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