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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Autism's environmental exposome (part 2)

Back in June 2012, I posted an entry on this blog titled: 'Autism's environmental exposome: fish and pharmaceuticals' covering some work by Michael Thomas & Rebecca Klaper [1] (open-access). In it, authors suggested that unmetabolized psychoactive pharmaceuticals (UPPs) - residues from certain medicines - present in drinking (or in the case of this work, swimming) water may "induce autism-like gene expression patterns in fish."

The UPPs in question were "FLX [fluoxetine], VNX [venlafaxine], and CBZ [carbamazepine] in a 3-component mixture" and the lucky fish volunteers were fathead minnows who got to swim with those UPPs. The data were interesting insofar as the potential "ability to induce ASD-like gene expression patterns in developing brains" as a function of exposure to those UPPs, albeit with concentrations used in the Thomas/Klaper study "higher than observed environmental concentrations". The idea being that drug residues are present in the environment around us and some, either alone or in combination, may potentially host some important biological effects.

Enter then further work from this group in the form of the paper by Gaurav Kaushik and colleagues [2] (open-access) who undertook some rather interesting network analysis among other things and concluded that: "protein products from gene sets with enriched expression in fish brains and human neuronal cells, due to an exposure of psychoactive pharmaceuticals, were comparatively more inter-connected to other neighboring proteins than protein products of non-enriched gene sets." Further: "these genes are more likely to experience altered expression upon exposure to PPCPs [pharmaceuticals and personal care products], causing further dysregulation of the whole interactome due to a ripple effect."

I'll be honest with you and say that I'm not altogether au fait with all the goings-on reported by Kaushik et al and their bioinformatics approach adopted so you'll have to take my interpretation with a pinch of salt.  What they appear to be suggesting is that the effects of UPP exposure may not be just centred on the gene expression patterns they previously reported but rather having something of a wider knock-on effect on how gene products are expressed and how this might map onto something like autism. Interestingly, this time around researchers also introduced valproate (VPA) into their investigations given the growing evidence base that "VPA is known to induce ASD [autism spectrum disorder]-like phenotypes in mice" (see here for more information) as it might in people [3]. They reported some potentially important connections - "enrichment effects of clinical doses of VPA are similar to those for environmental concentrations of pharmaceutical mixtures."

Accepting how the word 'chemical' has been very wrongly demonised over the years, the idea that environmental 'exposures' either singularly or as combinations, might have important effects on development and behaviour is something that requires quite a bit more investigation when it comes to something like autism. The idea that gene expression for example, can be modified by said exposures adds an extra layer of complexity to the rather too simplistic idea of 'genes vs. environment' when it comes to autism risk. One might also be minded to take into account gender/sex (see here) too particularly in light of some of the findings reported by Werling & Geschwind [4] recently...

Oh, and UPPs might not be the only pharmaceuticals requiring further research attention with wastewater and minnows in mind...

Music: Dinosaur Jr. - Freak Scene.

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[1] Thomas MA. & Klaper RD. Psychoactive pharmaceuticals induce fish gene expression profiles associated with human idiopathic autism. PLoS One. 2012;7(6):e32917.

[2] Kaushik G. et al. Psychoactive pharmaceuticals as environmental contaminants may disrupt highly inter-connected nodes in an Autism-associated protein-protein interaction network. BMC Bioinformatics 2015, 16(Suppl 7): S3.

[3] Wood AG. et al. Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy. Epilepsia. 2015. 11 May.

[4] Werling DM. & Geschwind DH. Recurrence rates provide evidence for sex-differential, familial genetic liability for autism spectrum disorders in multiplex families and twins. Molecular Autism 2015, 6:27.

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Gaurav Kaushik, Michael A Thomas, & Ken A Aho (2015). Psychoactive pharmaceuticals as environmental contaminants may disrupt highly inter-connected nodes in an Autism-associated protein-protein interaction network BMC Bioinformatics