May 27, 2013

expert reaction to bisphenol A and brain development in mice

Repeated exposure to low doses of bisphenol A (BPA) were found to cause sex-specific changes in DNA methylation and gene expression in the brain, as well as anxiety-like behaviours on the offspring of female mice, a study in PNAS found. 

Prof Andrew Smith, MRC Toxicology Unit, University of Leicester, and Royal Society of Chemistry’s Toxicology Group, said:

“This publication is in line with other reports suggesting that in pregnant experimental animals bisphenol A may influence the methylation of genes so controlling their action and leading to subtle differences in physiology of offspring.  The work is well organised but its findings emphasize the need for more fundamental research in this area.  Although administered by the authors at relatively low doses possibly compatible with human experience, there are important issues of the degree of exposure to bisphenol A versus the direction of methylation and behavioural/brain changes.   These must be confirmed, clarified and mechanisms resolved before any extrapolation can be made to the human context especially in relation to mental and cognitive disorders.  Indeed, it is unclear how understanding consequences of low bisphenol A exposure fit in the landscape of human exposure to other chemicals.”

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

“This study shows that exposure of pregnant mice to bisphenol A can cause changes in gene expression/function in the brains of offspring after birth and also lead to changes in certain aspects of behaviour. In general the study is well conducted and uses a route of exposure that is human relevant (>95% of our bisphenol A exposure is via our diet), although the method of results analysis is not the most reliable.

“Whilst these findings raise the possibility that comparable effects of bisphenol A could occur in humans, several factors suggest this is unlikely. First, the lowest dose use is still 10-20 times higher than normal human bisphenol A exposure. Second, the endpoints measured showed huge between-animal variation and considering that there were low numbers per group for some endpoints, the likelihood of false positive results is high, and no information on reproducibility of the results is provided (i.e. if the experiment was repeated would the same changes be detected).  Third, if the effects described work through an oestrogen mechanism, they are unlikely to be human relevant because pregnancy levels of oestrogens in humans are far higher than in mice and would swamp any weak oestrogenic effects of bisphenol A.”

Prof Tamara Galloway, Professor of Ecotoxicology, University of Exeter, said:

“The doses of BPA in the study are in an appropriate concentration range, spanning the suggested recommended tolerable limit for BSA in humans of 50 micrograms/kg body weight/day. As the authors quite rightly point out, there are differences in metabolism of BPA between humans and rodents, and they have taken account of this as far as they can in their planning. The doses have been administered orally, which is in line with current thinking on appropriate route of exposure. Earlier experiments by other groups have been criticised for administering BPA intravenously, which would bypass normal routes of metabolism in the gut.

“The non-monotonic dose response curves that the authors have obtained for many of the measured endpoints have also been reported by many other researchers, including ourselves, in both in vivo human population studies and in vitro laboratory experiments. I agree with their conclusion that environmentally relevant doses of BPA may induce very different effects dependent on the level of exposure and support the view that appropriate risk assessment of BPA toxicity should consider multiple low dose exposures.”

‘Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure’ by Kundakovic et al., published in PNAS.