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| Picture: Carl Warner: http://www.carlwarner.com/ |
I'm serving up two peer-reviewed papers for your reading delight today which draw attention to the ideas that (a) the 'causes' of autism are likely complex and as heterogeneous as the label itself, (b)
gene x environment interactions affecting risk of autism are starting to get some good scientific research airtime and (c) don't 'dis the broccoli [chemical] autism connection just yet...
The
first paper by Brandon Pearson and colleagues [1] (open-access) has already found some media interest as per
the Guardian headline: '
Agricultural fungicides are 'bad news for neurons'
, study suggests'. Exposing mouse neurons - "
cortical neuron-enriched cultures" - to several hundred chemicals (
careful of that word) found in the modern environment, researchers concluded that several compounds "
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)." That is, several types of chemicals quite commonly found in the modern environment seemed to alter gene expression in those mouse neuron enriched cultures that weren't a million miles away from that noted previously in conditions such as autism for example.
Mouse neurons, you might be thinking? Well, obviously one has to be a little cautious about extrapolating from mouse to humans (
see here) but researchers did include some comparison analysis looking at "
the gene expression profile of our cultures with brain cell-type-specific expression data sets and human brain gene expression data sets." The result: "
cortical cultures show strong transcriptional similarities to the human brain."
Clustering chemicals based on "
concordant gene expression changes", six groups emerged. Cluster 2 chemicals, containing such pesticides as
rotenone,
pyridaben and
fenpyroximate and also various compounds under the heading of the
strobilurins seemed show some particularly interesting results insofar as they "
mimicked the transcriptional changes of two post-mortem ASD [autism spectrum disorder]
brain expression data sets in a bidirectional manner." The effects of this cluster of compounds also seemed to unite various conditions with autism including Alzheimer’s disease and Huntington’s disease and the "
aging brain". My interest was particularly piqued by that last association in light of other research results (
see here).
When it came to the 'effects' of those chemicals in terms of genetic and biological processes, researchers put forward some not unfamiliar potential roles: "
These chemicals, most of which inhibit mitochondrial complex I or III, stimulated free radical production and disrupted microtubules." Words like '
oxidative stress' start to emerge as they have done in previous autism research (
see here) and yet again, inflammation or inflammatory processes
seem also to be indicated. Indeed, the authors also make mention of how effects such as free radical production "
can be reduced by pretreating with a microtubule stabilizer, an antioxidant, or with sulforaphane." Yes indeed,
sulforaphane - the chemical found in broccoli - might indeed be moving back up the autism research agenda (
see here for some previous background).
There is obviously lots more work to do in this area before anyone gets too carried away. The authors note: "
While usage and residue levels of cluster 2 chemicals on conventionally grown foods are increasing, in the absence of causality, it is premature to draw correlations with the increased prevalence of ASD and other brain disorders." Lessons could be learned from other blanket suggestions about 'chemicals' and autism (
see here) as well as an appreciation for the concept of the the plural autisms (
see here). Then there are the practicalities of whether ingesting such compounds on food or in water is the same as direct exposure to cortical neuron-enriched cultures? Or indeed,
whether there may be other routes of contact? I might also suggest that further studies should focus on
looking for the metabolites of such agents too [2] bearing in mind the concept of statistically significant thresholds...
If you're still here after all that, the second paper I want to talk about
is that from Sarah Wong and colleagues [3] that has
also received a bit of media attention. The focus this time was on a gene called
p53 (
see here for some background) and how issues with this gene might be 'over-represented' when it comes to autism
following on from other work by some of the same authors [3]. First of all, please don't get too fixated by mention of the words 'cancer gene' when it comes to
p53 given it's [protein]
tumour suppressing capabilities. As I've discussed before, the risk of cancer does not seem to be elevated any more than the general population risk when it comes to autism (
see here). Perhaps of greater relevance to the Wong findings is the idea that
p53 has other 'activities' such as that related to oxidative stress (yes, that again) and "
DNA repair, bioenergetics and mitochondrial DNA (mtDNA) copy number maintenance."
Based on data from CHARGE (
beincharge!), researchers garnered blood samples from 66 children diagnosed with an autism spectrum disorder (ASD) and "
race-, gender-, and age-matched typically neurodeveloping children (n = 46)" (authors words not mine). They analysed for mtDNA copy number and deletions and
p53 gene copy ratios and found them to be "
more common in children with AU [autism]
and their fathers." The authors translate their findings as pointing to "
a role for deficient DNA repair capacity not driven by paternal age." They also suggest that environment might intersect with genetics in relation to 'severity' scores of autism obtained for their cohort: "
gene x environment interaction seems to play a greater role in children with autism with less severe symptoms."
Taken together the Pearson and Wong findings point to some interesting 'associations' potentially relevant to [some] autism. The idea that certain components of the modern-day environment might increase the risk of autism
is nothing new but the way that Pearson
et al went about studying the possible relationship is. The results from Wong
et al suggesting that there might be issues with the gene 'whose role is to suppress cellular damage from environmental stressors' suggests that exposure patterns might not necessarily be where it's all at when looking at compound/chemical X or Y in relation to autism risk. I'm also inclined to direct you to some previous discussion about the caspases and autism (
see here) in light of the involvement of
p53 with the process of
apoptosis (programmed cell death) in mind. As I've mentioned before, the biological mechanisms for how people deal with various
xenobiotics needs a lot more investigation in autism research circles (
see here); something that might similarly extend to genetic mechanisms too.
Oh, and just in case you think that I'm pushing the either/or of genetic and environment when it comes to autism, I'm not,
as words like epigenetics spring to mind and the idea that genomic instability might, for example, have quite a few different dimensions (
see here)...
To close, I'm thinking of branching out...
football (soccer) pundit perhaps?
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[1] Pearson BL.
et al. Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration.
Nat Commun. 2016 Mar 31;7:11173.
[2] Domingues VF.
et al. Pyrethroid Pesticide Metabolite in Urine and Microelements in Hair of Children Affected by Autism Spectrum Disorders: A Preliminary Investigation.
Int. J. Environ. Res. Public Health 2016; 13: 388.
[3] Wong S. et al. Role of
p53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study.
Pediatrics. 2016. March 31.
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Pearson, B., Simon, J., McCoy, E., Salazar, G., Fragola, G., & Zylka, M. (2016). Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration Nature Communications, 7 DOI: 10.1038/ncomms11173
Wong, S., Napoli, E., Krakowiak, P., Tassone, F., Hertz-Picciotto, I., & Giulivi, C. (2016). Role of p53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study PEDIATRICS, 137 (4) DOI: 10.1542/peds.2015-1888
The findings reported by Conor Kerley and colleagues [1] provide the brief blogging fodder today. Researchers, who are no stranger to the research area that is vitamin D and autism (see here), decided to conduct a 'post-hoc analysis' of data from two controlled trials where vitamin D supplementation was experimentally tested for children with autism and children with asthma. They were specifically looking at the "serum response to vitamin D supplementation" rather that the amount of vitamin D supplemented as potentially being important to the clinical results obtained. They concluded that "children with ASD [autism spectrum disorder] had a lower increase in 25(OH)D levels with supplementation." Further: "Potential mechanisms include altered absorption/metabolism as well as well genetic factors."
