Prenatal and early life diesel exhaust exposure disrupts cortical lamina organization: Evidence for a reelin-related pathogenic pathway induced by interleukin-6

Abstract

Several epidemiological studies have shown associations between developmental exposure to traffic-related air pollution and increased risk for autism spectrum disorders (ASD), a spectrum of neurodevelopmental disorders with increasing prevalence rate in the United States. Though animal studies have provided support for these associations, little is known regarding possible underlying mechanisms. In a previous study we found that exposure of C57BL/6J mice of both sexes to environmentally relevant levels (250-300 μg/m 3) of diesel exhaust (DE) from embryonic day 0 to postnatal day 21 (E0 to PND21) caused significant changes in all three characteristic behavioral domains of ASD in the offspring. In the present study we investigated a potential mechanistic pathway that may be of relevance for ASD-like changes associated with developmental DE exposure. Using the same DE exposure protocol (250-300 μg/m 3 DE from E0 to PND21) several molecular markers were examined in the brains of male and female mice at PND3, 21, and 60. Exposure to DE as above increased levels of interleukin-6 (IL-6) in placenta and in neonatal brain. The JAK2/STAT3 pathway, a target for IL-6, was activated by STAT3 phosphorylation, and the expression of DNA methyltransferase 1 (DNMT1), a STAT3 target gene, was increased in DEexposed neonatal brain. DNMT1 has been reported to down-regulate expression of reelin (RELN), an extracellular matrix glycoprotein important in regulating the processes of neuronal migration. RELN is considered an important modulator for ASD, since there are several polymorphisms in this gene linked to the disease, and since lower levels of RELN have been reported in brains of *

Air pollutants reinforce autism–like behavior in the VPA-Induced – rat model of autism

“…Mostafa, et al [84] hypothesized that lead as a one of the main neurotoxicants acting as environmental triggers for ASD through neuroin ammation, and autoimmunity. While the PM 2.5 , and components in it are likely candidates for inducing autism-like phenotype, it is possible that gaseous pollutants mainly nitrogen oxides, also contribute to induced ASD [26,85].…”

“…This test assesses general locomotor activity levels and willingness to explore in a novel environment. It was conducted as previously described by Chang et al [26] with some modi cations. At PND43, each rat was placed in a clean acrylic cage (60*60*60 cm) with no bedding for 30 minutes, and a video was recorded using a Microsoft LifeCam HD-6000.…”

“…reported that mice exposed to air pollution during their early postnatal period developed characteristics of autism spectrum disorder, and early postnatal exposure to airborne ne particulate matter induced autism-like phenotypes in male rats [25]. Chang et al [26] reported that prenatal, and early-life exposure to diesel exhaust induced autism-like behavioral changes in mice.…”

Connections between Early-Life Neuroinflammation, Neural Stem Cells and Progenitors and Origins of Neuropsychiatric Disorders

“…Recent studies have aimed at uncovering the underlying mechanisms leading to the cognitive and behavioral deficits seen in ASD. For instance, exposure to diesel exhaust gases during intrauterine development, an environmental factor associated with ASD, leads to behavioral alterations in adult mice reminiscent of ASD [48]. These mice displayed elevated brain IL-6 at birth, as well as abnormally high levels of phosphorylated STAT3 and decreased levels of reelin.…”

“…These mice displayed elevated brain IL-6 at birth, as well as abnormally high levels of phosphorylated STAT3 and decreased levels of reelin. At P60, reelin co-localizes with an accumulation of calretinin+ cells in the inner layers of the cortex, suggesting that increased levels of IL-6 during development inhibits interneuron migration and consequently disrupts proper cortical lamination and, therefore, upsets the balance of inhibitory and excitatory synapses [48].…”