ROUND-UP: Consumer chemical affects development of isolated neurons (PNAS*) – experts respond

Tue Feb 26, 2013

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Bisphenol A (BPA), a chemical commonly found in plastics, may interfere with the formation of healthy neurons in developing embryos, say US scientists. The authors found exposure to BPA disrupted the chemical balance of isolated developing neurons, which they say could lead them to grow abnormally.

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Emeritus Professor Michael Moore is a toxicologist and former director of the National Research Centre for Environmental Toxicology at the University of Queensland

“Bisphenol A (BPA) has had a lot of bad press in recent years. It has been linked to a number of human neurological conditions. This ‘in vitro’ study has examined the effects of bisphenol A on cortical neurons from rats, mice and humans. The results it has produced are consistent with the epigenetic mechanisms seen by others and with NIEHS position of 2007 that ‘in vitro’ studies can help to dissect complex ‘in vivo’ outcomes that are cell and tissue specific.

It is generally agreed that, in humans, exposure to BPA is low and continuous both’ in utero’ and in later life. It remains unclear whether consequences of such exposure can be accommodated to ameliorate the changes engendered by exposure to BPA. There are a number of health outcomes, which have been linked to BPA exposure, including anxiety and ADHD. However these have largely been associated with animal studies and may not necessarily relate to human outcomes. Short-term ‘in vitro’ experiments of the type seen in this study of provide valuable pointers towards probable mechanisms that might be observed in humans but are two steps removed from proof of causation of disease. Future human studies possibly of an epidemiological nature will benefit from the outcomes of studies like the current one which provides us with at least one mechanistic reason for changes in brain function.

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Dr Ian Musgrave is a Senior Lecturer in the Faculty of Medicine, University of Adelaide

“This is a very interesting study. Unfortunately, it’s linkage to environmental exposure to Bisphenol A is misleading, in that the concentrations used in this study are hundreds to thousands of times higher than humans would be exposed to through the maximal permissible level of BPA in food. Thus this study, while it throws light on

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aspects of gene regulation, is not relevant to human exposure to this chemical.

In the first part of the study, cultured nerve cells were exposed to relatively low levels of BPA. However, these low levels are around 100 times greater than the blood levels expected from exposure to the highest permitted levels of BPA. Also, direct exposure of these cells to BPA does not reflect the levels that brain cells in the body would be exposed to.

In the second part of the study, female mice were fed BPA containing food and the effects on the brain of the offspring were studied. In terms of human exposure, the concentrations of BPA fed were 1000 times higher than the maximal permitted level in human food, so not relevant to human exposure.

While the study establishes that it is possible to manipulate how genes are switched on in the developing brain, and that some of these genes may have a significant effect on processes relevant to brain function, the concentrations of BPA in this study are well beyond that which would be experienced by humans.”

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Professor Andrew Bartholomaeus is Adjunct Professor of Toxicology and Pharmacy, School of Pharmacy, University of Canberra

“This study seeks to identify a mechanism for effects that have not been demonstrated to occur, using a method that is not relevant to the normal route of exposure. More specifically, the study uses techniques that bathe excised tissues in BPA, in a form not found in the body from BPA consumed in food, in a non-physiologically meaningful environment. BPA consumed in food or drink is rapidly and essentially completely metabolised before it enters the blood stream so cells within the body are not exposed to free BPA. The effects claimed to be caused by BPA in many of the references cited were produced by injecting BPA directly into the body of animals or directly into the blood stream and are therefore not relevant to human exposure to minute levels of BPA in the food or drink consumed. The paper by Cabaton for example (ref 11) used osmotic pumps inserted under the skin of the animals to deliver the BPA, a route of administration not commonly associated with soft drink consumption. Other studies cited in reviews referenced by the authors as a basis for the proposed effect they are investigating, use injections under the skin, insertion of implants under the skin and other approaches that bypass the protective metabolism of BPA that is ingested as food or drink. Human studies purporting to show associations between BPA ingestion or excretion and a myriad of health effects are generally cross sectional epidemiological studies. These types of studies are the weakest form of epidemiological study and routinely throw up associations that cannot be confirmed as real by better designed and more robust approaches. That is, they are more likely to be irreproducible than real. Claimed associations between BPA metabolites in urine and developmental outcomes in humans are of this type.”

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Professor Ian Rae is Honorary Professorial Fellow in the Faculty of Arts at the University of Melbourne and Former President of the Royal Australian Chemical Institute

“The clinical results show that sensitive tissues exposed to very low concentrations of BPA experience adverse effects. It is not clear whether these tissues would ever be exposed in this way given normal ingestion patterns and known elimination pathways for BPA . Population studies are impossible, of course. Studies listed on the website of Food Standards Australia New Zealand (www.foodstandards.gov.au) have indicated very low levels of threat from BPA toxicity, but it would be prudent for them to be revisited from time to time since this is an active area of clinical research and new findings need to be carefully assessed.”

Additional comment from our colleagues at the UK SMC:

Prof Richard Sharpe, Research Group Leader/Professor, MRC Centre For Reproductive Health, Edinburgh University said:

“This is an interesting and well-conducted study that has explored the potential effects of bisphenol-A on human and rodent neuronal development in vitro. Clear effects of exposing the neuronal cells to 100nM bisphenol A are shown. Interesting though the effects are from a mechanistic point of view, they have no relevance to human health because the concentration of bisphenol A used, exceeds human exposure by ~100,000 times (and this is probably a conservative estimate). As the motivation for the studies was publications suggesting an association between bisphenol A exposure and later behavioural problems in children, this would not provide any linking/supporting evidence because of lack of credibility with the doses used.

This study is reminiscent of many similar studies with bisphenol A in vitro or in animal studies – many show convincing effects on various biological processes relevant to human health, but they always involve doses that are in a different ballpark to human exposure. When realistic doses are applied (i.e. those to which humans are internally exposed), no effects are found – although I hasten to add that most such studies never explore human-relevant doses.”

[*Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter, Yeo, M. et al., PNAS Online Early Edition, February 25, 2013-March 1, 2013]