Autism-Like Behavior and Epigenetic Changes Associated with Autism as Consequences ofIn UteroExposure to Environmental Pollutants in a Mouse Model

Abstract

We tested the hypothesis that in utero exposure to heavy metals increases autism-like behavioral phenotypes in adult animals and induces epigenetic changes in genes that have roles in the etiology of autism. Mouse dams were treated with cadmium, lead, arsenate, manganese, and mercury via drinking water from gestational days (E) 1–10. Valproic acid (VPA) injected intraperitoneally once on (E) 8.5 served as a positive control. Young male offspring were tested for behavioral deficits using four standardized behavioral assays. In this study, in utero exposure to heavy metals resulted in multiple behavioral abnormalities that persisted into adulthood. VPA and manganese induced changes in perseverative/impulsive behavior and social dominance behavior, arsenic caused changes only in perseverative/impulsive behavior, and lead induced abnormalities in social interaction in comparison to the control animals. Brain samples from Mn, Pb, and VPA treated and control animals were evaluated for changes in CpG island methylation in promoter regions and associated changes in gene expression. The Chd7 gene, essential for neural crest cell migration and patterning, was found to be hypomethylated in each experimental animal tested compared to water-treated controls. Furthermore, distinct patterns of CpG island methylation yielded novel candidate genes for further investigation.

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products

“…high levels of mercury, lead, arsenic, antimony and cadmium in hair samples of autistic children [44] See heavy metals and epigenetic effects (above) [38] Cadmium Retrospective air levels in birth areas related to autism in 2 year old children: Reviewed in [3] See heavy metals and epigenetic effects (above) [38] Chromium See heavy metals (above) [38] Mercury Birth residence air levels associated with autism: Reviewed in [3] See heavy metals (above) [38] Molybdenum High hair levels found in autistic children [39,44] [98] of GABAergic and glutamatergic neurones and of autism-related genes in the offspring [29].…”

Prenatal exposure to neurotoxic metals is associated with increased placental glucocorticoid receptor DNA methylation

“…26 Findings from animal models similarly indicate that gestational exposure to cadmium, mercury, manganese, and lead can modulate the mouse epigenome, particularly in regions related to neural crest cell migration, and in turn contribute to abnormal neurobehavior. 33 Also in mice, gestational zinc deficiencies have been linked to epigenetic dysregulation to metallothionein genes (a protein involved in the inactivation and detoxification of metals; a protective mechanism) 34 ; animal work also suggests early life zinc deficiency contributes to increased DNA methylation to BDNF (a stress related gene modulated by the HPA axis), and subsequent cognitive impairment. 35 Taken together, these studies indicate that prenatal neurotoxic metals exposure may contribute to offspring epigenetic alterations indicative of future neurobehavioral morbidity.…”

Modulation of the Isoprenoid/Cholesterol Biosynthetic Pathway During Neuronal Differentiation In Vitro

“…The function of the adult brain depends critically on the correct execution of these developmental events. Interference with neuronal differentiation due to genetic factors, drug treatment or environmental factor exposure can provoke late neurologic or psychiatric symptoms [Chaudhury et al, ; Hill et al, ; Nuttall, ]. For example, valproic acid treatment or bacterial infections during pregnancy can cause autism in offspring [Jensen, ].…”