ALSPAC does... prenatal mercury exposure and autism or autistic traits

The ALSPAC - Avon Longitudinal Study of Parents and Children - mentioned in the title of this post is something of quite a regular feature on this blog (see here and see here for examples).

On this particular blogging occasion I'm heading into the findings reported by Jean Golding and colleagues [1] who utilised this fabulous research resource to examine whether "prenatal exposure from total maternal blood Hg [mercury] in the first half of pregnancy is associated with the risk of autism or of extreme levels of autistic traits." They concluded that there were "no adverse effect of prenatal total blood Hg on autism or autistic traits provided the mother ate fish."

OK, mention of the heavy metal mercury in the context of autism and/or autistic traits can be a touchy subject for some. I'm talking about the various 'discussions' that have taken place both in the lay and peer-reviewed science arenas concerned with the exposure patterns relevant to mercury in the context of autism (see here and see here). This, on the basis that mercury exists in several 'forms', and those different forms have different potential exposure routes.

Golding et al relied on some of the gold-standard analytical methods for the analysis of whole blood Hg collected in the most part "at < 18 weeks gestation": "inductively coupled plasma dynamic reaction cell mass spectrometry (ICP-DRC-MS)." Variations on this method - ICP mass spectrometry - have been previously reported on in the context of mercury and autism research (see here and see here). Alongside, they looked at measured levels of mercury in relation to various behavioural and other variable groupings: "(1) direct comparison of 45 pregnancies resulting in children with diagnosed autism from a population of 3840, (2) comparison of high scores on each of the four autistic traits within the population at risk (n~2800), and (3) indirect measures of association of these outcomes with proxies for increased Hg levels such as frequency of fish consumption and exposure to dental amalgam (n > 8000)." They however cautioned that: "Although we accounted for several important confounders which are relevant to Hg levels and autism, the possibility of unmeasured confounding cannot be ruled out." I can think of one potential confounder that was not seemingly included in their list outside of fish consumption and dental amalgams but ho-hum...

Alongside their overall 'no relationship' results, a few other details are noteworthy. First: "all correlations indicated that with increasing levels of [maternal] mercury, the signs of autism [in offspring] were slightly less, but none were statistically significant." Interesting idea - higher maternal levels of mercury during pregnancy 'correlates' with 'less' autistic traits in offspring in childhood - but to reiterate, not statistically significant. Second was that 'provided the mother ate fish' detail attached to the main findings. So: "we have shown a differential relationship between the social cognition trait and prenatal Hg exposure, such that there was a significant difference in apparently protective effects contingent upon whether the mother ate fish." The authors opine as to what it is about fish consumption that might "counteract any possible adverse cognitive and behavioral differences that may be caused by prenatal exposure to Hg" including "the beneficial components of fish such as the omega-3 fatty acids, iodine, and vitamins D and B2." This in the context that omega-3 fatty acids have some research form in relation to autism (see here) as does the sunshine vitamin/hormone that is vitamin D (see here).

One has to be slightly careful with the Golding results given the focus on prenatal exposure, and prenatal exposure at only one early point in pregnancy, as well as also not actually looking at mercury levels in the children themselves. The current results say nothing for example, about any possible direct or acquired role for mercury in relation to autism as per other findings published during the same period [2]. Neither do they offer any additional information on the idea that exposure issues to such heavy metals may be only one part of the story, and that the biological processes involved in removing such heavy metals may be somehow perturbed in relation to some autism (see here).

But... set within the idea that prenatal mercury exposure may be linked to the 'etiology' of at least some autism, the Golding findings represent pretty strong evidence suggestive of no connection.

Music to close, and could I recommend the soundtrack to Sonic 3 while you work?

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[1] Golding J. et al. Prenatal mercury exposure and features of autism: a prospective population study. Molecular Autism. 2018; 9: 30.

[2] Qin YY. et al. A comparison of blood metal levels in autism spectrum disorder and unaffected children in Shenzhen of China and factors involved in bioaccumulation of metals. Environ Sci Pollut Res Int. 2018 Apr 22.

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Mercury levels and autism meta-analysed

"Indeed, if someone is looking for yet another systematic review and meta-analysis topic, there you go - you're welcome." Those are my words on a previous blogging occasion earlier this year discussing yet another peer-reviewed article on the topic of heavy metals and autism (see here). The findings reported by Tina Jafari and colleagues [1] have seemingly done just that with their meta-analysis of the collected science literature up to June 2017 looking at assessing the "relationship between ASD [autism spectrum disorder] and mercury levels in hair, urine, blood, red blood cells (RBC), and brain."

OK, I know that mention of mercury in the context of autism can be a bit of hot potato in terms of the different types of mercury and their potential sources (see here). I don't want to get into any specific debates on wheres-and-hows in this post but rather focus on what the peer-reviewed science currently says (see here). Jafari et al describe how from the 40+ articles they included for analysis, several themes emerged: (1) blood and brain levels of mercury seemed to be generally elevated in cases of autism vs. controls, and (2) hair levels were typically lower in autism vs controls. Urinary mercury levels were described as "not significantly different" comparing autistic and non-autistic groups although I'll draw your attention to some 'technical talk' in this area that could potentially affect any results produced (see here).

The authors go on to talk about how "detoxification and excretory mechanisms are impaired in ASD patients which lead to accumulation of mercury in the body" which - minus sweeping generalisations - is a conclusion that I've pretty much settled on when talking about some of the findings in this area down the years. There are likely many mechanisms involved in the removal of heavy metals such as mercury from the body but one group in particular, the intersecting "redox and methylation" pathways [2] stand out in view of other research on glutathione levels and autism for example (see here). Other research has pointed to other biological mechanisms that may be worth research consideration [3].

What can and should be done in this area? Well minus any medical or clinical advice given or intended, there are protocols in place as and when mercury poisoning is diagnosed in the general population. There is no reason to assume that these same protocols shouldn't be followed if and when mercury poisoning is diagnosed alongside autism or ASD save any further health inequalities appearing. Autism science needs to also continue it's interest in this area and perhaps make move towards what can be done for example, to 'prop up' biological mechanisms that aid in the detoxification of things like mercury. This may take the form of some rather peculiar research directions (see here) but nonetheless is an area that could potentially be important. Finally, there is the idea that if there are biological issues associated with the removal of several heavy metals including mercury in cases of autism, greater focus on 'avoidance' might also be important. I say this on the basis of findings such as those by Jia Ryu and colleagues [4] who for example, observed that "blood mercury levels at late pregnancy and early childhood were associated with more autistic behaviors in children at 5 years of age." Yes, correlation is not the same as causation, but can we/should we take the chance that the two are connected particularly knowing how detrimental heavy metals can be to human health?

Music to close: Ain't That A Shame by Fats. RIP.

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[1] Jafari T. et al. The association between mercury levels and autism spectrum disorders: A systematic review and meta-analysis. J Trace Elem Med Biol. 2017 Dec;44:289-297.

[2] Hodgson NW. et al. Decreased glutathione and elevated hair mercury levels are associated with nutritional deficiency-based autism in Oman. Exp Biol Med (Maywood). 2014 Jun;239(6):697-706.

[3] Gump BB. et al. Background lead and mercury exposures: Psychological and behavioral problems in children. Environmental Research. 2017; 158: 576-582.

[4] Ryu J. et al. Associations of prenatal and early childhood mercury exposure with autistic behaviors at 5 years of age: The Mothers and Children's Environmental Health (MOCEH) study. Science of The Total Environment. 2017; 605-606: 251-257.

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Mercury and autism: where the science currently stands

Yes, I know that on the 'hot potato' scale, to talk about mercury and autism still moves the needle up to somewhere approaching furnace level for some people despite discussions on this heavy metal still figuring in several quarters. This is however a blog based on peer-reviewed science (for the most part) and so with mucho, mucho caveats included I want to draw your attention to the review paper by Janet Kern and colleagues [1] (open-access available here) and the observation that: "The preponderance of the evidence indicates that mercury exposure is causal and/or contributory in ASD [autism spectrum disorder]." I might add that this authorship group are no strangers to this particular topic (see here).

As per the 'review' heading accompanying the Kern paper, this was an analysis (inventory) of the up-to-date - "1999 to February 2016" - peer-reviewed studies done around the topic of mercury and autism. The authors present the data based on tissue type, ASD vs. not-ASD and various other parameters detailing the back-and-forth of relationship and no relationship that seems to percolate through the autism research scene. They conclude that "the vast majority (74%) of those studies suggest that mercury is a risk factor for ASD" and that any effect is likely to consist of "both direct and indirect effects of mercury exposure." This direct and indirect effects explanation is accompanied by a graphic highlighting the many and varied ways that mercury exposure might be linked to cases of autism. They also direct readers to a similar paper on this topic [2] that "also found that 74% of studies support a link between mercury exposure and ASD."

Without courting controversy as to the sources of and relative role that mercury might have on cases of autism I was drawn to a particular conclusion made by the authors that "children with ASD are more susceptible to mercury than typically developing children." I've seen and blogged about enough autism research down the years to understand that for some people on the autism spectrum, behavioural 'symptoms' can be accompanied by various genetic and biological 'issues' linked to the handling of various toxicants and other environmental agents. I'm not yet convinced with the argument that universally people diagnosed with autism are somehow preferentially exposed to greater levels of mercury than the rest of the population but I am warming to the idea that their 'handling' of such a heavy metal (and others) might to some extent be 'impaired' and that this could have some impact on body burden levels as well as clinical presentation.

Obviously, more research is implied.

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[1] Kern JK. et al. The relationship between mercury and autism: A comprehensive review and discussion. J Trace Elem Med Biol. 2016 Sep;37:8-24.

[2] Desoto MC. & Hitlan RT. Sorting out the spinning of autism: heavy metals and the question of incidence. Acta Neurobiol Exp (Wars). 2010;70(2):165-76.

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Kern JK, Geier DA, Sykes LK, Haley BE, & Geier MR (2016). The relationship between mercury and autism: A comprehensive review and discussion. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS), 37, 8-24 PMID: 27473827

Autism, urinary porphyrins and mercury

I appreciate that the title of this post is probably going to result in an immediate 'click away' for some folk but for those who've endured it I'd like to talk briefly about the findings reported by Eman Khaled and colleagues [1]. Namely the observation that: "ASD [autism spectrum disorder] children in the present study had increased blood Hg [mercury] and Pb [lead] levels compared with healthy control children indicating that disordered porphyrin metabolism might interfere with the pathology associated with the autistic neurologic phenotype."

OK, language and terminology first. I don't like the use of the term 'healthy control children' set in the context of autism research it has to be said. Whilst the label of autism does indeed place someone at a significantly greater risk of various health-related complaints (see here), the connotation that someone with autism is 'unhealthy' solely as a function of their autism label is not universally borne out by the research data. Why not therefore just call controls 'control children' eh?

Next up, porphyrins in the context of autism have been covered before on this blog (see here). Although linked to processes such as heme synthesis, there have been suggestions that analysis of urinary porphyrins might also provide some important information on "renal mercury content" [2]. Mercury (Hg) has been a hot potato in the context of autism for quite a few years (see here) and discussions on this topic have sometimes turned pretty nasty (see here). The sweeping idea that all autism is 'caused' by mercury poisoning (and there are various types of the stuff) has not been supported by the peer-reviewed literature on this topic (see here) but there have been some important outliers detected (see here) potentially indicative of some role for at least some on the autism spectrum. As for lead (Pb), well let's just say that few people have anything good to say about lead exposure, particularly when it comes to childhood lead exposure (see here) and with autism in mind, the label seemingly does not guarantee lead safety (see here).

So, Khaled et al went about looking at levels of various urinary porphyrins as a function of both diagnostic status (autism, controls, siblings of autism participants) and also Hg and Pb load. They found that: "children with ASD had significantly higher levels of Hg, Pb, and the porphyrins pentacarboxyporphyrin, coproporphyrin, precoproporphyrin, uroporphyrins, and hexacarboxyporphyrin compared to healthy controls and healthy siblings of the ASD children." Again, sorry for the 'healthy' bit (these are the authors' words and not mine). They also observed that: "Mothers of ASD children showed a higher percentage of dental amalgam restorations compared to the mothers of healthy controls suggesting that high Hg levels in children with ASD may relate to the increased exposure to Hg from maternal dental amalgam during pregnancy and lactation."

This work is by no means flawless. I could go on about the preferred method of analysis - "high-performance liquid chromatography (HPLC)" - used to separate/detect urinary porphyrins (with fluorescence detection as per other research by authors on this paper [3]) as not exactly being the gold-standard for example. I might also quibble about the idea that 'dental amalgam restoration' rates are no replacement for actually measuring circulating levels of maternal mercury either (bearing in mind this would need to be done in archived samples too). There are holes in this work, of that there is no doubt.

But... it is a rather uncomfortable observation that time and time again, some children diagnosed with autism seem to be in possession of a somewhat higher than expected body burden of mercury, or at least testing positive for such a burden. Science has yet to fully understand the hows and whys of such findings for at least a group of people diagnosed with autism and what might be done to reduce any biological load and its various impacts on biological systems. Whether as Khaled and colleagues observe "a significant positive correlation between the levels of coproporphyrin and precoproporphyrin and autism severity" stands up to further independent scientific scrutiny is another question but I'm minded not to just glaze over these and other findings in the peer-reviewed literature as if they did not exist. They do exist and for those children/adults potentially registering with high levels of mercury (or other heavy metals) the onus is on treating such toxicities rather than just further adding to some growing health inequalities simply as the result of a label called 'autism'...

Oh, and adding to the 'hot potato' theme, I'll be coming to the paper by Kerns and colleagues [4] on this topic quite soon.

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[1] Khaled EM. et al. Altered urinary porphyrins and mercury exposure as biomarkers for autism severity in Egyptian children with autism spectrum disorder. Metab Brain Dis. 2016 Jul 13.

[2] Pingree SD. et al. Quantitative evaluation of urinary porphyrins as a measure of kidney mercury content and mercury body burden during prolonged methylmercury exposure in rats. Toxicol Sci. 2001 Jun;61(2):234-40.

[3] Macedoni-Lukšič M. et al. Levels of metals in the blood and specific porphyrins in the urine in children with autism spectrum disorders. Biol Trace Elem Res. 2015 Feb;163(1-2):2-10.

[4] Kern JK. et al. The relationship between mercury and autism: A comprehensive review and discussion. J Trace Elem Med Biol. 2016 Sep;37:8-24.

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Khaled EM, Meguid NA, Bjørklund G, Gouda A, Bahary MH, Hashish A, Sallam NM, Chirumbolo S, & El-Bana MA (2016). Altered urinary porphyrins and mercury exposure as biomarkers for autism severity in Egyptian children with autism spectrum disorder. Metabolic brain disease PMID: 27406246

Heavy metals, heavy conflicts and autism?

Two papers are presented for your reading delight today, both based on the often contentious issue of heavy metals and autism.

The first paper is from Farida El Baz Mohamed and colleagues [1] (open-access available here) and further substantiates the claim that for whatever reason(s) the levels of various heavy metals seem to be increased or raised in some children diagnosed with an autism spectrum disorder (ASD). The second paper by Janet Kern and colleagues [2] (open-access available here) provides results based on a systematic review of the literature on one specific heavy metal, mercury (Hg), with autism in mind and concludes that: "of the studies with public health and/or industry affiliation, 86 % reported no relationship between Hg and ASD" whilst "among studies without public health and/or industry affiliation, only 19 % find no relationship between Hg and ASD."

The Mohamed paper continues a theme that for some on the autism spectrum (remember: the autisms) there may be quite a bit more to see when it comes to the burden of heavy metals (see here). Based on hair analysis for various heavy metals - "mercury, lead, and aluminum" - researchers looked at samples from 100 children diagnosed with ASD compared with 100 age- and gender-matched controls. "Comparison between cases and controls as regards heavy metal levels shows that the mean levels of the three toxic heavy metals in hair were significantly higher among the studied ASD cases than the controls" was the primary finding. The authors further report that said heavy metal findings correlated with "maternal fish consumptions, living nearby gasoline stations, and the usage of aluminum pans" and that: "Environmental exposure to these toxic heavy metals, at key times in development, may play a causal role in autism."

I know that to talk about issues with mercury for example, can be a contentious topic with autism in mind but as uncomfortable as it might be to accept, there is some evidence of a 'connection' between elevated levels of the stuff and at least some autism (see here). The link is not, I might add, seemingly generalisable to all autism (see here) but for those children/adults presenting with elevated levels of this heavy metal, further inspection is warranted save any further health inequalities appearing when the label of autism is discussed. As to the suggestion of a connection between some autism and lead (Pb) exposure, well, again this is not the first time that this has been mentioned in the peer-reviewed literature following a more general assertion that there is nothing very good to come from when lead and children in particular meet (see here).

The paper by Kern and colleagues pours further fuel on to something of an on-going debate in some autism circles about how much factors such as conflicts of interest and research transparency may impact on autism research. Focused specifically on the issue of mercury and autism (again), the authors argue that public health or pharmaceutical industry affiliation seems to show something of a potential relationship with study outcomes when it comes to mercury and autism research. So: "over 80 % of the studies without public health or industry affiliation found evidence a relationship between Hg exposure and ASD." This contrasted with something quite a bit less when it came to studies with a public health or industry affiliation slant. Further: "The dramatic discrepancy in these results... provides evidence of biased outcomes, indicative of a conflict of interest."

The authorship group involved in the Kern paper have something of a peer-reviewed research history when it comes to this topic [3] including independent findings that hair levels of mercury might show an association with autism [4]. Their mention of mercury related compounds found in certain vaccines [5] as potentially showing a correlation with risk of autism makes for controversy in some quarters in view of the 'hot potato' that such as association has become down the years.

Appreciating that whilst the Kern findings report something of a connection between affiliations and research outcomes, I'm hard-pressed to suggest that this is hard evidence of some sort of deliberate scheme to exonerate mercury of any potential role in the very wide autism spectrum. Taking for example one paper that is cited in the Kern analysis - the paper by Barry Wright and colleagues [6] - which I've discussed before on this blog (see here) who found no overall connection between urinary mercury levels and autism, they did also call for further research in this area in light of 'outliers' being reported in their autism and their learning disability group. To quote: "further research is warranted to better understand whether a subgroup with autism or learning disabilities have mercury poisoning or excretion difficulties." In these days of plural autism (see here) one can see the logic in such a suggestion.

Music: Radiohead - Lucky.

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[1] Mohamed Fel B. et al. Assessment of Hair Aluminum, Lead, and Mercury in a Sample of Autistic Egyptian Children: Environmental Risk Factors of Heavy Metals in Autism. Behav Neurol. 2015;2015:545674.

[2] Kern JK. et al. Systematic Assessment of Research on Autism Spectrum Disorder and Mercury Reveals Conflicts of Interest and the Need for Transparency in Autism Research. Sci Eng Ethics. 2015 Oct 27.

[3] Geier DA. et al. Thimerosal: Clinical, epidemiologic and biochemical studies. Clinica Chimica Acta. 2015; 444: 212-220.

[4] Geier DA. et al. Hair toxic metal concentrations and autism spectrum disorder severity in young children. Int J Environ Res Public Health. 2012 Dec 6;9(12):4486-97.

[5] Geier DA. et al. A two-phase study evaluating the relationship between Thimerosal-containing vaccine administration and the risk for an autism spectrum disorder diagnosis in the United States. Translational Neurodegeneration. 2013;2:25.

[6] Wright B. et al. A Comparison of Urinary Mercury between Children with Autism Spectrum Disorders and Control Children. PLoS ONE. 2012;7(2):e29547.

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Mohamed, F., Zaky, E., El-Sayed, A., Elhossieny, R., Zahra, S., Salah Eldin, W., Youssef, W., Khaled, R., & Youssef, A. (2015). Assessment of Hair Aluminum, Lead, and Mercury in a Sample of Autistic Egyptian Children: Environmental Risk Factors of Heavy Metals in Autism Behavioural Neurology, 2015, 1-9 DOI: 10.1155/2015/545674




Kern JK, Geier DA, Deth RC, Sykes LK, Hooker BS, Love JM, Bjørklund G, Chaigneau CG, Haley BE, & Geier MR (2015). Systematic Assessment of Research on Autism Spectrum Disorder and Mercury Reveals Conflicts of Interest and the Need for Transparency in Autism Research. Science and engineering ethics PMID: 26507205

Mercury, autism and mitochondrial dysfunction?

Appreciating that to mention the words 'mercury and autism' in the same sentence can lead to furrowed brows and invoke eye-rolling in some quarters, I don't want to shy away from the results reported by Shannon Rose and colleagues [1] (open-access here) and their suggestion that: "the epidemiological link between environmental mercury exposure and an increased risk of developing autism may be mediated through mitochondrial dysfunction". Further that their result: "support the notion that a subset of individuals with autism may be vulnerable to environmental influences with detrimental effects on development through mitochondrial dysfunction."

Having previously talked about research from this group (see here) based on their examinations of lymphoblastoid cell lines (LCLs) from people with autism, their latest paper seems to be something of an extension of this project. Based on investigations on LCLs from 16 autism/control pairings, mitochondrial respiration was examined as and when said cells were exposed to ethylmercury. A subgroup of LCLs from the autism group "exhibited a greater reduction in ATP-linked respiration, maximal respiratory capacity, and reserve capacity when exposed to ethylmercury, compared to control LCLs." Interestingly, the pre-administration of NAC (N-acetlycysteine) "reduced (normalized) baseline respiratory parameters and blunted the exaggerated ethylmercury-induced reserve capacity depletion." That being said: "LCLs derived from children with autism exhibit significant abnormalities in mitochondrial respiration at baseline with these abnormalities worsening following exposure to ethylmercury" so one has to be a little guarded about making too many universal judgements.

OK. Wearing the cold, dispassionate and [hopefully] objective blinkers of science, there may be a few important implications from this work. First is the idea that for some on the autism spectrum, the puzzle that is mitochondria and mitochondrial dysfunction may require quite a bit more investigation (see here). In these days of plural autisms (see here) the focus perhaps needs to be on subgroups too. Second, as per their previous efforts in this area [2] is the idea that various factors might have the ability to impact on mitochondrial function for some people on the autism spectrum. Third, although still very much a source of deep division within the autism and wider community, the suggestion that ethylmercury (a metabolite of the preservative thiomersal / thimerosal) might have the ability to impact on mitochondrial function for at least some on the autism spectrum perhaps requires further scrutiny. I say this based on the small participant numbers included in the Rose study and their specific focus on LCLs. The doses of ethylmercury used might also require further investigation in terms of translating results from lab to real world.

Finally, the idea that pre-treatment of LCLs with NAC might carry a protective role is rather interesting. Aside from the 'oxidative stress' implications of their findings, I wonder if such an observation might also carry some link to the suggestion that post-vaccination administration of paracetamol (acetaminophen) might be 'implicated' in cases of autism [3]. I say this from a rather non-expert stance in this area but with the knowledge that paracetamol has an effect on glutathione stores under certain circumstances. Glutathione by the way, is one part cysteine and has cropped up in other autism research (see here) as well as subsequently [4]. Separately, given also that glucuronidation is a primary pathway for metabolising paracetamol and with the work from Stein and colleagues [5] in mind (see here), I wonder if there may indeed be more to see here (although accepting that there may be other effects from such antipyretic use).

This is not the first time that mitochondrial dysfunction and "impaired oxidative–reduction" have been studied from the point of view of downstream metabolites of thiomersal as per the paper by Geier and colleagues [6]. Again, the focus on that occasion was cell lines and so one has again to be a little cautious about extrapolating results beyond that. That also other research, in studies of mouse models for example [7], have not tended to support a connection between thiomersal exposure and 'neurodevelopmental disorders' is an important point to make, bearing in mind that mice are mice and not people. Similar sentiments apply to the important recent results from Curtis and colleagues [8] too.

But... the Rose findings cannot be readily dismissed particularly with their focus being potentially relevant to a subgroup of those on the autism spectrum. Adding the paper from Mady Hornig (a very well-respected researcher) into the mix (again based on mice) [9]: "Host differences in maturation, metabolism, nutrition, sex, and autoimmunity influence outcomes" when it comes to the potential of "thimerosal-related neurotoxicity" and quite a bit more research is perhaps indicated.

Music then. Bobby Womack - Across 110th Street.

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[1] Rose S. et al. Increased susceptibility to ethylmercury-induced mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines. J Toxicol. 2015;2015:573701.

[2] Rose S. et al. Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines. Transl Psychiatry. 2014 Apr 1;4:e377.

[3] Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008 May;12(3):293-307.

[4] Abdel-Salam OME. et al. Nuclear Factor-Kappa B and Other Oxidative Stress Biomarkers in Serum of Autistic Children. OJMIP. 2015; 5: 1.

[5] Stein TP. et al. Bisphenol A Exposure in Children With Autism Spectrum Disorders. Autism Research. 2015. Jan 13.

[6] Geier DA. et al. Mitochondrial dysfunction, impaired oxidative-reduction activity, degeneration, and death in human neuronal and fetal cells induced by low-level exposure to thimerosal and other metal compounds. Toxicol Environ Chem. 2009 Jun;91(3-4):735-749.

[7] Berman RF. et al. Low-level neonatal thimerosal exposure: further evaluation of altered neurotoxic potential in SJL mice. Toxicol Sci. 2008 Feb;101(2):294-309.

[8] Curtis B. et al. Examination of the Safety of Pediatric Vaccine Schedules in a Non-Human Primate Model: Assessments of Neurodevelopment, Learning, and Social Behavior. Environ Health Perspect. 2015. Feb 18.

[9] Hornig M. et al. Neurotoxic effects of postnatal thimerosal are mouse strain dependent. Mol Psychiatry. 2004 Sep;9(9):833-45.

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Rose, S., Wynne, R., Frye, R., Melnyk, S., & James, S. (2015). Increased Susceptibility to Ethylmercury-Induced Mitochondrial Dysfunction in a Subset of Autism Lymphoblastoid Cell Lines Journal of Toxicology, 2015, 1-13 DOI: 10.1155/2015/573701

Autism research in Jamaica

For the past couple of years I've been tracking some rather interesting publications coming out of data from Jamaica on the topic of autism / autism spectrum disorder (ASD) specifically looking at the possible overlap between genes and various environmental factors. I thought now would be a good time to bring this collection of papers to the blogging table and summarise their findings based on the analysis of data collected from The Jamaican Autism study. The fact that their latest research foray mentions some of the genetics of glutathione [2] with autism in mind is very interesting in light of some other findings in this area (see here). There's more on this shortly.

You're not Absolem. I'm Absolem. Stupid girl.

So:

Study 1: Maternal and paternal age are jointly associated with childhood autism in Jamaica [2].
Higher parental age - both mother and father age - seemed to be associated with a diagnosis of autism/ASD in offspring. Higher maternal age in particular, survived further statistical analysis as being a potentially important factor. This is a topic which has cropped up in autism research circles before (see here).

Study 2: Seafood consumption and blood mercury concentrations in Jamaican children with and without autism spectrum disorders [3].
"Our findings do not support an association between blood mercury concentrations measured in Jamaican children 2–8 years of age and ASD case status." Such a conclusion was based on the analysis of blood mercury concentrations between ASD cases and a control group, and took into account important factors such as seafood consumption bearing in mind what is known about such a foodstuff and environmental exposures (see here).

Study 3: The role of drinking water sources, consumption of vegetables and seafood in relation to blood arsenic concentrations of Jamaican children with and without Autism Spectrum Disorders [4].
Blood arsenic levels were the focal point of this study, and a familiar conclusion to the previous study: "Our results do not support an association between postnatal total blood arsenic measured in Jamaican children 2-8 years of age and ASD case status." Again the consumption of certain foodstuffs seemed to be important correlates related to any elevated levels of arsenic detected.

Study 4: Role of fruits, grains, and seafood consumption in blood cadmium concentrations of Jamaican children with and without Autism Spectrum Disorder [5].
Cadmium levels this time around, and again: "we did not find any significant differences between ASD cases and typically developing (TD) controls with respect to the 75th percentile of blood cadmium concentrations." Food (yes again) seemed to be a good correlate linked to differences in blood cadmium levels.

Study 5: Blood manganese concentrations in Jamaican children with and without autism spectrum disorders [6].
Manganese, and wait for it... "Our results do not indicate a relationship between postnatal BMC [blood manganese concentrations] and ASD case status of Jamaican children ages 2–8 years."

Study 6: Blood Lead Concentrations in Jamaican Children with and without Autism Spectrum Disorder [7].
Lead (Pb), a favourite topic of this blog, was the metal of choice when it came to analysis to see if there was any connection between the stuff and autism. Er,... "Our results do not support an association between postnatal blood lead concentration measured in Jamaican children 2–8 years of age and ASD case status."

I think you can see the trend coming out of this data examining samples of children living in Jamaica with and without autism. Perhaps just as important are the various discussions about the ways and means that participants might have been exposed to these various metals and how one needs to be aware of how food in particular, could be a significant source of exposure. This perhaps puts a new slant on previous studies which have suggested an increased body burden of certain metals to be associated with autism (see here) and the question of whether dietary sources of such metals have adequately been taken into account. Don't get me wrong, I'm still very keen to see more 'metallomics' applied to autism research (see here), perhaps just controlling for a few more potentially important confounders.

The Jamaican Autism study also provides quite a nice template for setting up further geographically distinct initiatives to compare and contrast with/against. I note for example that the recent study from Hodgson and colleagues [8] looking at autism in Oman (itself the topic of quite a few peer-reviewed publications) suggested some rather different results for their cohort: "Mercury levels were markedly elevated in the hair of autistic subjects vs. control subjects" albeit based on hair analysis not blood. With the previous caveat about confounders in operation, one wonders whether there may be more to see across different countries particular when bringing into play the potential importance of that glutathione connection which has also previously received some mention in the Jamaican autism studies [9].

And then some music. Jamaica and music, mmm... One Love.

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[1] Rahbar MH. et al. nteraction between GSTT1 and GSTP1 allele variants as a risk modulating-factor for autism spectrum disorders. Research in Autism Spectrum Disorders. 2015; 12: 1-9.

[2] Rahbar MH. et al. Maternal and paternal age are jointly associated with childhood autism in Jamaica. J Autism Dev Disord. 2012 Sep;42(9):1928-38.

[3] Rahbar MH. et al. Seafood consumption and blood mercury concentrations in Jamaican children with and without autism spectrum disorders. Neurotox Res. 2013 Jan;23(1):22-38.

[4] Rahbar MH. et al. The role of drinking water sources, consumption of vegetables and seafood in relation to blood arsenic concentrations of Jamaican children with and without Autism Spectrum Disorders. Sci Total Environ. 2012 Sep 1;433:362-70.

[5] Rahbar MH. et al. Role of fruits, grains, and seafood consumption in blood cadmium concentrations of Jamaican children with and without Autism Spectrum Disorder. Res Autism Spectr Disord. 2014 Sep 1;8(9):1134-1145.

[6] Rahbar MH. et al. Blood manganese concentrations in Jamaican children with and without autism spectrum disorders. Environ Health. 2014 Aug 23;13:69.

[7] Rahbar MH. et al. Blood Lead Concentrations in Jamaican Children with and without Autism Spectrum Disorder. Int J Environ Res Public Health. 2014 Dec 23;12(1):83-105.

[8] Hodgson NW. et al. Decreased glutathione and elevated hair mercury levels are associated with nutritional deficiency-based autism in Oman. Exp Biol Med (Maywood). 2014 Jun;239(6):697-706.

[9] Rahbar MH. et al. Role of metabolic genes in blood arsenic concentrations of Jamaican children with and without autism spectrum disorder. Int J Environ Res Public Health. 2014 Aug 6;11(8):7874-95.

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Rahbar MH, Samms-Vaughan M, Loveland KA, Pearson DA, Bressler J, Chen Z, Ardjomand-Hessabi M, Shakespeare-Pellington S, Grove ML, Beecher C, Bloom K, & Boerwinkle E (2012). Maternal and paternal age are jointly associated with childhood autism in Jamaica. Journal of autism and developmental disorders, 42 (9), 1928-38 PMID: 22230961

Probiotics to counter heavy metal toxicity?

"In summary, this work has demonstrated the potential value of long-term probiotic-based interventions to counter mercury and arsenic exposure in vulnerable populations, particularly in pregnant women".

Sounds like an '80s man to me...

That was one of the primary conclusions reported by Jordan Bisanz and colleagues [1] (open-access) examining "at-risk populations of pregnant women and in children in Mwanza, Tanzania". The idea being that alongside the use of metal chelating medicines such as dimercaptosuccinic acid (DMSA) and ethylenediaminetetraacetic acid (EDTA) indicated for 'acute' exposure to heavy metals, there may be other ways and means of treating heavy metal exposure over longer periods and where resources may not be as plentiful. Some media about this study can be seen here.

The Bisanz paper is open-access but a few pointers might be in order:

• The study was based on the idea that certain strains of bacteria are known to have "an affinity for many toxic metals, including lead and cadmium" as documented in papers such as the one by Monachese and colleagues [2]. Further, that so-called "probiotic yogurt kitchens that service economically disadvantaged people" as a source of potentially beneficial bacteria are already working at the particular location selected by the study authors.
• So, two studies were implemented: (a) looking at school-aged children (SAC) (initial N=44) randomised to receive either a probiotic yoghurt containing "1 × 1010 CFU Lactobacillus rhamnosus GR-1 per 250 g" or "an equivalent portion of ultra-heat-treated milk as a control devoid of lactic acid bacteria" daily for 24 days; and (b) "60 pregnant women [PW] were recruited, of which 26 received a probiotic yogurt containing 1 × 1010 CFU L. rhamnosus GR-1 per 250 g and supplemented with 4.3 g of Moringa, a micronutrient-rich plant, to enhance maternal nutrition". The study entries in the US National Institutes of Health (NIH) database can be found here and here respectively. 
• Analysis of blood metal levels ("blood lead, total mercury, total arsenic, and cadmium") were undertaken at enrolment and follow-up for all participants across the two studies. Analysis of fecal samples for children in study (a) was also undertaken pre- and post-intervention to test for any differences across the yoghurt vs. milk groups. Local fish were also analysed for heavy metal content to ascertain dietary exposure alongside dietary patterns of participants.
• Results: there were quite a few... levels of heavy metals in SAC and PW studied were elevated compared to "levels present in a developed country (Canada)" somewhere in the order of over 6 times greater for lead and mercury. Children (SAC) were particularly vulnerable to an increased heavy metal burden. The authors noted: "Metal exposure from dietary fish intake likely explains why we saw elevated blood levels of mercury in both the SAC and PW groups".
• "The studies provided the first positive evidence for the use of probiotics to combat toxic heavy metal exposure in vulnerable human populations". Well, sort of, is probably the best way that I can comment on this assertion, as the authors noted: "no statistically significant differences were detected in blood metal levels in SAC receiving the probiotic or milk control, although we noted that there was a weak trend of reduced blood levels of lead and arsenic". They did find that in the control group in receipt of milk, "blood levels of mercury and arsenic increased" between the testing occasions "but remained stable in the probiotic group". So concluding that levels of certain heavy metals didn't get any worse following the use of a probiotic is probably a more accurate way of looking at things.
• Insofar as the gut bacteria analysis side of things: "Administration of the probiotic was not observed to have an effect on the gut bacterial community composition". But the authors did report that: "Elevated blood lead was associated with increases in Succinivibrionaceae and Gammaproteobacteria relative abundance levels in stool".

There are some important results to be derived from the Bisanz paper but not necessarily in the way that I think the authors hoped, bearing in mind this was a very short study limited to one specific probiotic strain. That being said, the idea that probiotics might have some kind of protective effect - "probiotic administration may be especially advocated at peak exposure times" - is an interesting one, worthy of quite a bit more investigation. 

I know discussions in certain quarters about the use of chelation therapy for certain conditions have the ability to furrow brows (see here). This despite the fact that when clinically indicated, chelation can provide some powerful results as demonstrated in the recent paper by Thurtle and colleagues [2] (open-access) on the use of oral DMSA for severe lead poisoning in Northern Nigeria. If we are to assume that certain types of bacteria might potentially be able to prevent or reduce uptake of something like heavy metals in the gastrointestinal (GI) tract from oral sources (i.e. food), I'd be minded to say that such inexpensive and potentially safer methods protecting against heavy metal poisoning, might be something to explore. And hopefully I'm talking out of turn when I mention some of the literature on lead and mercury exposure when it comes to autism (see here) as another possible avenue for more formal investigation.

Next up: probiotics and influenza anyone? (With the need for a lot more research and certainly nothing like medical or clinical advice given or intended by me on this topic).

Music then. Domino by Jessie J.

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[1] Bisanz JE. et al. Randomized Open-Label Pilot Study of the Influence of Probiotics and the Gut Microbiome on Toxic Metal Levels in Tanzanian Pregnant Women and School Children. mBio. 2014. 7 October.

[2] Thurtle N. et al. Description of 3,180 Courses of Chelation with Dimercaptosuccinic Acid in Children ≤5 y with Severe Lead Poisoning in Zamfara, Northern Nigeria: A Retrospective Analysis of Programme Data. PLoS Medicine. 2014; 11: e1001739.

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Jordan E. Bisanz, Megan K. Enos, Joseph R. Mwanga, John Changalucha, Jeremy P. Burton, Gregory B. Gloor, & Gregor Reid (2014). Randomized Open-Label Pilot Study of the Influence of Probiotics and the Gut Microbiome on Toxic Metal Levels in Tanzanian Pregnant Women and School Children mBio : 10.1128/mBio.01580-14

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

Prenatal and neonatal blood mercury levels and autism

Acknowledging that some topics have the ability to furrow brows when it comes to autism research, mercury and autism is becoming something of a frequent talking point on this blog as a function of a whole slew of articles appearing in the peer-reviewed domain. If I were to [very tentatively] summarise the collected literature so far, it would be to say something like:

Mosaic of mercury @ Wikipedia 

(i) there is quite a bit more research to be done on some sources of mercury being 'linked' to cases of autism i.e. air pollution, fish consumption (see here),
and
(ii) the body burden of mercury for some on the autism spectrum is elevated (see here) compared to other groups and potentially linked to "a decreased ability to excrete mercury due to a combination of lowered reduced glutathione, emergence of oxidative stress, and excessive use of oral antibiotics" according to the review by Francesca Gorini and colleagues [1] (open-access).

I know some people may not like hearing that summary but that's my interpretation of the various reviews and meta-analyses conducted so far. I should add that I'm not though passing any specific comment on whether mercury 'causes' autism bearing in mind what we know about the developmental consequences of exposure.

The paper by Vincent Yau and colleagues [2] looking at maternal serum and infant newborn bloodspot levels of mercury adds to that literature with their conclusion: "levels of total mercury in serum collected from mothers during mid-pregnancy and from newborn bloodspots were not significantly associated with risk of ASD [autism spectrum disorder]". I believe we had seen this data presented before at the 2011 IMFAR conference too (see here).

A few details first:

• Based on data obtained from the EMA (Early Markers of Autism) study, a cohort "identified from the California Department of Developmental Services (DDS)" records, mid-pregnancy maternal serum samples and the wonderful resource that is the neonatal bloodspots related to some 84 children diagnosed with an ASD were analysed for total mercury content (inorganic and organic mercury). Blinded results were compared with 159 population controls (asymptomatic) and 49 children diagnosed with a learning (intellectual) disability or developmental delay.
• ICP mass spectrometry was the name of the analytical game, which as I've talked about before, is one of the methods of choice when it comes to the analysis of the metallome. Archived blood spot samples were subject to laser ablation as a function of their mounting. 
• Results: "Maternal serum and infant blood mercury levels were significantly correlated among all study groups". In other words, maternal mercury burden seemed to be associated with neonatal offspring burden (albeit with a correlation coefficient ~0.4 which is OK but not exactly great).
• Further: "Results for mercury levels in newborn blood samples were similar" across the groups. Ergo, at birth, levels of total mercury from neonatal bloodspots "were not significantly associated with risk of ASD". That's not to say that there weren't some differences in average levels of blood mercury levels across the groups, just that such differences were not deemed to elevate the risk of ASD overall.

Like quite a lot of the science in this area, there are several ways you could interpret these results. You could, for example say that the maternal burden of mercury during pregnancy was not associated with offspring risk of autism. You could also say that 'at or shortly after birth' (remember those words), blood mercury levels do not seem to correlate with the risk of autism. Therefore mercury is not a factor in relation to autism as per other results in this area [3]. You could say those things, as you might for several other variables supposedly related to autism... vitamin D for example? (see here and then see here).

But you might also consider the bank of research which has reported elevated levels of mercury in various biofluids and tissues particularly focused on slightly older infants and children with autism as illustrative of something potentially important: increasing exposure to mercury with age. Take for example the paper by Majewska and colleagues [4] and their findings reporting: "Autistic children significantly differed from healthy peers in the concentrations of mercury in hair: younger autistics had lower levels, while older - higher levels than their respective controls". The results from Hertz-Picciotto and colleagues [4] (open-access here) also implied that behaviour might play a role in blood mercury levels: "Interestingly, although few children had Hg amalgams, those who did and who also either chewed gum or had bruxism appeared to have experienced sufficient release of inorganic Hg to be measurable in blood". I say this noting that not every child with autism has mercury amalgams, as neither do they all partake in teeth grinding.

The Yau results make an important contribution to the issue of mercury and autism in terms of maternal contribution and mercury load at birth. As part of some further investigations, and bearing in mind that participants in the EMA initiative might also be involved in other State initiatives (beincharge!), I would like to see further follow-up of participants and if and how their mercury load might have changed as they matured. Analysis of other parameters mentioned in that Gorini review paper - such as glutathione measures for example - might also offer some important accompanying data on whether excretion factors are part of the issue here and what might be done to help relieve any excess burden of the troublesome heavy metal that is mercury. Oh, and given that genetic factors might also play some role in mercury accumulation as per the findings by Llop and colleagues [5] (open-access), there may also be more research to do here too...

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[1] Gorini F. et al. The Role of Heavy Metal Pollution in Neurobehavioral Disorders: a Focus on Autism. Review Journal of Autism and Developmental Disorders. 2014. June 27.

[2] Yau VM. et al. Prenatal and neonatal peripheral blood mercury levels and autism spectrum disorders. Environ Res. 2014 Jun 27;133C:294-303. 

[3] van Wijngaarden E. et al. Autism spectrum disorder phenotypes and prenatal exposure to methylmercury. Epidemiology. 2013 Sep;24(5):651-9. 

[4] Hertz-Picciotto I. et al. Blood mercury concentrations in CHARGE Study children with and without autism. Environ Health Perspect. 2010 Jan;118(1):161-6.

[5] Llop S. et al. Polymorphisms in ABC transporter genes and concentrations of mercury in newborns--evidence from two Mediterranean birth cohorts. PLoS One. 2014 May 15;9(5):e97172. 

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Yau VM, Green PG, Alaimo CP, Yoshida CK, Lutsky M, Windham GC, Delorenze G, Kharrazi M, Grether JK, & Croen LA (2014). Prenatal and neonatal peripheral blood mercury levels and autism spectrum disorders. Environmental research, 133C, 294-303 PMID: 24981828