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.
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