Bisphenol A (BPA) and autism continued

"Descriptive analyses indicated that prenatal exposure to maternal BPA [Bisphenol A] concentrations were related to higher levels of anxiety, depression, aggression, and hyperactivity in children. BPA exposure in childhood was associated with higher levels of anxiety, depression, hyperactivity, inattention, and conduct problems."

That was the conclusion reached in the systematic review by Maede Ejaredar and colleagues [1], that provides one of two studies brought to the blogging table today. With the aim of looking at the current collected peer-reviewed literature on the topic of "prenatal and childhood BPA exposure" and offspring/childhood outcomes, the authors suggest that there may indeed be more to see in this area, but with the important requirement for further "Prospective cohort studies" to clarify any relationship.

BPA, by the way, is a chemical of some note in modern society given its quite widespread use in plastics and related materials. Although some agencies have provided current guidance to the effect that BPA is 'safe' and poses no health risk at current levels of exposure, not everyone is so convinced by such sweeping statements about safety.

Indeed to make the point, the findings reported by Meda Kondolot and colleagues [2] add to an existing body of scientific literature suggesting that when it comes to at least 'some' autism, there may be something of an increased biological burden of BPA present. Based on the analysis of 50+ children diagnosed with an autism spectrum disorder (ASD) and an equivalent number of asymptomatic - not autism - controls, a range of metabolites were looked for including "plasma phthalates and BPA" and compounds linked to "oxidant/antioxidant status." The authors reported that: "Plasma BPA levels of children with PDD-NOS [Pervasive Developmental Disorder-Not Otherwise Specified] were significantly higher than both classic autistic children and controls." Combined with some interesting findings potentially reflective of issues with oxidative stress in relation to their participant group, authors speculate that there may be some issues with the metabolism of things like BPA in relation to some autism. I might however also add that the chosen method of analysis of samples used by Kondolot et al - high performance liquid chromatography (HPLC) - is not the most sensitive of methods when used minus it's important detection counterpart, mass spectrometry; particularly when analysing such a complicated medium such as plasma. It implies that further, more technical investigation of samples, is perhaps required.

Being careful not the fall into any 'chemophobic' traps ('chemicals' is a word that has received a bad rap in my opinion), I continue to believe that there is more to see in this area of research. I draw back from any sweeping generalisations that have been put forward with other chemicals in relation to autism (see here for example) because I'm not convinced that all autism is due to BPA or any other single compound. Anyone who follows this blog regularly knows about my fascination with plural autisms (see here) and the fact that autism rarely exists in some sort of diagnostic vacuum (see here). That also takes into account the range of 'chemical exposures' that modern-day life brings.

I would however like to see further investigation on a few aspects: (i) is autism (some autism) associated with an increased exposure risk to certain chemicals? Y'know, the sort of data that is coming out of Vietnam for example (see here); and (ii) are there genetic and/or biological reasons why some people on the autism spectrum have issues with the metabolism of a range of xenobiotics? Under that last category, there are numerous examples in the literature of various compounds being elevated in terms of biological load (see here for example) combined with quite a bit of discussion about 'issues' with methods/systems for removing such compounds from the body (see here). Such findings could be just epiphenomenal to autism but could also represent something rather more central and important [3].

There is quite a bit more science to do in this area.

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[1]  Ejaredar M. et al. Bisphenol A exposure and children’s behavior: A systematic review. Journal of Exposure Science and Environmental Epidemiology. 2016. March 9.

[2] Kondolot M. et al. Plasma Phthalate and Bisphenol A Levels and Oxidant-Antioxidant Status in Autistic Children. Environmental Toxicology and Pharmacology. 2016. March 9.

[3] Kardas F. et al. Increased Serum Phthalates (MEHP, DEHP) and Bisphenol A Concentrations in Children With Autism Spectrum Disorder: The Role of Endocrine Disruptors in Autism Etiopathogenesis. J Child Neurol. 2016 Apr;31(5):629-35.

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Ejaredar M, Lee Y, Roberts DJ, Sauve R, & Dewey D (2016). Bisphenol A exposure and children's behavior: A systematic review. Journal of exposure science & environmental epidemiology PMID: 26956939




Kondolot, M., Ozmert, E., Ascı, A., Erkekoglu, P., Oztop, D., Gumus, H., Kocer-Gumusel, B., & Yurdakok, K. (2016). Plasma Phthalate and Bisphenol A Levels and Oxidant-Antioxidant Status in Autistic Children Environmental Toxicology and Pharmacology DOI: 10.1016/j.etap.2016.03.006

Endocrine disruptors and autism?

"Children with autism spectrum disorder had significantly increased serum MEHP, DEHP, and BPA [mono-(2-ethylhexyl)-phthalate (MEHP), di-(2-ethylhexyl)-phthalate (DEHP), and bisphenol A (BPA)] concentrations."

So said the findings reported by Fatih Kardas and colleagues [1] looking at whether there may be more to see when it comes to phthalate metabolism and autism among other things. For those who might be rolling their eyes at this point, I'll draw your attention to other occasions when similar results have been reported (see here and see here) and the place that the Kardas results seem to share.

This time around nearly 50 children diagnosed with an autism spectrum disorder (ASD) and some 40 asymptomatic controls provided serum samples that were screened for MEHP, DEHP, and BPA. The analytical weapon of choice was high-performance liquid chromatography (HPLC), I assume coupled to something like UV and/or fluorescence detection. The results by group suggested that "endocrine disruptors may have a role in the pathogenesis of autism spectrum disorders" according to the authors. I might add that we have had previous clues that this research was coming to publication [2].

These are interesting results. Whilst the use of HPLC (as a separative method) is not necessarily on its own the most accurate method of assaying for such compounds (that would be coupled to something like mass spectrometry) there are some potentially important things to learn from such findings. Although it would be easy to correlate such results with something like a higher exposure to such compounds in cases of autism, I'm not ready to accept that as an explanation given the frequency with which we all come into contact with them. I'd perhaps favour a hypothesis whereby the ability to metabolise such xenobiotics is differentially affected in at least some cases of autism as per the discussions by Stein and colleagues [3]. Such a metabolic difference could be a genetic issue tied into something like all that chatter about sulphation and glucuronidation and autism down the years (see here). It could also be something a little more functional in terms of how those trillions of wee beasties that call us home (the gut microbiome) might also affect such processes [4] too given the growing interest in the microbiome in relation to autism (see here). At this point I'll also draw your attention to some similarly interesting work on how functional bowel habits and gut microbiota might be linked with some autism in mind [5].

Acknowledging that autism research is still fumbling around a bit when it comes to the precise hows and whys of how environment (non-genetic factors) might fit into autism (see here) and it's relative contribution, I'm a great believer in how the technology we have at our disposal can help. The rise and rise of the various -omics and the concept of a systems biology approach with an autism slant (see here) means that we are getting better at not only analysing genetic and biological parameters but also in putting any potential connections together. Acknowledging that there may be many different types of autism (the autisms) with various different comorbidity patterns accompanying (see here), it is only a matter of time before patterns start to emerge and discussions can move on from simply genetics vs. environment.

Music: The Score - Oh My Love.

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[1] Kardas F. et al. Increased Serum Phthalates (MEHP, DEHP) and Bisphenol A Concentrations in Children With Autism Spectrum Disorder: The Role of Endocrine Disruptors in Autism Etiopathogenesis. J Child Neurol. 2015 Oct 8. pii: 0883073815609150.

[2] Kardas F. et al. P174 – 2732: Increased serum phthalates (MEHP, DEHP) and bisphenol A concentrations in children with autism: The role of endocrin disruptors in autism aetiopathogenesis. Euro J Pediatr Neurology. 2015; 19: Suppl. 1: S142-S143.

[3] Stein TP. et al. Bisphenol A Exposure in Children With Autism Spectrum Disorders. Autism Res. 2015 Jun;8(3):272-83.

[4] Rowland IR. Metabolism of Di-(2-ethylhexyl) phthalate by the contents of the alimentary tract of the rat. Food and Cosmetics Toxicology. 1974; 12: 293-302.

[5] Gabriele S. et al. Slow intestinal transit contributes to elevate urinary p-cresol level in Italian autistic children. Autism Res. 2015. October 6.

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Kardas F, Bayram AK, Demirci E, Akin L, Ozmen S, Kendirci M, Canpolat M, Oztop DB, Narin F, Gumus H, Kumandas S, & Per H (2015). Increased Serum Phthalates (MEHP, DEHP) and Bisphenol A Concentrations in Children With Autism Spectrum Disorder: The Role of Endocrine Disruptors in Autism Etiopathogenesis. Journal of child neurology PMID: 26450281

Bisphenol A Exposure in Children With Autism

The paper by T. Peter Stein and colleagues [1] suggesting an "association" between BPA (Bisphenol-A) and autism spectrum disorder (ASD) was always bound to create some interest. Reporting results based on the analysis of urine samples from a group of children diagnosed with an autism spectrum disorder (ASD) (n=46) compared to controls (n=52), authors concluded that: "there is an association between BPA and ASD." Association... note that word.

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BPA has been around for quite a few years. An important chemical in the production of certain plastics and resins, in more recent times quite a volume of science has suggested that caution should be applied to the use of and exposure to BPA particularly with reference to its potential estrogenic properties [2]. As with everything in life, the effects or not of BPA continue to be the source of some discussion, with concerns even been raised about the alternatives to BPA (see here) being put forward. In short, it's very, very complicated.

Stein and colleagues started from the premise that: "The major pathway for BPA metabolism and excretion is via glucuronidation." Glucuronidation involves the addition of glucuronic acid to a particular metabolite thus aiding the removal of said metabolite from the body. Those of you who have come across the whole sulphation and autism story might remember how glucuronidation and sulphation share some history with [some] autism in mind as per papers like the one from Alberti and colleagues [3]. Stein et al have some research form when it comes to glucuronidation and autism as per papers such as this one [4] (open-access) that concluded that: "The glucuronidation pathway may differ in some children with ASD." They reported lower levels of glucuronidation which impacted on the metabolism of phthalates among other things (see here).

Anyhow, the analytical weapon of choice in the BPA-autism study by Stein et al was mass spectrometry (MS). Again, this research group have some interest/experience in this area as per other research of theirs which has crossed my blogging path (see here). Looking at those urine samples from participants with ASD vs asymptomatic controls, researchers reported a few important details including that: "about 20% of the ASD children had BPA levels beyond the 90th percentile (>50 ng/mL) of the frequency distribution for the total sample of 98 children." They also reported "significant differences (P < 0.05) between the groups in total and % bound BPA" (bound BPA referring to BPA glucuronide). Reiterating their conclusion: "The results suggest there is an association between BPA and ASD."

Bearing in mind how the word 'chemical' has been mis-represented down the years, there is quite a body of work emerging suggestive that there is quite a bit more to do when it comes to environmental exposures potentially linking into at least some cases of autism. This is not the first time that BPA has been examined with autism in mind as per discussions like the one from de Cock and colleagues [5] and some animal model work such as that from Wolstenholme et al [6]. The paper from Kaur and colleagues [7] suggesting that: "BPA may act as an environmental risk factor for autism in genetically susceptible children by inducing oxidative stress and mitochondrial dysfunction" offers some tantalising areas of further research tallying with other non-autism research [8]. I might also bring your attention to the paper by Lichtensteiger and colleagues [9] (thanks to @autismepi) perhaps providing another important area for further research.

Further study is of course implied from the Stein work and other research in this area. That and quite a bit more investigation of the biological systems implicated in any effect from BPA on cases of autism brings the focus back to a model of genes and environment [variably] interacting on the very wide autism spectrum...

Music: Madonna - Papa Don't Preach. Well, preaching is what we do best!

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

[2] Sharpe RM. Is it time to end concerns over the estrogenic effects of bisphenol A? Toxicol Sci. 2010 Mar;114(1):1-4.

[3] Alberti A. et al. Sulphation deficit in "low-functioning" autistic children: a pilot study. Biol Psychiatry. 1999 Aug 1;46(3):420-4.

[4] Stein TP. et al. Autism and Phthalate Metabolite Glucuronidation. J Autism Dev Disord. Nov 2013; 43(11): 2677–2685.

[5] de Cock M. et al. Does perinatal exposure to endocrine disruptors induce autism spectrum and attention deficit hyperactivity disorders? Review. Acta Paediatr. 2012 Aug;101(8):811-8.

[6] Wolstenholme JT. et al. Gestational exposure to low dose bisphenol A alters social behavior in juvenile mice. PLoS One. 2011;6(9):e25448.

[7] Kaur K. et al. Bisphenol A induces oxidative stress and mitochondrial dysfunction in lymphoblasts from children with autism and unaffected siblings. Free Radic Biol Med. 2014 Nov;76:25-33.

[8] Veiga-Lopez A. et al. Impact of Gestational Bisphenol A on Oxidative Stress and Free Fatty Acids: Human Association and Interspecies Animal Testing Studies. Endocrinology. 2015. Jan 20.

[9] Lichtensteiger W. et al. Differential Gene Expression Patterns in Developing Sexually Dimorphic Rat Brain Regions Exposed to Anti-androgenic, Estrogenic, or Complex Endocrine Disruptor Mixtures: Glutamatergic Synapses as Target. Endocrinology. 2015 Jan 21: en20141504.

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Stein, T., Schluter, M., Steer, R., Guo, L., & Ming, X. (2015). Bisphenol A Exposure in Children With Autism Spectrum Disorders Autism Research DOI: 10.1002/aur.1444