Dioxin exposure and autistic traits?

As promised in a previous post, today I'm turning my attention to the paper by Muneko Nishijo and colleagues [1] and their conclusion of "a specific impact of perinatal TCDD [2,3,7,8-tetrachlorodibenzo-p-dioxin] on autistic traits in childhood, which is different from the neurotoxicity of total dioxins (PCDDs/Fs) [polychlorinated dibenzo-p-dioxins/furans]".

TCDD @ Wikipedia 

With all the recent chatter about [surrogate] environmental markers and the numbers of cases of autism spectrum disorders and environmental toxicants and autism risk it is indeed timely that the Nishijo paper comes to publication now. Environmental factors, however you wish to define this, are certainly no stranger to autism research, and are fast finding a place in the autism research psyche, perhaps in part due to the rise and rise of the science of epigenetics (see here) as a bridge between genetics and environment. Genes, or rather the blueprint that is your genome, might not necessarily be your destiny and all that jazz...

The Nishijo paper in a little more detail:

• Set in Vietnam, which it has to be said, has seen more than its fair share of chemical exposures in recent history, the authors looked at the possibility of perinatal dioxin exposure being linked to the presence of autistic traits based on a sample of 153 infants. This follows other work by this group looking at dioxin exposure and more generalised infant neurodevelopment [2] as part of a wider research agenda. Dioxins for those who might not know, are categorised as environmental pollutants, and because of their biological persistence, are deemed pretty hazardous to human and other animal health (see the WHO fact sheet here). It's accurate that I mentioned Agent Orange in reference to the chemical load witnessed in Vietnam because Agent Orange was contaminated with TCDD - the chemical name for dioxin -  and there are some very scary quotes about TCDD being for example "perhaps the most toxic molecule ever synthesized by man". The US IOM report 'Veterans and Agent Orange' provides some sober reading on the topic.
• Scare tactics aside, the authors assessed the levels of TCDD in breast milk as part of a larger analysis of various other dioxins (PCDDs, PCDFs) based on analysis of samples via GC-MS. Actually quite a good overview of their methods can be found in another paper by this group [3] (open-access). Data from these analyses were transformed to form something called the TEQ (Toxic Equivalent) which basically gives you some idea of the toxicity of these classes of compounds relative to TCDD. TCDD has a value of 1 so setting the gold standard of toxicity. 
• Offspring were followed-up based on the use of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) and specifically with autism in mind, the Autism Spectrum Rating Scales (ASRS).  
• Results: exposure groups (mild and high) were determined according to a cut-off level of 3.5 pg/g fat of TCDD being detected and results were reported according to gender. So: "The high-2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposed groups... showed significantly higher Autism Spectrum Rating Scale (ASRS) scores for both boys and girls than the mild-TCDD exposed groups, without differences in neurodevelopmental scores". This indicates some kind of dose-dependent relationship between TCDD exposure and autistic traits in study participants. When it came to looking at any connection between other PCDDs/Fs and autistic traits, nothing significant was picked up. Ergo, TCDD exposure seemed to have specifically impacted on infant autistic traits.

These are interesting results, of that there is no doubt. I could start to go on about correlation not being the same as causation, or how the ASRS might not necessarily have been the best instrument to use in this particular instance given it being standardised on American children and not officially translated into Vietnamese. That also it is not a professionally-administered instrument is another potential gap. But I'm not going to let all that get too far in the way of the Nishijo findings.

I see from some of the additional data from this paper that there were some other differences noted across the high and mild TCDD exposure groups which may be relevant to the results. When comparing boys and girls in the high and mild exposure groups, I note that mean birth weight was lower in the high exposed group compared to the mild exposed group (average 2920g vs. 3298g respectively) for boys. Realising that low birth weight is not an exclusively autism-correlated phenomena (see here) one might however consider this to be something which could potentially have affected the results obtained.

As per the discussions about the geographical location of this study [4], one of the question which then needs to be asked is whether the possibility of a TCDD exposure link is something applicable to other areas and other cases of autism/autistic traits. I'm no expert on TCDD so cannot readily answer this question aside from directing you to some data from the US Environmental Protection Agency on sources of TCDD. It does appear that there are quite a few potential sources of TCDD; although food seems to be the most widely cited source of exposure in modern times. By saying that I'm not trying to panic anyone, given that many countries do monitor foods for dioxin levels (see here) and act accordingly when high levels are detected.

Still, if we assume that there may be many roads towards a diagnosis of autism or the presentation of autistic traits, and that those roads may not be the same in every part of the world, the Nishijo results make for an interesting addition to the research landscape. As to mechanisms of effect, well take your pick; TCDD is categorised an endocrine disruptor so potentially falling into the same type of effect as that discussed by Rzhetsky and colleagues [5]. I also note some research chatter about TCDD and GABA [6] with specific mention of GAD (see here for some description of what this is). Jumping on the epigenetics bandwagon however, one might also suggest some further inquiry in that area if results like those by Manikkam and colleagues [7] are anything to go by, bearing in mind the continued focus on sperm and eggs and autism risk. That all being said, I don't doubt that it's going to be a complicated effect from TCDD with various factors involved.

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[1] 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.

[2] Tai PT. et al. Dioxin exposure in breast milk and infant neurodevelopment in Vietnam. Occup Environ Med. 2013 Sep;70(9):656-62.

[3] Nishijo M. et al. Impact of perinatal dioxin exposure on infant growth: a cross-sectional and longitudinal studies in dioxin-contaminated areas in Vietnam. PLoS One. 2012;7(7):e40273.

[4] Banout J. et al. Agent orange footprint still visible in rural areas of central Vietnam. J Environ Public Health. 2014;2014:528965.

[5] 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.

[6] Hays LE. et al. Evidence that GABAergic neurons in the preoptic area of the rat brain are targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin during development. Environ Health Perspect. 2002 Jun;110 Suppl 3:369-76.

[7] Manikkam M. et al. Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations. PLoS ONE. 2012; 7(9): e46249.

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Nishijo M, Pham TT, Nguyen AT, Tran NN, Nakagawa H, Hoang LV, Tran AH, Morikawa Y, Ho MD, Kido T, Nguyen MN, Nguyen HM, & Nishijo H (2014). 2,3,7,8-Tetrachlorodibenzo-p-dioxin in breast milk increases autistic traits of 3-year-old children in Vietnam. Molecular psychiatry PMID: 24637425