Developmental neurotoxicity of inhaled ambient ultrafine particle air pollution: Parallels with neuropathological and behavioral features of autism and other neurodevelopmental disorders

Abstract

Accumulating evidence from both human and animal studies show that brain is a target of air pollution. Multiple epidemiological studies have now linked components of air pollution to diagnosis of autism spectrum disorder (ASD), a linkage with plausibility based on the shared mechanisms of inflammation. Additional plausibility appears to be provided by findings from our studies in mice of exposures from postnatal day (PND) 4-7 and 10-13 (human 3rd trimester equivalent), to concentrated ambient ultrafine (UFP) particles, considered the most reactive component of air pollution, at levels consistent with high traffic areas of major U.S. cities and thus highly relevant to human exposures. These exposures, occurring during a period of marked neuro- and gliogenesis, unexpectedly produced a pattern of developmental neurotoxicity notably similar to multiple hypothesized mechanistic underpinnings of ASD, including its greater impact in males. UFP exposures induced inflammation/microglial activation, reductions in size of the corpus callosum (CC) and associated hypomyelination, aberrant white matter development and/or structural integrity with ventriculomegaly (VM), elevated glutamate and excitatory/inhibitory imbalance, increased amygdala astrocytic activation, and repetitive and impulsive behaviors. Collectively, these findings suggest the human 3rd trimester equivalent as a period of potential vulnerability to neurodevelopmental toxicity to UFP, particularly in males, and point to the possibility that UFP air pollution exposure during periods of rapid neuro- and gliogenesis may be a risk factor not only for ASD, but also for other neurodevelopmental disorders that share features with ASD, such as schizophrenia, attention deficit disorder, and periventricular leukomalacia.

Cognitive Effects of Air Pollution Exposures and Potential Mechanistic Underpinnings

“…Mice exposed developmentally to concentrated ambient UFP in our studies showed male-specific increases in IBA-1 in anterior commissure at postnatal day (PND) 14, and at PND55 in hippocampus (76, 77), and marked increases in corpus callosum when measured at PND270, regardless of whether exposure was during development, as adults, or both (58). Exposure of male rats to PM from pre-natal through adulthood increased cortical levels of the oxidative stress marker malondialdehyde and reduced levels of [superoxide dismutase]/[catalase] (60).…”

Environment matters: microglia function and dysfunction in a changing world

“…Similarly, administration of UFP to male and female mouse pups from P4-13 led to a persistent increase in microglia number in males only, as far out as P270 [65]. Further there were changes in corpus callosum size and reduced myelination in males, and an excitatory-inhibitory imbalance in the frontal cortex in both males and females– consistent with many patients with autism [66,67].…”

Surface area-dependence of gas-particle interactions influences pulmonary and neuroinflammatory outcomes

“…Studies assessing UFP exposure have shown various outcomes including oxidative stress, IL-1α and TNF- α expression in the brain [52], altered MAPK signaling, and elevated GFAP indicative of astrocyte activation in ApoE −/− mice [53]. Early postnatal exposure to UFP results in differential microglial responses dependent on sex and region of the brain, with some areas, such as the hippocampus, responding to UFP via increased microglial activation [31, 54], suggesting enhanced vulnerability to UFP exposure during neurodevelopment. UFP exposure exacerbates natural aging mechanisms in the brain via translocation to brain regions resulting in chronic neuroinflammation concurrent with neurodegenerative outcomes [55–57].…”