viernes, 1 de abril de 2016
Chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration.
More than 480,000 chemicals are registered for use in the environment.
Environmental factors, including pesticides, have been linked to autism and neurodegeneration risk using retrospective epidemiological studies. Here we sought to prospectively identify chemicals that share transcriptomic signatures with neurological disorders, by exposing mouse cortical neuron-enriched cultures to hundreds of chemicals commonly found in the environment and on food. We find that rotenone, a pesticide associated with Parkinson’s disease risk, and certain fungicides, including pyraclostrobin, trifloxystrobin, famoxadone and fenamidone, produce transcriptional changes in vitro that are similar to those seen in brain samples from humans with autism, advanced age and neurodegeneration (Alzheimer’s disease and Huntington’s disease).
Powerful new sequencing technologies have been used to systematically identify hundreds of candidate gene mutations associated with autism spectrum disorder (ASD) risk. Heritability studies suggest that environmental factors also contribute to autism risk.
Indeed, gestational exposure to pesticides, including maternal proximity to pesticide applications and runoff, is reproducibly associated with increased ASD risk in epidemiological studies.
However, epidemiological studies are retrospective and cannot ascertain prospectively, precisely or systematically which chemicals, of the 480,000 chemicals registered for use in the environment, have the greatest potential to harm the developing or adult brain.
Existing in vivo neurodevelopmental and neurotoxicological assays with animal models are labour intensive and costly, thus hindering throughput, whereas higher-throughput toxicological assays frequently use non-neuronal cells or focus on neuron death as an end.
As a result, these tests fail to interrogate molecular and physiological processes that are unique to neurons or that differentiate normal from diseased human brains.
There is growing recognition that brain transcriptional changes are associated with ASD.
This ASD transcriptional signature is defined by reduced expression of genes involved in synaptic transmission and elevated expression of genes involved in immune and microglial function.
Here we hypothesized that this transcriptional signature might guide the prospective identification of candidate chemical risks for ASD. To test this hypothesis, we exposed mouse cortical neuron-enriched cultures to hundreds of environmental-use chemicals and then monitored global transcriptional changes.
We identify six chemical groups, one of which mimics the transcriptional changes seen in ASD, but surprisingly also shares transcriptional similarity to the aged brain and certain neurodegenerative conditions. Our findings suggest these neurological conditions share a molecular pathology, as hypothesized by others, despite different ages of onset and distinct behavioral symptoms. Moreover, this study shows that a transcriptional approach can be used to systematically scan a diverse chemical space and identify potential environmental threats to the human brain.
Source: Brandon L. Pearson et al., Nature Communications DOI: 10.1038/ncomms11173.