Thursday, 6 September 2012

PCB congeners and 15q11-q13 duplication autism

Contains PCBs @ Wikipedia
The science news is currently awash with talk about results from the Encyclopedia of DNA Elements (ENCODE) project (see here for a good description). The net results have been summarised by quite a few media outlets including the BBC, including the suggestion that junk DNA might not be as junk as first thought (see this post from MJ over at Autism Jabberwocky).

I was interested to see that the words DNA methylation cropped up quite a few times during the course of the various discussions, and how the switching on and off of genes might actually be pretty important to our lives. It all got me thinking back to everyone's favourite gene-environment science, epigenetics (see here).

With all this in mind, a recent paper by Mitchell and colleagues* provides some food for thought. Including a significant authorship contingent from that autism research favourite, the MIND Institute, the paper abstract makes a striking assertion: "These results demonstrate a novel paradigm by which specific POPs [persistent organic pollutants] may predispose to genetic copy number variation of 15q11-q13".

I admit that I did a bit of a double-take when I read this sentence given that it seems to suggest some involvement of POPs in what is a genetic condition.

OK let's just back it up a little and take this one step at a time. 15q11-q13 duplication autism spectrum disorder refers to an issue with chromosome 15 and in particular with something called the PWS/AS critical region; that is a genetic area thought to be linked to the presentation of Prader-Willi syndrome (PWS) and Angelman syndrome (AS) depending on whether inheritance is maternal or paternal. Autism has also been tied into the 15q11-q13 region as per studies like this one from Cook and colleagues**. There is quite a bit of other research on 15q11-q13 and autism in the scientific literature which can be browsed here.

POPs are basically those chemicals/compounds which stick around in the environment and seem not to be easily environmentally degradable. POPs include a range of compounds (see here) some (many?) of which also have the ability to bioaccumulate and potentially cause some quite serious effects on health as per what happened with Yushō disease. I don't want to get too heavily into the nitty-gritty of the health impacts of POPs simply because it is a very complicated area of environmental health sciences.

Certain POPs have been mentioned previously with autism / autistic behaviours in mind as per these archive posts on polybrominated diphenyl ethers (PBDEs) and autism and the flame-proofed mice with a Rett syndrome mutation study. This last study incidentally is also from Prof Janine LaSalle who also heads the current paper.

Mitchell et al report a few things in their study. I'm sorry that I can't post a link to the full-text paper, so you'll have to take my word for it:

  • The lipid-rich brain tissue of one hundred and seven human postmortem brain samples were analysed for the presence of 8 polychlorinated biphenyl (PCB) and 7 PBDE congeners via GC-MS among other things. Samples were derived from deceased patients who were diagnosed with various neurodevelopmental disorders of 'known' origin (PWS, AS, Rett syndrome, 15q11-q13 duplication syndromes; n=32), idiopathic autism "of unknown etiology" (n=32) and asymptomatic controls (n=34). Age ranges were wide; between 4 - 61 years old at death across the groups.
  • "Unexpectedly, PCB 95 was significantly (p<0.001) higher in the genetic neurodevelopmental group, but not idiopathic autism, as compared to neurotypical controls". Indeed out of 8 PCB congeners analysed, the genetic neurodevelopmental group showed the greatest mean concentration in  5 (although not significantly different levels).
  • Furthermore, levels of PCB 95 seemed to be specifically tied to those diagnosed with a maternal15q11-q13 duplication (Dup15q) or deletion in Prader-Willi syndrome.
  • Further analysis based on birth date pre- and post- 1976 (used because of the introduction of the 1976 Toxic Substances Control Act which is looking to be replaced by the Safe Chemicals Act of 2011) suggested that levels of PCB 95 were highest in the genetic neurodevelopmental group both pre- and post-1976. 
  • A possible connection between PCB 95 and DNA methylation levels in Dup15q samples was undertaken by pyrosequencing for repetitive LINE-1 methylation levels ('similar' to this method). As would probably be expected, significant DNA hypomethylation was recorded compared with control samples (approximately 2% decrease in average methylation). That being said, year of birth was a confounder in that those controls born in the 1980s-1990s tended to show lower methylating functioning than those born in the 1960s-1970s. 
  • PBDE levels showed little significant differences across the groups aside that is from one congener, PBDE 153, which showed a greater mean concentration in the control group compared to the other symptomatic groups (p<0.05).

I'm intrigued. To quote again from this study: "Our results demonstrated that 3/6 Prader-Willi syndrome and 5/6 Dup15q brain samples showed detectable levels of PCB 95 suggesting that this exposure should be investigated as a potential environmental contributor of the differing copy number variation rates in different regions".

Now I'm not saying that POPs 'cause' 15q11-q13 duplication autism spectrum disorder; the evidence just isn't there to suggest something so direct. As with every study which includes a postmortem element to it, there is always the sensitive issues of why the person died and whether comorbidity (epilepsy, learning disability?) might play an interfering role in any results obtained. It certainly is however an area that needs a lot more investigation.

I've often talked about mutations like SNPs and CNVs in relation to autism and a few other conditions (see here for example); the latest being that stark quote "no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level" from the paper by Richard Anney and colleagues (see post here). Where SNPs and/or CNVs do occur however, particularly when described as de novo as in the recent paper on paternal age and de novo mutations (see here), the question has to be why do such mutations occur outside of just a generic 'randomly based on age' argument? Without tempting too much criticism, I have to admit that 'random' just doesn't wash with me; there has to be a reason. One candidate outside of just maturation has to be environment.

A few final points to make and then I'm done. This is not the first time that PCB 95 has cropped up and interestingly has been previously tied into autism and calcium signalling as per this study by Wayman and colleagues*** (full-text). The issue of DNA hypomethylation and autism has also been covered on this blog previously so I'm not going to get too involved in that at this time.

And relax.

Despite the small participant numbers included in the study, I will say once again that I am intrigued by the results presented by Mitchell and colleagues and very much look forward to hearing more from this research group and others on our seemingly very delicate relationship with the modern environment around us.


* Mitchell MM. et al. Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder. Environmental & Molecular Mutagenesis. August 2012.

** Cook EH Jr. et al. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. American Journal of Human Genetics. 1997; 60: 928-934.

*** Wayman GA. et al. PCB-95 Modulates the Calcium-Dependent Signaling Pathway Responsible for Activity-Dependent Dendritic Growth. Environmental Health Perspectives. 2012; 120: 1003-1009.

---------- Mitchell MM, Woods R, Chi LH, Schmidt RJ, Pessah IN, Kostyniak PJ, & Lasalle JM (2012). Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder. Environmental and molecular mutagenesis PMID: 22930557