June 2, 2017

expert reaction to fetal and postnatal metal dysregulation in autism

Publishing in Nature Communications, researchers have used twin studies to look at associations between metal uptake during fetal and post natal development and autism spectrum disorders.

Prof Sir Colin Berry, Emeritus Professor of Pathology, Queen Mary University London (QMUL), said:

“I would not read too much into the implications of this paper as viewing this from a toxicology and epidemiology perspective, there are a number of concerns.

“The first issue is that there are no hypotheses presented here – the authors are looking at teeth as heavy metals gravitate to bone, but they don’t all act the same way and their different effects will differ at different stages in a child’s development. This further complicated as once a heavy metal has been bound to the teeth, it will then interact differently with other heavy metals and so on.

“Second, the sample size is tiny.

“Third, the fact this study is apparently non-blinded is important and it makes interpretation less robust. This is made even more difficult as the graphs presented in figure 3 don’t use the same scales, making comparison between the different types of twin pairs very tough, which suggests some problems.

“When done properly, as with the studies on Minamata disease, we see what can be done with stored biological material (in that case placentas and umbilical cords) but in that case there were far more samples and a more consistent and readily-documented symptomatology.”

Dr Georgina Warner, Research Manager, Autistica, said:

“There is no conclusive evidence that exposure to toxic metals is linked to autism but this new study highlights the need for more studies to tease out the poorly understood links between genetics and environmental triggers. It’s important to note that, although this study observed differences in exposure between those with autism and those without, they could not demonstrate that toxic metals were a cause of autism. Indeed, there could be many possible reasons why some of the children developed autism that have not been accounted for in the research. Further high quality studies are needed and it is far too early to make recommendations to families.”

Dr Rosa Hoekstra, Lecturer in Psychology, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, said:

“This paper addresses an important and so far understudied topic: the potential role of environmental exposure to toxic metals and essential elements in the risk for autism.  Most research to date has focused on genetic risk mechanisms; a strength of this study is that by using a discordant twin design (comparing twin pairs where only one of the twins within a pair has autism) it can control for genetic risk factors.

“Important to note is that this paper is strongly exploratory: it uses a very small sample size, and explored several time windows in which toxic metals and essential elements may have affected prenatal and early postnatal development, without an a priori hypothesis which time window would be most important.  This exploratory nature makes it likely that some of the findings reported are simply due to chance.  As the authors acknowledge themselves, this study requires replication in bigger samples before any firm conclusions can be drawn.  Another important caveat highlighted by the authors is that their findings do not establish causality: having somewhat atypical levels of metal concentrations in teeth does not necessarily infer these metals caused the development of autism.

“An important opportunity for future research would be to replicate this study in a population living in a low-income country, where exposure to toxic metals and nutritional elements is typically much more varied than in high-income countries (where food security and health and safety regulations are typically better controlled).

“Two methodological comments to bear in mind when interpreting the findings: firstly, the graphs presented in Figure 3 are on inconsistent scales, both on the Y axis and the X axis – this makes comparisons between the different types of twin pairs (concordant typically developing (non-ASD), discordant, concordant ASD) rather difficult.  Secondly, the paper does not make explicit whether the researchers involved in the biomarker analysis were blind for diagnostic status or twin pair type.  If the analysts were non-blind this may have unconsciously affected their analytic strategy.

“Overall this is an interesting study that addresses a potentially important and previously underexplored topic.  However, the study is largely exploratory; no firm conclusions can be drawn based on this work alone.”

Prof Dorothy Bishop, Professor of Developmental Neuropsychology, University of Oxford, said:

“The method used here is ingenious, as it involves using analysis of children’s teeth to work out what was going on very early in development, when the tooth was being formed. Results obtained here are provocative but also rather surprising. The main focus of the study is on 13 twin pairs: in 6 of these, both twins had autism, and in 7, just one twin had autism. There were a further 19 twin pairs where neither had autism. The odd feature is that evidence for differences in metal uptake in those with autism came from analysis of features of teeth that are laid down prenatally: so you might have expected both twins to have similar profiles, since they are together in the same uterus. This study, then, does not suggest that different exposure to toxic metals in pregnancy causes autism; rather than there may be differences between fetuses in how the developing body responds to toxic metals.

“The description of the statistical methods sounds adequate to take into account the numerous metals and time periods that were considered, but was sufficiently complicated to be hard to evaluate. Twin samples like this are very rare, and the sample is understandably small. The authors note that the results should be replicated in a non-twin sample.  These results may be useful to stimulate further research, but I do not think they have practical implications for families.”

* ‘Fetal and postnatal metal dysregulation in autism’ by Arora et al. was published in Nature Communications on Thursday 1st June.

Declared interests

Prof Sir Berry:  “Sir Colin consults for a number of agrochemical and pharmaceutical companies and for the MHRA. He is advises the European Risk Forum.”

Dr Warner: “I have no conflicts of interest.”

Dr Hoekstra: “I have no CoI to report.”

Prof Bishop: “I have no conflict of interest to declare”