"sufficient evidence supporting an association between developmental PBDE exposure and reduced IQ"

The results of the systematic review and meta-analysis published by Juleen Lam and colleagues [1] (open-access available here) make for interesting if rather worrying reading. Looking at the body of research examining whether developmental exposure to PBDEs - polybrominated diphenyl ethers - might have some effect on either developmental/behavioural outcomes of offspring or IQ (Intelligence Quotient), authors concluded that there was "sufficient evidence supporting an association between developmental PBDE exposure and reduced IQ." Such a specific conclusion was reached on the basis of four studies measuring something called BDE-47 in maternal serum during pregnancy or at birth that also looked at full scale intelligence quotient in offspring between 4 and 7 years of age and found a possible *association*.

When looking at the possibility that PBDE exposure might also be linked to "Attention Deficit/Hyperactivity Disorder (ADHD) and attention-related behavioral conditions in humans" the authors concluded that the available data was not up to the same standard as that connecting PBDE exposure and IQ.

"Preventing developmental exposure to PBDEs could help prevent loss of human intelligence." Such a conclusion might seem rather dramatic insofar as words such as a 'loss of human intelligence'. The implication being that like various other exposure events at critical times of development that can and do affect aspects of cognition - think lead for example - our environment seems to shape some important human functions. Despite the fact that PBDEs are apparently being phased out, there is still continuing cause for concern as a consequence of their quite excessive historic use, their ability to persist in the environment as well as their propensity to "bioaccumulate up the food chain."

And whilst we're on the topic of PBDEs and behavioural correlates, I might also draw your attention to other research that has been covered on this blog (see here) talking about the possible results of on-going PBDE exposure.

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[1] Lam J. et al. Developmental PBDE Exposure and IQ/ADHD in Childhood: A Systematic Review and Meta-analysis. Environ Health Perspect. 2017 Aug 3;125(8):086001.

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[Objective] exposure to flame retardants and social behaviours

Although a few details of the study reported by Shannon Lipscomb and colleagues [1] (open-access) interested me, I was particularly taken by their use of "a silicone passive wristband sampler [worn] around his/her wrist or ankle" to "assess the child’s exposure to flame retardants" as part of their investigation "to determine if flame retardant exposure was associated with measurable differences in social behaviors among children ages 3–5 years."

I've covered the topic of potential adverse effects associated with exposure to flame retardants such as brominated diphenyl ethers (BDE) before on this blog (see here and see here for examples). Such compounds are listed as POPs (persistent organic pollutants) because of their ability to endure in the environment, accumulate in the body and potentially [adversely] affect various biological systems. In other words, these are compounds that might well have served an important purpose at one time - flame retardants - but are now realised to have quite a risk profile attached to them. Sounds familiar doesn't it?

Anyhow, Lipscomb et al relied on other research [2] suggesting that various compounds/chemicals can be sequestered from silicone wristbands - those plastic things that many people wear for various causes - with the right equipment and under the right circumstances. To any analytical chemist, this is probably scientific music to their ears. They "extracted and analyzed for 41 different flame retardant compounds using gas chromatography mass spectrophotometry" and focused on 11 compounds "PBDE-47, PBDE-99, PBDE-153, PBDE-154, PBDE-49, PBDE28 + 33, tris(1,3-dichloro-2-propyl) phosphate], TPP [e.g. triphenylphosphate], TCPP [e.g tris(1-chloro-2-propyl) phosphate], and TCEP [e.g. tris(2-chloroethyl) phosphate" that were quite readily present in 60% or more of wristbands. For some of the compounds the authors generated a 'sum of' score; for example: "ƩPBDEs is the total amount of PBDE-47, PBDE-99, PBDE-153, PBDE-154, PBDE-49, and PBDE28." Social behaviours by the way, were scored by teachers in the preschool setting of participants using the Social Skills Improvement System - Rating Scales.

Results: 92 children were initially recruited onto the study but only 77 children returned their wristbands intact (i.e. some of them 'went through the laundry'). Further: "a final sample size of 69 children with complete data... were included in the final analyses." Then: "Bivariate analysis revealed modest correlations between flame retardant exposure and some of the social behavior subscales." What this suggests is that there may be some evidence that such compounds (including organophosphate-based flame retardants (OPFRs)) might impact on aspects of social skills development but there are constraints based on the sample size used and the reliance on one primary measure of social skills for examples.

As per the previous sentence, I'm not totally convinced by this data but am still really interested in the use of wristband samplers described by Lipscomb and colleagues. I can see how this kind of objective measure of exposure could really add another dimension to lots of different areas of research on environmental exposures in relation to various labels. Take for example the quite complicated area of research talking about maternal air pollution exposure and offspring autism risk (see here). Instead of just relying on postcode (zip code) in relation to mapping (estimating) pollution exposure, one could potentially adapt the chemical assay to screen for particulate matter for example, as collected on those wristbands. Certainly an easier way than lugging around a portable air monitor I would have thought. No doubt there are also other uses for such simple solutions...

Music: Europe - The Final Countdown. 80s rock hairstyles at their best and perhaps an apt song given what happened here in Blighty yesterday...

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[1] Lipscomb ST. et al. Cross-sectional study of social behaviors in preschool children and exposure to flame retardants. Environmental Health 2017; 16: 23.

[2] O'Connell SG. et al. Silicone Wristbands as Personal Passive Samplers. Environ. Sci. Technol. 2014; 48: 3327–3335.

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Lipscomb ST, McClelland MM, MacDonald M, Cardenas A, Anderson KA, & Kile ML (2017). Cross-sectional study of social behaviors in preschool children and exposure to flame retardants. Environmental health : a global access science source, 16 (1) PMID: 28274271

Environmental exposure and autism continued

In a post not-so-long-ago I talked about the paper by Andrey Rzhetsky and colleagues [1] and their assertion that environment (various facets of environment) might correlate with the increasing numbers of cases of autism being diagnosed. As per what was said on that post, there were lots of media headlines generated about the findings; some balanced and some a little sensational.

Luc Viatour / www.Lucnix.be @ Wikipedia 

One of the main caveats I had with the Rzhetsky study was the reliance on statistical models onwards to their conclusions; so using surrogate markers of exposure and modelling trends but not actually looking at people in any biochemical or genetic sense or importantly, the metabolites of various candidate exposure compounds appearing in biofluids. Today therefore, I'm talking about the paper by Braun and colleagues [2] (open-access here) and some of the accompanying research looking at various measured chemical exposures in relation to autism.

The Braun paper is open-access but here are a few details:

• The aim: "To identify gestational EDC [endocrine disrupting chemical] exposures associated with autistic behaviors" was accomplished by screening 175 pregnant women who were part of the HOME study (looking at "the impact of low-level fetal and early childhood exposures to environmental chemicals on health developmental and behavioral outcomes") for various suspected EDCs in urine and serum mid-pregnancy.
• Said EDCs included "phthalate metabolites", "polychlorinated biphenyls (PCBs)", "brominated flame retardants" (including the PBDEs) and "perfluoroalkyl substances" (see here).
• Keeping the analytical data in mind, mothers then completed the Social Responsiveness Scale (SRS), a standardised instrument which quite accurately seems to perform when it comes to autism screening [3] when offspring were 4-5 years of age.
• Results: "Most of the EDCs were associated with negligible absolute differences in SRS scores", so no smoking gun but... "maternal serum concentrations of trans-nonachlor and PBDE-28 were associated with higher SRS scores". Indeed it's worth pointing out that some of the EDCs actually seemed to negatively correlate with SRS scores as for example: "PBDE-85, PCB-178, β-HCH, and PFOA concentrations were associated with less autistic behaviors".
• That also the authors "adjusted for numerous potential confounders including gestational tobacco smoke exposure, socioeconomic factors, perinatal factors, caregiving environment, maternal IQ, and maternal depressive symptoms" when analysing their results is an important strength of their study.

I was intrigued by the Braun results for several reasons. Bearing in mind this was a study looking at maternal biofluids and in-utero exposures correlating with autistic behaviours (not specifically diagnoses) there are some interesting details requiring follow-up. BDE-28 (one of the congeners of the PBDEs) crop up quite a bit in research terms as per the the findings from Daniels and colleagues [3] looking at human milk samples. As Daniels et al suggest however: "The consequences of exposure to PBDEs are unknown" so I don't think we can draw too many conclusions from that one; indeed as per one of my previous posts on PBDEs and autism, there are a few more studies which could be done. That also another PBDE congener (PBDE-85) was actually associated with lower SRS scores - "consistent with less autistic behaviors" - is another example of just how complicated this area actually is.

Although maternal phthalate metabolites were not seemingly connected to scored offspring autistic behaviours, I'm not quite ready to trash any connection in this area. The paper by Testa and colleagues [4] (open-access here) looking at "primary and secondary metabolites of DEHP [di-(2-ethylhexyl) phthalate] in children with ASD [autism spectrum disorder]" offers some preliminary evidence for a potential role for phthalates exposure and autism. Compounded by the data presented by Stein and colleagues [5] on "a decreased capacity for detoxification via glucuronidation of compounds in the DEHP metabolic pathway" in their cohort with autism, and there are still questions to be answered about this group of compounds. And just in case you are still furrowing your brow at this association, there is the data from Larsson and colleagues [6] (open-access here) to look at, bearing in mind the suggestion that "the use of soft PVC as flooring material may increase the human uptake of phthalates in infants" [7].

Pinpointing one or more single pollutants as being tied into the increasing numbers being diagnosed with autism is always going to be an uphill struggle. Not only do we have very little data on the multitude of 'chemicals' (remember the mis-use of that word) we're all exposed to as part of modern living (or indeed that our parents were exposed to) but examining the synergistic effects of various multiple exposures is going to be problematic at best. As per the Stein research, we've also got to consider how an individual processes or metabolises their pollutant load which must have a bearing on the physiological effect from any exposure. Thinking back also to the recent air pollution - autism work starting to ask about gene x environment interactions, there are multiple dimensions to this work which aren't necessarily going to be answered by just looking at what a person is exposed to.

Oh, and I'll be coming to the paper by Nishijo and colleagues [8] titled "2,3,7,8-Tetrachlorodibenzo-p-dioxin in breast milk increases autistic traits of 3-year-old children in Vietnam" at some point quite soon.

To close, Rock Lobster...

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[1] Rzhetsky A. et al. Environmental and state-level regulatory factors affect the incidence of autism and intellectual disability. PLoS Comput Biol. 2014 Mar 13;10(3):e1003518.

[2] Braun JM. et al. Gestational Exposure to Endocrine-Disrupting Chemicals and Reciprocal Social, Repetitive, and Stereotypic Behaviors in 4- and 5-Year-Old Children: The HOME Study. Environ Health Perspect. 2014 Mar 12.

[3] Norris M. & Lecavalier L. Screening accuracy of Level 2 autism spectrum disorder rating scales. A review of selected instruments. Autism. 2010 Jul;14(4):263-84.

[4] Testa C. et al. Di-(2-ethylhexyl) phthalate and autism spectrum disorders. ASN Neuro. 2012 May 30;4(4):223-9.

[5] Stein TP. et al. Autism and phthalate metabolite glucuronidation. J Autism Dev Disord. 2013 Nov;43(11):2677-85.

[6] Larsson M. et al. Associations between indoor environmental factors and parental-reported autistic spectrum disorders in children 6-8 years of age. Neurotoxicology. 2009 Sep;30(5):822-31.

[7] Carlstedt F. et al. PVC flooring is related to human uptake of phthalates in infants. Indoor Air. 2013 Feb;23(1):32-9.

[8] Nishijo M. et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin in breast milk increases autistic traits of 3-year-old children in Vietnam. Mol Psychiatry. 2014 Mar 18.

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Braun JM, Kalkbrenner AE, Just AC, Yolton K, Calafat AM, Sjödin A, Hauser R, Webster GM, Chen A, & Lanphear BP (2014). Gestational Exposure to Endocrine-Disrupting Chemicals and Reciprocal Social, Repetitive, and Stereotypic Behaviors in 4- and 5-Year-Old Children: The HOME Study. Environmental health perspectives PMID: 24622245

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.

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* 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.

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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

Top 10 environmental pollutants and autism

I did promise in a recent post on rich/poor kids, older mums/dads and autism, that I would pass comment on the editorial by Landrigan and colleagues* (full-text) published in the journal Environmental Health Perspectives. I couldn't let this paper go by without some reference given that it provides quite a bit of background as to where autism research should be looking if we are to assume that certain aspects of the environment might play a role in symptom onset in at least some cases of autism and perhaps other related conditions.

Indeed there are several other papers in the same journal which might also be relevant to this post, including:

• This one by Sheldon and colleagues** (open-access) looking at pesticide exposure and autism,
• This paper by Kalkbrenner and colleagues*** (open-access) looking at maternal smoking during pregnancy,
• This paper by Wayman and colleagues**** (open-access) looking at non-dioxin like polychlorinated biphenyls (PCBs) and dendritic growth,
• and another paper by Wayman and colleagues***** (open-access) on ryanodine receptor dysregulation following PCB exposure.

I have to say that I don't have the time, energy or expertise to go through each and every one of these papers but would instead refer to quite a nice summary here on two of the papers and invite any comments from those that did read them. Please also consider this entry as a sort of continuation of my interest in pesticide exposure and health as per this and this post.

There are a few things to note about the Landrigan commentary including:

• Acceptance that autism is a family of conditions of which the authors suggest that about 30-40% of cases might be attributable to genetic inheritance.
• An estimated 3% of all neurobehavioural conditions are "caused directly by toxic environmental exposures" and some 25% caused by interactions between environmental factors and inherited susceptibilities.
• There is accumulating 'proof of principle' evidence for some role for environmental factors in cases of autism. 
• Added to what is already known about the neurological and developmental effects of some of these environmental agents combined with the growth and growth in areas such as epigenetics, there are some pieces of the research puzzle which seem to overlap with evidence from autism research.
• A workshop titled 'Exploring the Environmental Causes of Autism and Learning Disabilities' generated a list of 10 chemicals widely persistent in the environment which might cause developmental neurotoxicity. These were: Lead, Methylmercury, Polychlorinated biphenyls (PCBs), Organophosphate (OP) pesticides, Organochlorine (OC) pesticides, Endocrine disruptors, Automotive exhaust, Polycyclic aromatic hydrocarbons (PAHs), Brominated flame retardants, Perfluorinated compounds. The chemicals with links will take you to previous posts on this blog which have covered the compound in question; some with autism in mind, others with a more peripheral connection.

I'm sure you will agree that there are quite a few very bold statements included in this editorial not least the top 10 chemical targets for further research. I imagine that there will be some discussions on the rights and wrongs of naming and shaming the potential chemical offenders as time goes on.

The good news about these chemicals / compounds is that with the technology available these days, all are perfectly testable, and can be analysed in various biological fluids. One would therefore imagine that designing a large enough study covering people with autism, their parents, even siblings and appropriate comparators, controlling for comorbidity, even incorporating some degree of 'endophenotype' research and genetic / epigenetic elements is a perfectly feasible way of testing one or more of the '10 chemical hypotheses'.

Assuming some connection is confirmed and bearing in mind the complexity of cause-and-effect, the next question might be 'what can we do about it'? Minimising contact with these agents, particularly during conception and pregnancy and into early childhood, utilising the various ways and means available to remove these chemicals from the body - yes, even using that dreaded biomedical 'mumbo-jumbo' word detox - and assessing outcome both behavioural and biochemical (see here). Who knows perhaps even looking at the various detoxification mechanisms such as glutathione and its relations which have ascended up the evidence ranks quite recently to note any possible association.

Stop already with the speculation, I hear you cry. And I will.

To finish, do you feel compelled to walk like an Egyptian?

* Landrigan P. et al. A research strategy to discover the environmental causes of autism and neurodevelopmental disabilities. Environmental Health Perspectives. April 2012
DOI: 10.1289/ehp.1104285

** Sheldon JF. et al. Tipping the balance of autism risk: potential mechanisms linking pesticides and autism. Environmental Health Perspectives. April 2012
DOI: 10.1289/ehp.1104553

*** Kalkbrenner AE. et al. Maternal smoking during pregnancy and the prevalence of autism spectrum disorders using data from the Autism and Developmental Disabilities Monitoring Network. Environmental Health Perspectives. April 2012
DOI: 10.1289/ehp.1104556

**** Wayman GA. et al. PCB 95 promotes dendritic growth via ryanodine receptor-dependent mechanisms. Environmental Health Perspectives. April 2012
DOI: 10.1289/ehp.1104832

***** Wayman GA. et al. PCB 95 modulates calcium-dependent signaling pathway responsible for activity-dependent dendritic growth. Environmental Health Perspectives. April 2012
DOI: 10.1289/ehp.1104833

Flame-proofed genetically-engineered mice and autism

If you clicked on to this post expecting to see the very latest in 'superhero' mice complete with special flame-resistant powers, I'm afraid that you are going to be disappointed. If however you are interested in how genes and environment wrapped up in 'the new kid on the block discipline' of epigenetics might provide some clues about autism-like behaviours, you might just be in luck.

Not quite Mickey @Paul Whiteley

The study in question is this one by Woods and colleagues* with some interesting observations on what happens to a genetically-engineered mouse exposed to polybrominated diphenyl ethers (PBDEs). PBDEs have been covered on this blog previously with regards to autism. The net result of the work so far suggested that just about everyone is carrying some level of these POPs in them but perhaps some responses to these chemicals might be slightly altered in cases of autism for whatever reason (see here).

The latest study from Woods et al went one stage further:

• Mice were genetically-engineered to carry a defect in the methyl-CpG-binding protein 2 gene MECP2 (Mecp2-308) similar to that seen in Rett syndrome (RTT).
• These female mice were exposed perinatally to BDE-47, mated with male wild-type mice and their offspring examined for various developmental, behavioural and epigenetic outcomes.
• The main results: Mecp2-308 females exposed to BDE-47 were less fertile. Their female offspring also engaged in less social interaction with familiar mice alongside some issues with learning and memory coinciding with global hypomethylation of adult brain DNA (changes to DNA methyltransferase 3a, Dnmt3a). 
• In short: epigenetic pathways were implicated in social and cognitive outcomes.

There are a few important points to note from this research. Primary among them is the issue of whether Rett syndrome, or more specifically the mutation associated with Rett syndrome, is the same as autism in a wider context. Looking at the current ICD and DSM listings, Rett syndrome (RTT) is a condition with a few ties to autism (at least for now).

First reported by Dr Andreas Rett, an Austrian physician, RTT is now known to be a genetic condition which almost exclusively affects girls (almost exclusive). Although still the source of some investigation, diagnosis of RTT is predominantly carried out on the basis of observed features and characteristics complemented by genetic testing for mutations on the X chromosome gene MECP2 and other less common mutations. The observed behaviours associated with RTT overlap with autism and also other conditions such as cerebral palsy. At least one of the authors on the Woods paper, Prof. Janine LaSalle, has a bit of an interest in the epigenetic links between RTT and autism.

Translating results from a mouse model to real-life autism has been covered on this blog in previous posts so I'm not going to get too deeply into that argument. Suffice to say that rodent models are still finding some favour as models of autism**. I suppose the fact that female offspring of dams with mutation & exposure were the ones where most of the interesting results were found at least provides some support for the whole nature-nurture relationship observed and the focus on the X-chromosome (females = XX, males = XY).

This is an important study and certainly sets a precedent for looking at the effects of environmental factors on other genetic findings related to autism via the engineered mouse model approach. Having said that I am trying not to get too excited about such findings given the lack of consistent genetic markers for autism, the wide heterogeneity and numerous comorbidities present and the number of potential environmental factors potentially at work.

To finish, a song from Sheffield's rock-tastic royalty called animal.

* Woods R. et al. Long-lived epigenetic interactions between perinatal PBDE exposure and Mecp2308 mutation. Human Molecular Genetics. February 2012.
DOI: 10.1093/hmg/dds046

** Buxbaum J. et al. Optimizing the phenotyping of rodent ASD models: Enrichment analysis of mouse and human neurobiological phenotypes associated with high-risk autism genes identifies morphological, electrophysiological, neurological, and behavioral features. Molecular Autism. Feburary 2012.
DOI: 10.1186/2040-2392-3-1

Polybrominated diphenyl ethers (PBDEs) and autism

The beautiful game of football (soccer) is a bit of national obsession here in the UK. In the bracing North-East of England, we have a particularly loyal following of fans who, every Saturday (or thereabouts) dress up in either red and white or black and white depending on their affinity to the Black Cats or the Magpies, and brave the elements to watch 90 minutes of sporting battle. Derby days when the two teams meet are something else!

I myself, whilst an interested follower of one of these teams (not saying which!), have never been as overly enthusiastic as some of my fellow North-Easterners, instead preferring to follow a different kind of sport, research. Funny you might think that he equates research with football, but it follows very similar principles: competition, goals, star players, money, esteem. Some would say that football is a matter of life or death; research is perhaps in some cases even more about life or death.

Within the autism research football division, several teams compete. At the moment, I would probably say that the team based at the UC Davis MIND Institute are the Manchester United of the Premier League. Indeed various papers from the MIND Institute have been covered on this blog. Their focus on the environmental as well as the genetic is perhaps what makes the MIND Institute stand out from the rest.

Why the long-winded introduction?

Well a paper has appeared recently which whilst outside of autism research could potentially tie into some areas covered by the MIND Institute team. The paper by Zota and colleagues* reports on a study looking at polybrominated diphenyl ethers (PBDEs) and related metabolites used as flame retardant materials alongside markers of thyroid function in pregnant mums based in California.

Many things contain PBDEs despite such compounds being banned in several parts of the world. Plastics, wire insulation, old furniture foam - much like asbestos, being banned does not necessarily mean that people are not exposed to such compounds (and for years after). Zota and colleagues sought to measure serum concentrations of PBDEs in mums-to-be who were in the second trimester of pregnancy. They found some of the highest concentrations of PBDE-related metabolites ever reported in pregnant women. Added to that they reported associations between PBDE findings and moderators of thyroid function such as thyroid-stimulating hormone (TSH).

Whilst it is not possible to say what specific effects such serum PBDE levels might have on the developing foetus bearing in mind their toxicity profile, it is fair to say that any potential disruption to maternal thyroid function caused by alterations in TSH levels is not likely to be good for the child. Foetal premature birth, low birth weight and even miscarriage and stillbirth have been noted in cases of gestational maternal hyper- and hypothyroidism.

So how does this relate back to the MIND Institute and autism research?

Levels of PBDEs and related metabolites in cases of autism have been examined by our intrepid UC Davis team. This paper from Hertz-Piciotto and colleagues measured serum PBDE levels in children with autism vs. developmental delay vs. asymptomatic controls. They did not report any significant differences among the groups, the groups made up of participants from California, but noted high levels of PBDEs in all. OK, you might say so there was no difference, but wait.. what if there might be some difference in the way that such compounds affect a person, a person with autism perhaps? During preliminary study this is what was hinted at in this paper by Ashwood and colleagues, who suggested an altered sensitivity to a specific PBDE, BDE-47 resulting in an increased inflammatory response in cells from people with autism spectrum conditions compared with controls. This finding follows other research suggestive of a potential association between BDE-47 and attention problems.

As with any environmental agent, it is nearly impossible to ascribe an effect in isolation because people do not live in a vacuum. As a population, we potentially face hundreds if not thousands of other exposures which might be contributory to any effect. Unless you measure them all, there is always doubt. Having said that, I don't want to take away from the findings of the study by Zota and colleagues. Findings which require replication and follow-up of infants born to mothers with such high levels, and if deemed necessary, urgent action to minimise any associated health or developmental risks.

I leave you with a song by a footballer which many North-Easterners will know well. It's probably not going to win a Grammy but harks back to happier times for the gentleman in question.

* Zota AR. Polybrominated diphenyl ethers (PBDEs), hydroxylated PBDEs (OH-PBDEs), and measures of thyroid function in second trimester pregnant women in California. Environmental Science & Technology. August 2011.