Aim #2). If successful, this research will validate the transformative concept that ASD is, for some, a disorder due to the direct effects of common environmental contaminants, and will identify a novel mechanism for one of the most visible public health concerns of our time.
In the last 20 years, rates of diagnoses for autism have increased at an alarming rate, and yet little is understood about its causes and treatment options are limited. By examining relatively common risk- related environmental factors ? namely air pollution and maternal immune activation by allergies / asthma ? we will challenge current paradigms and isolate specific mechanisms contributing to pathophysiology of autism. This hypothesis-driven study will address a major gap in autism research and provide critical information on the consequences of environmental contributions to risk for autism, helping to translate epidemiological observation into a functional model that can be utilized for further investigations and identify possible paths for prevention or treatment.
| Rose, Destanie R; Yang, Houa; Serena, Gloria et al. (2018) Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms. Brain Behav Immun 70:354-368 |
| Vogel Ciernia, Annie; Careaga, Milo; LaSalle, Janine M et al. (2018) Microglia from offspring of dams with allergic asthma exhibit epigenomic alterations in genes dysregulated in autism. Glia 66:505-521 |
| Castañeda, Alejandro R; Pinkerton, Kent E; Bein, Keith J et al. (2018) Ambient particulate matter activates the aryl hydrocarbon receptor in dendritic cells and enhances Th17 polarization. Toxicol Lett 292:85-96 |
| Schwartzer, Jared J; Careaga, Milo; Coburn, Morgan A et al. (2017) Behavioral impact of maternal allergic-asthma in two genetically distinct mouse strains. Brain Behav Immun 63:99-107 |
