Environmental toxins and microglia-synapse interactions in autism. It is increasingly evident that diverse genes and environmental exposure(s) combine or synergize to produce a spectrum of autism phenotypes dependent upon critical developmental windows. Multiple prenatal/maternal environmental toxins and exposures have been linked to human ASDs, but the associations of single agents have been relatively weak. This suggests it is the combination of multiple maternal exposures that increases vulnerability in offspring. We now recognize that non-chemical stressors, such as limited resources or social support of the mother, can increase vulnerability of the fetus to chemical stressor exposures (e.g., pollution or toxins), which could explain why a single exposure or risk factor in isolation is a modest predictor of autism risk. Models aimed at deciphering the mechanisms that contribute to ASD suffer from oversimplification, using single agents. We breach this gap by using a new model that employs the combined effects of an ethologically relevant maternal stressor and environmentally relevant pollutant, diesel exhaust, both of which have been implicated in autism. We show that maternal diesel exhaust particle (DEP) exposure combined with maternal stress (MS) (but neither in isolation) produces early-life communication deficits, and long-term cognitive deficits and strikingly increased anxiety in male but not female offspring. We show evidence that DEP exposure significantly alters microglial colonization of the male but not female embryonic brain, and combined prenatal DEP and MS exposure leads to persistent changes in the function of microglia of the same brain regions of males. Beyond their functions in innate immune defense of the brain, microglia are important regulators of experience-dependent synaptic remodeling during development. It is proposed that microglia prune inappropriate or weak synapses while sparing appropriate or strong connections. Autism has been well described as a disease of synaptic dysfunction, and functional network analyses have nearly all pointed out the importance of molecular pathways that control activity-dependent synaptic remodeling in the pathology of ASDs. Importantly, impaired microglia-mediated pruning in mice disrupts functional brain connectivity and social behavior, strongly suggesting that microglia-synapse interactions may contribute to autism?s pathophysiology. Thus, the specific hypothesis to be tested here is that microglial activation by combined environmental factors will cause aberrant synaptic pruning by these cells, leading to neural circuit dysfunction and ASD-like behaviors.

Public Health Relevance

Multiple prenatal/maternal environmental toxins and exposures have been linked to human autism spectrum disorders (ASDs), but the associations of single agents have been relatively weak; this suggests it is the combination of multiple maternal exposures that increases vulnerability in offspring. We breach this gap by using a new model that employs the combined effects of an ethologically relevant maternal stressor and environmentally relevant pollutant, diesel exhaust, both of which have been implicated in autism. If successful, these studies will establish a causal link between prenatal environmental stressors and neural circuit dysfunction in mice analogous to existing datasets in humans with ASD, and will provide a mechanism and specific signaling pathway by which environmental stimuli can lead to abnormal neural development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES025549-02
Application #
9352855
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lawler, Cindy P
Project Start
2016-09-30
Project End
2021-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
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