"parental asthma was associated with slightly elevated risk of ASD in offspring"

The paper by Tong Gong and colleagues [1] provides the blogging fodder today and the finding that "parental asthma was associated with slightly elevated risk of ASD [autism spectrum disorder] in offspring."

As unusual as it might sound to some people that a condition primarily affecting the lungs *might* show a connection to a developmental diagnosis in offspring, this is not the first time that asthma and autism has been talked about on this blog (see here and see here). Granted, much of that previous peer-reviewed research has been looking at the possible *connection* between asthma and autism diagnosed in the same person (albeit not necessarily always describing a link). But there is some research history connecting the two labels. Indeed, one of the primary comorbidities that can follow a diagnosis of autism - attention-deficit hyperactivity disorder (ADHD) - seems to have an even stronger *association* with asthma (see here).

Gong et al set out to investigate a few important issues: "the association between (a) maternal/paternal asthma and offspring ASD, and (b) prenatal exposures to β2-agonists, other asthma medications and offspring ASD." It would be difficult to describe the Gong study as 'underpowered' given that their use of those fabulous Scandinavian population registries - this time in Sweden - covering "all children (N=1,579,263) born in Sweden 1992-2007." From the total population, researchers identified some 22,000 children diagnosed with an ASD. They looked at their exposure to "parental asthma or prenatal asthma medications" and compared the data with other populations (not diagnosed with autism) including various degrees of siblings and extended family members.

As per the title of this post, a possible *association* was revealed between parental medical history of asthma and offspring risk of a diagnosis of ASD. Asthma in either parent seemed to show a connection, but maternal asthma showed the stronger connection. Also: "The risk of offspring ASD in mothers with asthma showed similar estimates when adjusting for shared familial factors among paternal half-siblings... full-cousins... and half-cousins." This suggests that familial factors were not 'confounding' factors. Another detail is important to mention: "Prenatal exposure to asthma medications among subjects whose mothers had asthma was not associated with subsequent ASD." This is an important detail. It mirrors the findings reported in the paper by Su and colleagues [2] looking at another Scandinavian cohort, and their conclusion: "children born to women who used β2AA [β2-adrenoreceptor agonist] during pregnancy have an increased risk of ASDs in later life" with the caveat that risk of offspring autism was "more likely due to underlying maternal diseases rather than the exposure to β2AA itself."

Implications? Well, several. Not least that more study is required looking at the biological and genetic links between autism and asthma. Y'know, something along the lines of the fact that 'autism genes are probably not just genes for autism' (see here) and how autism has been previously studied in the context of lung architecture too (see here).

What else? How about examining the possibility of some shared biological mechanisms also at work? Perhaps start with inflammation for example [3] and work through other potential immune-related issues as well (see here). And how about also thinking about the possibility of shared 'exposure' events being potentially important? Asthma is a condition affecting the lungs. Something like air pollution is therefore a prime suspect when it comes to the development and continuation of the condition. Likewise, air pollution is no stranger to the autism peer-reviewed research landscape (see here for example). Is it possible that air pollution might be implicated in asthma and autism?

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[1] Gong T. et al. Parental asthma and risk of autism spectrum disorder in offspring: a population and family based case-control study. Clin Exp Allergy. 2019 Feb 11.

[2] Su X. et al. Prenatal exposure to β2-adrenoreceptor agonists and the risk of autism spectrum disorders in offspring. Pharmacoepidemiol Drug Saf. 2017 Jul;26(7):812-818.

[3] Murdoch JR. & Lloyd CM. Chronic inflammation and asthma. Mutat Res. 2010;690(1-2):24-39.

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"an association between exposure to NO and ASD but no significant association with PM2.5 and NO2"

The title of this post - "an association between exposure to NO and ASD but no significant association with PM2.5 and NO2" - comes from the findings reported by Lief Pagalan and colleagues [1] who set out to "evaluate the association between prenatal exposures to airborne pollutants and ASD [autism spectrum disorder] in a large population-based cohort." NO mentioned in that quote refers to nitric oxide. NO2 refers to nitrogen dioxide. And PM2.5 refers to "particulate matter with a diameter less than 2.5 µm."

Some media about the Pagalan findings can be seen here. This was a study that continued an on-going research theme looking at a possible connection between exposure to air pollution during the nine months that makes us (gestation and pregnancy) and subsequent 'risk' of offspring autism (see here and see here).

This time around the records of nearly 130,000 children born during the mid to late 2000s were included for analysis. Said records contained lots of important information including whether or not children were ever formally diagnosed with an autism spectrum disorder (ASD). Researchers also analysed records pertinent to the average "monthly concentrations of ambient PM2.5, NO, and NO2 at the maternal residence during pregnancy." The datasets were married together.

Results: yes. Yes, Pagalan et al observed a possible *association* between prenatal exposure to nitric oxide (NO) and offspring autism. Specifically, with increasing levels of NO exposure during pregnancy so the risk of offspring autism increased. Ergo, a possible connection. But, one needs to be careful with such results. Careful because, as one commentator talking about the study results said: "In broad terms, the results of the study were much the same for all three pollutants... However, only nitric oxide went "over the conventional boundary of statistical significance... and only just over"." He's right of course, as per the use of: "Adjusted odds ratios... per interquartile range (IQR)" and results only just tipped over what would be considered just random chance. This also bearing in mind that exposure levels to those pollutants were calculated from average monthly concentrations and said nothing about actual personal exposure levels of mums-to-be.

This is an interesting area of autism research. I know some people don't like the idea that within the huge heterogeneity that is autism there might be one or two important variables that aren't 'genetic' but nevertheless might contribute to someones risk of receiving a diagnosis. That's fine. Personally, I go with the idea that genetic and non-genetic factors probably (variably) work in tandem as we've kinda had hints of in other pollution-autism research [2]. And on that basis, such a research stream should continue.

And speaking about air pollution and it's [possible] effects [3]...

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[1] Pagalan L. et al. Association of Prenatal Exposure to Air Pollution With Autism Spectrum Disorder. JAMA Pediatr. 2018 Nov 19.

[2] Volk HE. et al. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiology. 2014 Jan;25(1):44-7.

[3] Emerson E. et al. Risk of exposure to air pollution among British children with and without intellectual disabilities. Journal of Intellectual Disability Research. 2018. Nov 20.

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On genotype and environmental exposure patterns

I was rather interested to read the paper by Michela Traglia and colleagues [1] (open-access available here) concluding that: "maternal and fetal genetic make-up are important determinants of mid-gestational maternal circulating levels of some environmental organohalogens." Interested because, in these days of gene-environment interactions being applied to just about everything, the detail that is missing - which genes might potentially be linked to which environmental factors - has not yet been suitably addressed in the peer-reviewed science literature.

So, based on data - "serum levels of a set of 21 organohalogens in a subset of 790 genotyped women and 764 children" - derived from participants included in the Early Markers for Autism (EMA) Project, researchers set about assessing how genetics might impact on environmental pollutant exposure profiles. Maternal blood samples were collected at around 15-20 weeks pregnancy. Children provided blood samples via the fabulous resource that is the newborn screening program, where: "Newborn blood spots were collected on filter paper 1-2 days after birth." Maternal samples were analysed for various environmental pollutants and both sets of samples were analysed for the genetic material they contained pertinent to whether "circulating mid-gestational levels of organohalogens would be driven by common maternal genetic determinants, and that these results could shed light on the observed associations between the organohalogens and ASD [autism spectrum disorder]."

Results: yes, the authors "found evidence that a large proportion of maternal circulating levels of BB-153, BDE-47, -100, -153 [polybrominated congeners] and their sum was significantly controlled by common genetic factors." Those 'common genetic factors' typically referred to the presence of point mutations (SNPs) that litter everyone's genome and on occasion, can affect the function/production of specific biological processes. So: "Genome-wide association analyses identified significant maternal loci for p,p'-DDE... in the CYP2B6 gene and for BDE-28... near the SH3GL2 gene, both involved in xenobiotic and lipid metabolism." In other words, although the environmental pollutants measured are not great products in the first place (in terms of safety), a person's genetic make-up can influence how such products are eventually dealt with by the body and potentially onwards, what subsequent effects they might have.

Additionally: "results suggest that the maternal circulating levels of some compounds were more highly influenced by fetal genetic factors than maternal genetics." This leads into another aspect of the current study whereby foetal genetic factors might also play a part in "controlling the toxicant disposition between mother and fetus." Specifically, authors noted that aspects of the individual genetics of a foetus (distinct from its mother) "contributed to the levels of BDE-100... and PCB187... near the potential metabolic genes LOXHD1 and PTPRD, previously implicated in neurodevelopment."

And finally: "We confirmed that the serum levels of BDE-100, -153 and the total sum of PBDEs were significantly lower in mothers of ASD-affected children compared to mothers of control children." This is interesting in light of other discussions about PBDEs and autism in particular (see here). The authors do discuss various scenarios to account for their results not least that "transplacental transfer of organohalogens during pregnancy may be driven by the fetal genome expressed in placenta." Further analyses of the 'placentome' might therefore be indicated.

To reiterate, this is interesting research. It tells us that many [adverse] environmental exposures, whilst typically to be avoided, don't act on the body in a uniform way as a function of differing genomes and differences in the ways that the body 'handles' such exposures. With autism in mind, this is not necessarily new news (remember paraoxonase gene variants and organophosphate metabolism [2] and air pollution and offspring autism?) but is a useful reminder. Such work also provides a template for looking at the myriad of other environmental factors put forward to influence autism risk and whether individual product safety is necessarily the only or most important factor when it comes to assessing relative risk profiles.

I might finally also draw your attention to a recent interesting meta-analysis of the various environmental risk factors potentially linked to autism [3] (open-access) and another article talking about similar things [4] (open-access) (thanks Annabelle). Genes and environment, genes and environment...

Music: Petula Clark sings the Beatles? Personally, I think it's better than the original...

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[1] Traglia M. et al. Independent Maternal and Fetal Genetic Effects on Mid-gestational Circulating Levels of Environmental Pollutants. G3 (Bethesda). 2017 Feb 24. pii: g3.117.039784.

[2] D'Amelio M. et al. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Mol Psychiatry. 2005 Nov;10(11):1006-16.

[3] Modabbernia A. et al. Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses. Molecular Autism. 2017; 8: 13.

[4] Parker W. et al. The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism. Journal of International Medical Research. 2017. Jan 20.

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Traglia M, Croen LA, Lyall K, Windham GC, Kharrazi M, DeLorenze GN, Torres AR, & Weiss LA (2017). Independent Maternal and Fetal Genetic Effects on Mid-gestational Circulating Levels of Environmental Pollutants. G3 (Bethesda, Md.) PMID: 28235828

Particulate matter exposure and autism risk systematically reviewed?

"To conclude, the evidence from the studies allows us to conclude that there is an association between PM [particulate matter] exposure and ASD [autism spectrum disorder] whose strength varies according to the particle size studied with the association with PM2.5 and diesel PM being stronger."

Although probably not great sentence structure to begin a post with a conclusion, the 'bottom line' reported by María Morales-Suárez-Varela and colleagues [1] summarises the current research looking at particulate matter (a.k.a pollution) and risk of autism. Surveying the current research literature - well, a window "from November 2015 up to January 2016" - authors reported finding a majority of studies showing "positive associations restricted to specific exposure windows which however do not reach statistical significance at times." This adds to other reviews of the research in this area [2].

I don't want to dwell too much on this paper and topic because it's something that has already received quite a bit of attention on this blog (see here and see here for examples). As with most research areas focused on autism, there is evidence for and evidence against any association/correlation between air pollution exposure and risk of autism. Given the various factors included under the heading of pollution (type, particle size, how exposure is measured) it's perhaps not surprising that there is not yet any 'smoking gun' (pardon the pun) when it comes to any possible association.

I however, am taken by the ideas that (a) genes probably play a hand in translating air pollution exposure to a heightened risk of [offspring] autism and (b) other conditions linked to air pollution such as asthma might also feature in any connection (see here for example). Indeed, in these times of seemingly ever-increasing air pollution (see here) and lots of possible connections, further investigations are very much indicated.

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[1] Morales-Suárez-Varela M. et al. Systematic review of the association between particulate matter exposure and autism spectrum disorders. Environ Res. 2016 Dec 13;153:150-160.

[2] Lam J. et al. A Systematic Review and Meta-Analysis of Multiple Airborne Pollutants and Autism Spectrum Disorder. PLoS One. 2016 Sep 21;11(9):e0161851.

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Morales-Suárez-Varela M, Peraita-Costa I, & Llopis-González A (2016). Systematic review of the association between particulate matter exposure and autism spectrum disorders. Environmental research, 153, 150-160 PMID: 27984759

On (banned) organochlorine compounds and autism risk

'Chemicals banned decades ago linked to increased autism risk today' went the press release attached to the findings reported by Kristen Lyall and colleagues [1] (open-access).

Observing that "higher levels of some organochlorine compounds during pregnancy are associated with ASD [autism spectrum disorder] and ID [intellectual disability]" the Lyall results once again push environmental factors back into the research spotlight. Indeed, environmental factors that were banned decades ago.

Including a cohort of children diagnosed with autism (n=545), those diagnosed with ID (also known at learning disability) (n-=181) and general population (asymptomatic?) controls (n=418) researchers accessed archived biological samples taken from mothers during the second trimester of pregnancy. Using some pretty sophisticated chemical analysis methods - "gas chromatography isotope dilution high resolution mass spectrometry (GCIDHRMS)" - various chemical compounds considered as POPs (persistent organic pollutants) were assayed for. Most if not all of these compounds were banned in the 1970s because of their potential effects on health. Because of their chemical nature however (i.e. enjoying bathing in fats) they can and do still persist in the environment, particularly in the food chain.

Results: various PCBs (polychlorinated biphenyl ethers) and "persistent pesticides" were included in the chemical analysis of maternal samples. Some, but not all, were reported in samples across the different groups. After some statistical wizardry in terms of adjusting samples and the results for various factors ("children with ASD were approximately four times as likely to be male than female... have older parents, and mothers with higher education") authors concluded that a few of the metabolites looked at might be linked to autism risk; specifically: "that exposure to PCB congeners in utero may influence risk of ASD in offspring."

"Primary analyses highlighted PCB 138/158 and PCB 153 in association with ASD, though other correlated congeners also demonstrated associations above the null." PCB 138/158 also seemed to show some sort of connection to the risk of offspring ID too "suggesting the impact of exposure to this congener on neurodevelopment broadly." Conversely, none of the other organochlorine compounds seemed to show any (significant) connection to autism offspring risk. Something similar has been talked about before with this broad collection of compounds in mind under more direct analysis conditions (see here). The authors conclude that further research is required to both substantiate their findings and also ascertain some of the hows and whys of these compounds in relation to autism and ID. Importantly, they acknowledge that their list of compounds tested may not be the whole story in terms of the 'multiple chemicals' people are exposed to over a lifetime.

These are rather interesting results. Not least because the potential legacy of these compounds continues years and years after production of them had all but ceased following health concerns. That researchers also focused on maternal pregnancy blood samples again (see here) puts gestational 'exposure' front and centre when it comes to potential effects and mechanisms too. The idea that immune function could be a target effect of such compounds when it comes to offspring autism risk is also explored by the authors: "effects on the immune system is another particularly likely mechanism." This would also seem to tally with the growing evidence that maternal immune function during the nine months that made us might be an important part of aetiology for at least some autism and/or more general neurodevelopmental issues.

The story continues as it might with other compounds too [2] on this 'TENDR' area of research...

To close, Worf don't like the lute...

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[1] Lyall K. et al. Polychlorinated Biphenyl and Organochlorine Pesticide Concentrations in Maternal Mid-Pregnancy Serum Samples: Association with Autism Spectrum Disorder and Intellectual Disability. Environ Health Perspect. 2016. Aug 23.

[2] Jeddi MZ. et al. The role of phthalate esters in autism development: A systematic review. Environ Res. 2016 Aug 24;151:493-504.

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Lyall K, Croen LA, Sjödin A, Yoshida CK, Zerbo O, Kharrazi M, & Windham GC (2016). Polychlorinated Biphenyl and Organochlorine Pesticide Concentrations in Maternal Mid-Pregnancy Serum Samples: Association with Autism Spectrum Disorder and Intellectual Disability. Environmental health perspectives PMID: 27548254

Project TENDR and chemical exposures

Yes, I know I'm writing on a Sunday again, but it will be a short-ish post I promise you. The reason for the entry is this brief communication [1] reporting: "The TENDR [Targeting Environmental Neuro-Developmental Risks] authors agree that widespread exposures to toxic chemicals in our air, water, food, soil, and consumer products can increase the risks for cognitive, behavioral, or social impairment, as well as specific neurodevelopmental disorders such as autism and attention deficit hyperactivity disorder (ADHD)."

The press release accompanying the paper is here. Given the focus on neurodevelopmental disorders including autism it is perhaps not surprising that several of the signatories on the paper are stalwarts of the idea that 'environment' may play a not insignificant role when it comes to at least some autism. If you need examples, look no further than here and here.

I know there are still often heated discussions/arguments (delete as appropriate) about how environment - or non-genetic factors - might fit into the quite marked increase in the numbers of people being diagnosed with autism and various other developmental conditions. I think most people will appreciate that although there are clues in the current peer-reviewed literature to possible effects for some, a lot more science is needed to substantiate specific environmental risks and importantly, potential mode(s) of action when it comes to something like autism or ADHD as a clinical endpoint. There are however signs that science is starting to move in the right direction (see here)...

Set within changes to some of the regulatory affairs when it comes to how countries ensure 'chemicals' are safe (being careful about how one uses the word 'chemical') and perhaps because years of looking for the 'genetics of autism' has yielded only partial results (see here), it is starting to become better accepted that elements of our environment might also affect risk for many conditions, including those potentially affecting development.

To close, the news that Morrissey is returning to these hallowed shores naturally invites a song from the man driving a tractor...

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[1] Project TENDR: Targeting Environmental Neuro-Developmental Risks. The TENDR Consensus Statement. Environmental Health Perspectives. 2016.; 124: A118-A122.

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Bennett, D., Bellinger, D., Birnbaum, L., Bradman, A., Chen, A., Cory-Slechta, D., Engel, S., Fallin, M., Halladay, A., Hauser, R., Hertz-Picciotto, I., Kwiatkowski, C., Lanphear, B., Marquez, E., Marty, M., McPartland, J., Newschaffer, C., Payne-Sturges, D., Patisaul, H., Perera, F., Ritz, B., Sass, J., Schantz, S., Webster, T., Whyatt, R., Woodruff, T., Zoeller, R., Anderko, L., Campbell, C., Conry, J., DeNicola, N., Gould, R., Hirtz, D., Huffling, K., Landrigan, P., Lavin, A., Miller, M., Mitchell, M., Rubin, L., Schettler, T., Tran, H., Acosta, A., Brody, C., Miller, E., Miller, P., Swanson, M., Witherspoon, N., , ., , ., , ., , ., , ., , ., , ., , ., & , . (2016). Project TENDR: Targeting Environmental Neuro-Developmental Risks The TENDR Consensus Statement Environmental Health Perspectives, 124 (7) DOI: 10.1289/EHP358

Organic pollutants and behavioural severity in autism?

"This study supports the hypothesis that environmental exposure to organic pollutants may play a significant role in the behavioral presentation of autism."

Accepting that correlation is not the same as causation, the results published by Andrew Boggess and colleagues [1] (open-access here) make for some blogging fodder today and the idea that serum levels of various compounds headed under the description of organic pollutants (persistent or otherwise) might show some important connections to at least some autism.

To get a few things straight first, this and other related research does not say that every diagnosis of autism is somehow the product of a 'toxic' exposure. Nor does it belittle the substantial contribution that genetics (whether structural or non-structural issues) confer when it comes to diagnosis. To my mind, it adds another level of complexity to the [various] hows and whys relating to how autism might come about [2]. That, and offering some important biologically-led guidance on what might be done to decrease any body load of such pollutants as and when they are detected and there's quite a bit we can learn from such studies.

Anyhow, Boggess et al started from the position of wanting to "evaluate the relationship between organic pollutants and behavioral severity in children with ASD [autism spectrum disorder] and matched controls." Thirty children diagnosed with autism were matched (age and sex) with 30 children without autism. Quite a panel of diagnostic and screening instruments were included as part of the study protocol, including ADOS (Autism Diagnostic Observation Schedule) and interestingly, the ATEC (see here). Each participant provided a blood sample, and the serum portion of the sample was subject to analysis by GC-MS (Gas Chromatography-Mass Spectrometry) for various compounds. Compounds included: "Three volatile organic compounds (VOC), benzene, toluene, and o-xylene; one alkane, hexane; five polychlorinated biphenyls (PCB), IUPAC congeners 28, 52, 101, 138, and 153; two polybrominated diphenylethers (PBDE), IUPAC congeners 47 and 99; two organochlorine pesticides, metolachlor and acetochlor; one dinitroanaline pesticide, pendimethalin; one organophosphate pesticide, chlorpyrifos; one phthalate, bis (2-ethylhexyl) phthalate (DEHP); and the chlorocarbon perchloroethylene."

Results: well, looking directly at the metabolites under inspection and comparing the group results (autism group vs control group) in terms of individual quantified levels, there seemed very little see. The only compound that was statistically significant in terms of amounts between the groups was something called metolachlor, a herbicide, which was actually found in higher mean concentrations in the control group than the autism group. When also researchers compared "the pooled mean of all compounds from the ASD cohort to the pooled mean for all compounds in the control cohort" they similarly noted no significant difference. At this point you're probably thinking that this isn't particularly interesting data. Well, just hold it there...

Researchers further examined whether there was something to see when comparing the mean xenobiotic body-burden (MXB) and those ADOS scores. Xenobiotic by the way, is another way of saying (foreign) compounds that were being assayed for, and combined with ADOS scores was a way of looking at whether behavioural severity might show some link to the concentrations of those compounds being reported on. In this respect: "Pooled serum-concentration correlated significantly with increasing behavioral severity on the ADOS in the ASD cohort... but not controls." The authors go on to say that such findings and others are "a fundamental expectation from the hypothesis of genetic predisposition for susceptibility to environmental triggers."

Some other points are raised in the Boggess paper not least those connected to the various biological mechanisms designed to metabolise such compounds and where they may fit with regards to some autism. Personally, I think this is where the money is eventually going to be; with further work required on processes linked to glutathione (see here) and more specific genetic-biological issues (e.g. PON1 [3]) potentially showing how genetic fragility and non-genetic factors might combine specifically when it comes to getting rid of various pollutants from the body.

There are methodological issues with the Boggess paper that do need to be mentioned not least the small participant group and the reliance on one blood sample showing a snapshot of current biology (combined with a snapshot of current behaviour). This last point in particular tells us little about any historical issues and whether there are important time-frames where environmental exposures might exert a more significant effect and the impact of any genetic issues. But, in the context of other research talking about environmental factors potentially being linked to autism (see here for example) it would be unwise to rule anything out just yet...

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[1] Boggess A. et al. Mean serum-level of common organic pollutants is predictive of behavioral severity in children with autism spectrum disorders. Sci Rep. 2016 May 13;6:26185.

[2] Vijayakumar NT. & Judy MV. Autism spectrum disorders: Integration of the genome, transcriptome and the environment. Journal of the Neurological Sciences. 2016; 364: 167-176.

[3] Gaita L. et al. Decreased serum arylesterase activity in autism spectrum disorders. Psychiatry Res. 2010 Dec 30;180(2-3):105-13.

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Boggess A, Faber S, Kern J, & Kingston HM (2016). Mean serum-level of common organic pollutants is predictive of behavioral severity in children with autism spectrum disorders. Scientific reports, 6 PMID: 27174041

Prenatal air pollution and autistic traits NOT linked (in Europe)

"Prenatal exposure to NO2 [nitrogen oxide] and PM [particulate matter] was not associated with autistic traits in children from four to ten years of age in four European population-based birth/child cohort studies."

That was the conclusion reached in the study published by Mònica Guxens and colleagues [1] (open-access available here) crossing various European population-based cohorts as part of the "European Study of Cohorts for Air Pollution Effects (ESCAPE)" and looking at some 8,000 children in total. Outside of the grand study design and large participant number included in the Guxens study, I wanted to talk about this study to provide a little balance to the previous discussions on this blog about autism and air pollution which seemed to be coming to rather different conclusions (see here and see here for example).

The Guxens paper is open-access but here are a few pointers:

• First, take three population-based birth cohorts (GENERATION R, GASPII & INMA) and one "European longitudinal child and adolescent twin study: CATSS". 
• Follow a well-trodden path of estimating air pollution exposure based on birth home addresses and looking at air pollution levels "in the study areas" and "estimate annual average air pollution concentration at the participants’ birth home addresses."
• Next, assess your cohort(s) for the presence of autistic traits (not actual diagnoses) using various instruments (though not necessarily the same instrument for every country included for study). Control for possible confounders including urbanicity and various maternal characteristics including those during birth and apply statistics.
• Results: anywhere between 3-12% of children studied showed "autistic traits within the borderline/clinical range." Further: "between 0.7% and 3.6% were classified as having autistic traits within the clinical range." These were mostly boys and "had a higher proportion of mothers with low educational level and mothers who smoked during pregnancy compared to children without autistic traits."
• "We found no evidence for an association between prenatal air pollution exposure and autistic traits in children aged 4 to 10 years." Further: "These results were consistent for all air pollutants assessed, across countries, using different cut-offs of autistic traits, examining autistic traits as continuous variables, and after adjusting for several socioeconomic status variables and urbanicity."

Guxens et al note how their results are in direct contrast to the some of the previous and emerging research [2] in this area, citing some important references along the way. They explain this in a few ways including noting how: "previous case-control studies selected children with a diagnosis of ASD [autism spectrum disorder] whereas in our study we studied children with autistic traits from population-based birth/child cohorts." Further: "We hypothesize that prenatal exposure to air pollution could be related to ASD but not with broad autistic traits in children" but based on their data "found no indication of an association between prenatal air pollution exposure and autistic traits within the clinical range."

The idea that: "Further research including trace metal content of the PM such as lead or manganese is warranted to better understand the discrepant findings" is also banded about and I'm in agreement with them on this matter [3] given some of the previous findings on the metallome and autism (see here). Lead (Pb) and its health effects by the way, is also something that I've been interested in down the years of blogging (see here).

Without trying to turn null findings into positive findings, I'm also minded to bring another variable to the table that might be worth re-analysing for based on the findings from Heather Volk and colleagues [3] (one of the co-authors on the Guxens paper) who talked about gene x environment interactions when it comes to the possibility of a link between risk of autism and prenatal air pollution exposure (covered in a previous blog post). I say this bearing in mind that studying MET genotype on its own and without reference to the multitude of genetic and epigenetic factors that may also be involved, is but a drop in the scientific ocean; but at least it would be a start.

I end however with the statement that: "this study showed a null association between prenatal exposure to several air pollutants, including NO2 and PM, and autistic traits in children aged 4 to 10 years in four European population-based birth/child cohorts." Once again, autism research comes up with conflicting findings...

Music: AC/DC - Highway to Hell.

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[1] Guxens M. et al. Air Pollution Exposure during Pregnancy and Childhood Autistic Traits in Four European Population-Based Cohort Studies: The ESCAPE Project. Environ Health Perspect. 2015 Jun 12.

[2] Talbott EO. et al. Fine particulate matter and the risk of autism spectrum disorder. Environmental Research. 2015; 140: 414-420.

[3] Sanders AP. et al. Perinatal and Childhood Exposure to Cadmium, Manganese, and Metal Mixtures and Effects on Cognition and Behavior: A Review of Recent Literature. Current Environmental Health Reports. 2015. July 5.

[4] Volk HE. et al. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiology. 2014 Jan;25(1):44-7.

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Guxens M, Ghassabian A, Gong T, Garcia-Esteban R, Porta D, Giorgis-Allemand L, Almqvist C, Aranbarri A, Beelen R, Badaloni C, Cesaroni G, de Nazelle A, Estarlich M, Forastiere F, Forns J, Gehring U, Ibarluzea J, Jaddoe VW, Korek M, Lichtenstein P, Nieuwenhuijsen MJ, Rebagliato M, Slama R, Tiemeier H, Verhulst FC, Volk HE, Pershagen G, Brunekreef B, & Sunyer J (2015). Air Pollution Exposure during Pregnancy and Childhood Autistic Traits in Four European Population-Based Cohort Studies: The ESCAPE Project. Environmental health perspectives PMID: 26068947

Maternal smoking during pregnancy and offspring autism: no measurable association but...

Oh. Yes sir. How doth the little
bumblebee improve each...

"We found no evidence to support a measurable association between maternal prenatal smoking and ASD [autism spectrum disorder] in offspring."

That was the conclusion reached in the meta-analysis published by Brittany Rosen and colleagues [1] looking at the collected peer-review literature examining any correlation between maternal tobacco smoking during pregnancy and risk of offspring receipt of a diagnosis of autism or ASD. Based on a review of 15 studies in this area, researchers concluded that there was very little to see when it came to any association: "summary OR [odds ratio] 1.02, 95 % CI [confidence intervals] 0.93–1.12".

I think most people nowadays have probably seen or heard of the messages about the potential dangers of smoking during pregnancy and the benefits of abstaining/quitting to both mother and unborn child. That's not to say however that every mum-to-be has understood the risks as per the findings from Cnattingius [2]. Indeed without being judgemental, even at rare visits to my own local hospital, I have seen heavily pregnant women puffing away outside the maternity unit and can't help wondering why, particularly when so many alternatives or quitting aids (with caveats) are available these days.

Insofar as the various investigations into smoking with offspring autism in mind, there is quite a bank of research in this area. That's not to say that the evidence is all one-way when it comes to smoking during pregnancy and offspring risk of autism as per studies like the one from Phuong Lien Tran and colleagues [3] (open-access) who concluded that smoking during the whole of pregnancy might have a modest impact on autism risk, at least in Finland. The findings reported by Visser and colleagues [4] on smoking during pregnancy appearing to "contribute more to broadly defined (PDD-NOS) than to narrowly defined ASD (AD)" are also worthwhile including in these days of phenotypes and plural autisms. Indeed, the report from Amy Kalkbrenner and colleagues [5] (open-access) continues the theme: "The possibility of an association with a higher-functioning ASD subgroup was suggested, and warrants further study."

On the basis of these studies and others [6], I'd be minded to suggest that whilst the Rosen findings are reassuring for the more general concept of risk (i.e. autism overall) the message about quitting smoking before and during pregnancy as potentially affecting offspring autism risk, is not yet settled when it comes to specific types of autism or specific places on the autism spectrum being implicated. I say this not to add to any further burden about this or that 'causing autism' as per examinations on things like maternal infection during pregnancy (see here) or C-sections (see here) or maternal diabetes (see here) for example, but rather using science as a potential informer in raising awareness of this possible outcome. Indeed, if one is to assume that the [preliminary] evidence on air pollution and genetics mixing might also impact on autism risk (see here), the question of whether direct inhalation of several thousand pollutants can impact on foetal outcomes becomes rather more compelling including whether risk of certain comorbidity appearing alongside autism might also be influenced [7].

Oh, and father's tobacco habits might also be important [8]...

Music, and something quiet from Henry Rollins (not)...

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[1] Rosen BN. et al. Maternal Smoking and Autism Spectrum Disorder: A Meta-analysis. Journal of Autism and Developmental Disorders. 2014. November 29.

[2] Cnattingius S. The epidemiology of smoking during pregnancy: smoking prevalence, maternal characteristics, and pregnancy outcomes. Nicotine Tob Res. 2004 Apr;6 Suppl 2:S125-40.

[3] Tran PL. et al. Smoking during pregnancy and risk of autism spectrum disorder in a Finnish National Birth Cohort. Paediatr Perinat Epidemiol. 2013 May;27(3):266-74.

[4] Visser JC. et al. Narrowly versus broadly defined autism spectrum disorders: differences in pre- and perinatal risk factors. J Autism Dev Disord. 2013 Jul;43(7):1505-16.

[5] 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. Environ Health Perspect. 2012 Jul;120(7):1042-8.

[6] Habek D. & Kovačević M. Adverse pregnancy outcomes and long-term morbidity after early fetal hypokinesia in maternal smoking pregnancies. Arch Gynecol Obstet. 2011 Mar;283(3):491-5.

[7] Kovess V. et al. Maternal smoking and offspring inattention and hyperactivity: results from a cross-national European survey. Eur Child Adolesc Psychiatry. 2014 Nov 21.

[8] Laubenthal J. et al. Cigarette smoke-induced transgenerational alterations in genome stability in cord blood of human F1 offspring. FASEB J. 2012 Oct;26(10):3946-56.

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Rosen BN, Lee BK, Lee NL, Yang Y, & Burstyn I (2014). Maternal Smoking and Autism Spectrum Disorder: A Meta-analysis. Journal of autism and developmental disorders PMID: 25432101

Yet more air pollution and autism risk research

Air pollution and autism risk. It's a topic which has cropped up a few times on this blog (see here and see here and see here) with the majority of the research (but not all) suggesting that there may be something to see when it comes to such a correlation.

Enter then the paper by Amy Kalkbrenner and colleagues [1] to proceedings, and their conclusion: "Our study adds to previous work in California showing a relation between traffic-related air pollution and autism, and adds similar findings in an eastern US state, with results consistent with increased susceptibility in the third-trimester". I might add that Dr Kalkbrenner has some research form when it comes to looking at environment and autism and has appeared on this blog before (see here).

Based on two datasets covering the east and west coasts of the United States (North Carolina and "the San Francisco Bay Area in California") including nearly 1000 children diagnosed with an autism spectrum disorder (ASD) and some 14,000 asymptomatic controls, researchers compared estimated exposure patterns based on birth addresses. Specifically, they looked at exposure to particulates "less than 10 μm (PM10)" within a period starting from preconception through to the child's first birthday. They also took into account a whole slew of geographic and demographic variables which potentially may have influenced results. They reported odds ratios (ORs) - adjusted ORs - which seemed to indicate that exposure, "a 10 μg/m increase in PM10", particularly during the third trimester of pregnancy was associated with increased susceptibility to autism. Ergo, more evidence for a potential link between prenatal air pollution exposure and offspring autism risk.

If I'm reading the Kalkbrenner paper correctly however, PM10 exposure during the first and second trimesters of pregnancy was not associated with autism. Indeed for the first trimester at least (bearing in mind the confidence intervals) the adjusted OR was "0.86 (95% CI = 0.74-0.99)" which I'll leave to readers to decide whether it was important or not.

There's little more for me to say about this area of autism research aside from the usual caveats applying regarding the use of estimated exposure patterns over and above actual individual exposure levels and the further requirement to elaborate on any mechanism potentially pertinent aside from any general description such as a role for oxidative stress or inflammatory markers [2]. I say this acknowledging the preliminary observations made about genotype, air pollution and autism risk [3] which still require independent follow-up.

In light of the my recent discussions on asthma being a potential risk factor for autism (see here) and further research on atopy and autism [4] which I'll be blogging about soon, one wonders whether other manifestations of air pollution exposure might also play some role in such findings. That combined with the more general developmental effects thought to be had as a result of air pollution exposure [5], and the whole thing starts to get rather complicated and in need of much greater scrutiny...

Music then and at the risk of [musically] repeating myself: Alice Cooper and No More Mr Nice Guy...

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[1] Kalkbrenner AE. et al. Particulate Matter Exposure, Prenatal and Postnatal Windows of Susceptibility, and Autism Spectrum Disorders. Epidemiology. 2014 Oct 3.

[2] Volk HE. et al. Residential proximity to freeways and autism in the CHARGE study. Environ Health Perspect. 2011 Jun;119(6):873-7.

[3] Volk HE. et al. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiology. 2014 Jan;25(1):44-7.

[4] Chen MH. et al. Is atopy in early childhood a risk factor for ADHD and ASD? A longitudinal study. J Psychosom Res. 2014 Oct;77(4):316-21.

[5] Calderón-Garcidueñas L. et al. Air pollution and detrimental effects on children's brain. The need for a multidisciplinary approach to the issue complexity and challenges. Front Hum Neurosci. 2014 Aug 12;8:613.

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Kalkbrenner AE, Windham GC, Serre ML, Akita Y, Wang X, Hoffman K, Thayer BP, & Daniels JL (2014). Particulate Matter Exposure, Prenatal and Postnatal Windows of Susceptibility, and Autism Spectrum Disorders. Epidemiology (Cambridge, Mass.) PMID: 25286049

Temporal trends in US autism prevalence: mainly real increase

"Diagnosed autism prevalence has risen dramatically in the U.S over the last several decades 
and continued to trend upward as of birth year 2005. The increase is mainly real and has occurred mostly since the late 1980s".

"They call me Cha Cha because I'm the
best dancer at St. Bernadette's"

That was the conclusion reached in the paper by Cynthia Nevison [1] (open-access) following her analysis of temporal trends in autism diagnosis for birth years between 1970 and 2005. Based on an analysis of datasets derived from IDEA (Individuals with Disabilities Education Act) and the CDDS (California Department of Developmental Services), the author suggested that between 75-80% "of the tracked increase in autism since 1988 is due to an actual increase in the disorder rather than to changing diagnostic criteria". The question of what environmental factors might have been driving such an increase in cases is also discussed in the Nevison paper, with the author concluding "children’s exposure to most of the top ten toxic compounds has remained flat or decreased over this same time frame". That top 10 list by the way, seems to come at least partly from the Landrigan paper talked about a couple of years back (see here).

There is quite a bit of information included in the Nevison paper which I'm reluctant to write a mega-blog entry on at this time. This includes various caveats about the use of IDEA and CDDS databases and their constraints on for example, what ASDs (autism spectrum disorders) are included in the datasets. I will however summarise some of the main findings in relation to the environmental factors probed by the author bearing in mind that autism research does not appear to be her main area of scientific interest (with all due respect).

So:

• Air pollution... something which has cropped up with ever-increasing frequency in the peer-reviewed research on autism (see here and see here for example). Nevison concludes: "there is no obvious evidence to suggest that trends in estimated vehicular emissions or directly measured air pollution are consistent with the sharp temporal increase in U.S. autism". So no smoking tailpipe (exhaust) there then as per other recent research findings [2].
• Mercury in vaccines... a topic guaranteed to furrow brows and raise blood pressure in some quarters (see here and see here for example). Nevison discusses the phaseout of thimerosal (thiomersal) from paediatric vaccines used in the US concluding that "the expansion of thimerosal exposure in the late 1980s and early 1990s coincides closely with the rise in autism around that time". But... "the temporal trends in autism and thimerosal following the childhood vaccine thimerosal phaseout are incompatible". Other sources of mercury exposure get a similarly 'unlikely' mark from Nevison.
• Organophosphate (OP) pesticide exposure... an interesting area which again has been covered previously on this blog (see here and see here). Nevison points out the declining use of such pesticides in the US following "the adoption of crops genetically modified to produce Bt toxin, which repels targeted insect pests, thus reducing the need for external insecticides". Recognising that pesticides are not to be trifled with (see here) I've always been a little confused about the mechanism(s) through which OP exposure could theoretically impact on the presentation of autism. I know people have talked about PON1 and autism [3] (some autism) but I do feel as though the primary effect of OPs - acting on acetlycholinesterase -  is something in need of a lot more research with autism in mind before anyone gets too carried away. 
• There is however a caveat to the pesticides-autism conclusion by the author following some mention of "the rapidly increasing application of glyphosate, the active ingredient in the herbicide Roundup®". She continues: "it appears that glyphosate cannot be responsible for the first autism cases in the 1930s and is unlikely to have caused the late 1980s uptick, but could be interacting in recent years with other toxins to drive up the prevalence of U.S. autism". Depending on where you look, you'll get various different messages about the pros and cons of glyphosate. I remember reading a report a few years back (see here) authored by one of the researchers involved in that 'organic food might be better for you' paper recently (see here) which painted a rather disturbing picture of the product. For balance, I'm going to also refer you to the various documents provided by Monsanto (the producer of Roundup) for their response to safety concerns. When it comes to a search of PubMed with the terms 'autism and glyphosate' the current result is zero although it has been mentioned elsewhere in the peer-reviewed domain [4]. 
• Maternal obesity... I'm being quite careful here accepting the previous discussions in this area of autism research (see here). Nevison reports that: "the time trend in obesity among U.S. women correlates well to that of autism, suggesting maternal obesity may be a direct influence or a comorbid consequence of the dietary factors contributing to autism, or both". 

One needs to bear in mind that the United States was the focus on these findings and as such the conclusions may not pertain to other parts of the globe. I probably don't need to say it but one should also bear in mind the saying 'correlation is not the same as causation' too. There are also other issues which have been discounted by Nevison as being related to the autism prevalence. Lead (Pb) is one of them; something which I personally would not be so keen to disregard given the more recent evidence on even trace amounts of this stuff not being great for the developing child (see here). This on top of what has been talked about with autism in mind (see here). 

I have a few other points to make which were perhaps not readily implied in the Nevison paper: first is the assumption that autism is some kind of universal condition. What I think many people have come to realise over the past few years is that within the significant behavioural and developmental heterogeneity grouped under the label autism, also compounded by the increased frequency of various comorbid conditions, a more plural description - the autisms - might be more pertinent. What this implies is that different weightings for concepts like genetics or environment (or epigenetics!) are likely acting across risk of different types of autism. 

Second, and related to point one, is the concept of synergy across different 'causative' factors. In the same way that autism science has started to accept that there is no one gene linked to all cases of autism, so environmental examinations can't really expect there to be one environmental factor working alone pertinent to all autism. If one is to assume that various environmental factors (see here and see here for example) may be linked to autism onset, it is more likely that combinations of factors are playing a role or possibly specific environmental factors acting on specific types of autism. Take for example the early work on air pollution and genotype being potentially associated with autism risk [5] as one example.

At the risk of being too speculative, I'm also minded to bring to your attention an emerging idea which might also be relevant: transgenerational epigenetics. The idea is that what happened in previous generations might have an influence on subsequent generations without structurally altering DNA in terms of the physical language of the genome. There has been some media interest in this concept in recent times (see here). With autism in mind, we've seen hints of this idea in the peer-reviewed research literature as per discussions on how advancing grandparental age might be linked to an increased risk of autism (see here). Jill Escher also talked about past chemical exposures potentially impacting on "vulnerable fetal germline epigenetics" (see here for her presentation). The implication being that correlating current exposure patterns with current autism diagnosis prevalence might not necessarily be the best way of looking at whether (and which) environmental factors might have a bearing on autism prevalence...

The primary message from the Nevison report is that the numbers of cases of autism do appear to be on the rise in the United States, and as per other reports from geographical neighbours (see here) the debates are not yet over about the reasons for that increase. Something another study has also talked about recently [6]...

So then, Only Love Can Break Your Heart by Saint Etienne.

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[1] Nevison CD. A comparison of temporal trends in United States autism prevalence to trends in suspected environmental factors. Environmental Health 2014, 13:73

[2] Gong T. et al. Exposure to Air Pollution From Traffic and Neurodevelopmental Disorders in Swedish Twins. Twin Res Hum Genet. 2014 Sep 17:1-10.

[3] D'Amelio M. et al. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Mol Psychiatry. 2005 Nov;10(11):1006-16.

[4] Seneff S. et al. Is Encephalopathy a Mechanism to Renew Sulfate in Autism? Entropy 2013. 15; 372-406.

[5] Volk HE. et al. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiology. 2014 Jan;25(1):44-7.

[6] Dave DM. & Fernandez JM. Rising autism prevalence: real or displacing other mental disorders? Evidence from demand for auxiliary healthcare workers in California. Economic Inquiry. 2014. 25 August.

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Nevison, C. (2014). A comparison of temporal trends in United States autism prevalence to trends in suspected environmental factors Environmental Health, 13 (1) DOI: 10.1186/1476-069X-13-73

Autism and asthma yet again

"Asthma is approximately 35 % more common in autistic children".

Pipe down @ Wikipedia 

That was the finding reported by Stanley Kotey and colleagues [1] based on their analysis of the 2007 National Survey of Children's Health (NSCH) dataset, a resource looking at "the physical and emotional health of children ages 0-17 years of age" resident in the United States. I don't intend to dwell too much on the Kotey findings aside from pointing out: (a) the reported prevalence of autism came in at 1.8% which is not a million miles away from the latest US estimate made by the CDC and, (b) although the unadjusted odds ratio (OR) for asthma in cases of autism was 1.35 (CI: 1.18-1.55), the adjusted OR taking into account factors such as "age, gender, body mass index, race, brain injury, secondhand smoke and socio-economic status" dropped down to 1.19... so perhaps it was more accurate to conclude that asthma is approximately 20% more common in kids with autism. Oh and that OR and relative risk might not necessarily be one and the same [2].

The NSCH is a valuable resource which provides snapshots for lots of different aspects of child health and wellbeing (see here). A quick trawl of the sections pertinent to an autism and/or asthma diagnosis (see section 2 here) reveals how information about diagnosis is arrived at. I was taken by the fact that questioning about an autism spectrum disorder (ASD) diagnosis was "applicable for ages 2-17 years only" which perhaps ties into some of the issues raised in other papers when it comes to early diagnosis.

Asthma and autism is a topic not totally unfamiliar to this blog (see here). The quite recent paper from Tsai and colleagues [3] covered in a previous post (see here) detailing how asthma might be a risk factor for autism puts the Kotey findings into some potential context albeit not necessarily with the same directional association. The paper from Chen and colleagues [4] likewise also discussed in another post (see here) also implicates comorbidity (ADHD in that case) as a potential confounding variable bearing in mind the estimated rates of ADHD in cases of autism (see here).

When it comes to the hows and whys of any relationship between asthma and autism, a rather large void starts to appear outside of any link just being due to coincidence [5]. "[The] Autism-secondhand smoke interaction was insignificant" kinda suggests that tobacco smoke filled houses and cars were probably not a primary reason for any connection. Given what is known about asthma - a chronic lung condition characterised by inflammation of the airways - one might look to something like immune function as being a commonality between the conditions especially in light of recent meta-analyses with autism in mind. A couple of years back I did a sort of focus on some of the work from Kevin Becker (see here) including his paper on the hygiene hypothesis [6] (open-access here). I'm not necessarily saying that this is the primary connector, merely that the interaction between immune functions and environment might have some role to play. I might add that all the recent chatter on air pollution and autism (see here and see here and most recently here) might also be something to look at with further assiduity. Oh, and one might also think about certain medicines as perhaps being important to this relationship too (see here).

I would close with a last sentence from Kotey et al: "screening may be an efficient approach to reduce risk of morbidity due to asthma". In other words, asthma is yet another comorbidity for which a diagnosis of autism seemingly carries no protection, and the onus is on professionals to reduce any further health inequality...

So: Ben E King and Stand By Me. "Chopper! Sic'em, boy!"

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[1] Kotey S. et al. Co-occurrence of Autism and Asthma in a Nationally-Representative Sample of Children in the United States. J Autism Dev Disord. 2014 Jul 6.

[2] Davies HT. et al. When can odds ratios mislead? BMJ. 1998 Mar 28;316(7136):989-91.

[3] Tsai PH. et al. Increased risk of autism spectrum disorder among early life asthma patients: An 8-year nationwide population-based prospective study. Research in Autism Spectrum Disorders. 2014; 8: 381-386.

[4] Chen MH. et al. Asthma and attention-deficit/hyperactivity disorder: a nationwide population-based prospective cohort study. J Child Psychol Psychiatry. 2013 Nov;54(11):1208-14.

[5] Mrozek-Budzyn D. et al. The frequency and risk factors of allergy and asthma in children with autism--case-control study. Przegl Epidemiol. 2013;67(4):675-9, 761-4.

[6] Becker KG. Autism, asthma, inflammation, and the hygiene hypothesis. Med Hypotheses. 2007;69(4):731-40.

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Kotey, S., Ertel, K., & Whitcomb, B. (2014). Co-occurrence of Autism and Asthma in a Nationally-Representative Sample of Children in the United States Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-014-2174-y