Urinary phthalate metabolites and autism

I don't know if it is just me but investigations on the potential role of certain environmental factors in relation to at least some cases of autism spectrum conditions seem to be coming in thick and fast recently. I speak for example about the paper suggesting a role for high-fructose corn syrup (HFCS) and other factors; alongside other interesting papers published at the same time as the 'top 10 environmental factors' editorial discussed recently.

Appreciating that there are some gaps in the whole environmental area of investigation with regards to cause-and-effect, mixed in with the question of what might do what and to who, there is some interesting reading in amongst the various studies. This includes discussions around the concept of 'risk' and how autism research seems to be (partially) reinventing itself into a slightly more complicated hypothesis where environment and genes (variably) might play a role in aetiology rather than just genes, genes, genes. I get to say that word again.. 'epigenetics'.

Add then this paper by Testa and colleagues* (full-text) to the list of environmental question marks which was very quietly published recently looking at a possible connection between phthalate excretion and autism.

Phthalates (assuming I have spelled the word correctly) according to the US EPA, are a class of compounds called plasticisers as a result of their ability to make things more 'plastic' in terms of properties such as flexibility and durability. Whilst moves are underway to remove / limit phthalates in the industrial chain, their use is pretty widespread in products as diverse as cosmetics to food packaging, flooring to detergents.

As mentioned, there are moves to reduce the use of phthalates in the production of certain types of product as a result of growing evidence associating their exposure and unwelcome effects such as their endocrine disrupting potential. Just before you start looking around at what products you are surrounded by which might contain phthalates, the answer is probably quite a few; and in terms of exposure to these compounds, generally speaking we all have some of them circulating (or at least traces of them as per the analysis of biofluids like urine). Modern man and woman it seems are probably not going to grace the Visitors table as per an older post.

To the Testa paper:

• Based on the assumption that phthalates might be able to affect aspects of child development (particularly boys), the authors looked at urinary levels of primary and secondary metabolites of di(2-ethylhexyl)phthalate (DEHP) in a small-ish group of Italian children with autism (n=48) compared with an asymptomatic age- and gender-matched group (n=45). I say gender-matched but the authors use the word 'sex comparable' given that the autism group seemed to have a greater ratio of boys than the control group.
• The autism group were all DSM-IV diagnosed with autism and importantly all had ADOS and/or other data as some kind of confirmation of autism.
• First morning, spot urine samples were analysed by a favourite method, mass spectrometry, tandem mass spectrometry, preceded by quite a complicated extraction procedure based on the use of solid-phase extraction (SPE) to clean the sample up. I'm not going to go through the total list of metabolites they looked at but rather pick out the results that were significantly different.
• Results: levels of secondary metabolites, 5-OH-MEHP, 5-oxo-MEHP and MEHP were significantly increased in the autism group as a whole compared with controls. That being said, these metabolites were not detected in every sample from children in the autism group (52% & 46% & 79% respectively) bearing in mind the sensitivity of the assay used and lower limits of detection reported. Further comparison with a separate group of people diagnosed with Rett syndrome (RS) (n=10) - no age range described - suggested that the autism group excreted more secondary metabolites of DEHP (MEHP) than RS participants.
• One secondary metabolite, 5-oxo-MEHP, was suggested to show over 90% specificity when it came to identifying participants with autism.

As far as I can see, the authors are correct in their statement that this is the first time that phthalates have been directly looked for in the biological fluids of people with autism compared to controls. The research literature contains a couple of more speculative papers looking for example at in-door environment and autism (with accompanying reporting here) or reviewing the very limited available evidence on lots of endocrine disrupting compounds in relation to autism but not much else. There is other work in areas such as ADHD for example, again suggesting the possibility of some connection between reported ADHD symptoms and urinary phthalate content. Even executive functions get a look-in with regards to prenatal exposure. But that's your lot.

Where to go from here?

Well, we have to be slightly cautious in making too many assumptions from this current data. Yes, children with autism were better excretors of phthalates and yes, better to the degree that certain metabolites might even serve some identifying feature in comparison to control samples. But, and it is quite a large but(!), this paper does not provide a cause-and-effect role for phthalates in cases of autism. So for example, only urine was looked at and only individual spot samples at that. I could be a little bit pedantic and start asking whether circulating plasma levels of phthalates were any different or asking about levels in other tissues?

The authors did undertake some routine correlational analysis between phthalate metabolite levels and things like CARS scores, finding a positive association between MEHP and CARS scores such that increasing levels of one was correlated to increasing levels of the other. I do find this 'severity' relationship to be interesting although I perhaps would have liked to have seen confirmatory analysis from other tools including the ADOS.

Despite my queries about the results, what this study does offer is another potential target area to include when looking at environmental pollutants and any relationship to autism - add it to the list. Without wishing to seem like I'm too obsessed, I do wonder also about a gut bacterial connection as per other data, very preliminary data, on pesticides and bacteria. Sideways thinking is always advised.

To finish, a spot of New Order. Indeed since I am reminiscing about the Manchester scene, how about some Stone Roses too.

* Testa C. et al. Di(2-ethylhexyl)phthalate and autism spectrum disorders. ASN Neuro. April 2012.
DOI: 10.1042/AN20120015