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Synopsis by Pete Myers, Ph.D. |
New results published in the Proceedings of the National Academy of Sciences confirm that exposure to bisphenol A in the womb changes gene behavior in mice and thereby causes genetically identical animals to develop differently. The new findings focus on BPA's ability to remove 'protective molecules' that normally prevent genes from being turned on at the wrong time or in the wrong tissue.
The research team, from Dr. Randy Jirtle's laboratory at Duke University, also reports that the effect can be counteracted by supplementing the maternal diet during pregnancy with genistein, a phytoestrogen found in soy. |
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Over 50% of canned goods on US market shelves are lined with a BPA-based resin. The cans in this photograph have not been tested. It is not possible to identify the BPA lining via visual inspection.
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The study adds to the growing body of scientific literature on the crucial importance of epigenetics for health. While inheritance is one vital part of genetic risk, factors that alter how genes behave, once inherited, can have effects just as damaging as inheriting an abthat increases risk of disease. These factors, collectively referred to as 'epigenetic', control when inherited genes are expressed (turned on). Research now clearly shows that environmental factors, including contamination, diet and experience can alter epigenetic control of gene expression.
While the results might appear to imply that adverse impacts of BPA can be averted with dietary supplements, there are two key points that make that conclusion wrong:
- Genistein may counter this effect of BPA, but genistein itself has been linked to adverse effects following developmental exposure. According to Dr. Frederick vom Saal, an expert on endocrine disruption, "Trying to balance the effect of BPA with genistein would be like recommending that barbituates are fine if you also take methamphetamine. I can't imagine any physician would support that prescription."
- Bisphenol A works through multiple genetic pathways. There is no evidence to suggest that genistein is effective at balancing effects of BPA that are mediated by other mechanisms.
Context: How an organism develops depends crucially upon not just the genes it inherits, but also upon how those genes behave. Healthy development depends upon genes being turned on and off when they are needed, a process geneticists call 'gene expression.' As tissues begin to develop in the embryo, while they all contain the same genes, epigenetic factors control which genes are turned on or off in which tissues.
When gene expression goes awry, the consequences can affect life-long health, and even cause changes in adult health that are not detectable at birth. This process is called fetal programming. Many health conditions are affected by fetal programming, including heart disease, diabetes, obesity and cancers.
One of the genetic mechanisms involved in fetal programming is DNA methylation. This is the attachment of a methyl group, a carbon atom plus three hydrogen atoms, in a position on the gene that prevents signaling molecules from reaching the 'switch' --called a promotor site-- to turn the gene on. Genes methylated at very specific sites on the DNA are "silenced" --that is, unable to function-- so the proteins whose synthesis they encode are not produced. Methylation is a key natural process that allows cells to specialize despite the fact they all contain the same genes. They differ instead in epigenetic settings, like methylation, so that liver cells produce enzymes necessary for livers while toenails become toenails.
The yellow Agouti mouse has emerged as an important tool for studying epigenetic programming. It is named for the fact it has a mutation in the Agouti gene, which in mice affects hair color and weight and also influences risk of diabetes and tumors. The yellow Agouti's mutation makes yellow Agouti mice more likely to be yellow and also more likely to be obese. The reason why it has become important for studying epigenetics is because dietary and other factors can prevent the gene from being turned on.
The Agouti gene is especially interesting because it is what geneticists call a 'metastable epiallele.' Methylation patterns at certain points on the gene are set randomly early in development. This means that individuals with identical genes can nonetheless vary in how they appear because they differ in methylation patterns.
For example, previous work by Jirtle's lab has shown that genistein in the diet of yellow Agouti mice increases methylation of a specific gene responsible for the yellow color and also for an increase in obesity. With the gene unable to turn on, mice fed genistein and other methyl-rich dietary supplements are more likely to be colored like normal mice, and also not to be obese.
For an excellent general-audience introduction to epigenetics, including a discussion of Jirtle's research, read 'DNA is not destiny' (Discover Magazine). |
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What did they do? In the first round of experiments, Dolinoy et al. fed food contaminated with BPA to female mice beginning 2 weeks prior to mating from then daily through pregnancy and lactation. They estimate the daily intake was approximately 10 mg/kg body weight/day, which is high compared to work by Soto et al., vom Saal et al., etc., but one-fifth of the dose (50 mg/kg/day) that was used, along with a safety factor of 1000, by the EPA to set the current safe level (50 µg/kg/day).
They examined the coat color of the offspring and measured DNA methylation at nine sites in the Agouti gene, and also measured methylation on another metastable epiallele, CabpIAP.
In a second experiment, Dolinoy et al. repeated the procedures above-- feeding females BPA- contaminated food prior to pregnancy and then through lacation-- but this time they supplemented the food with nutrients known to increase DNA methylation, including genistein and folic acid.
What did they find? Exposure to BPA changed the percentage of different coat color types in the offspring (graph below). Yellow mice were more common while brown (psuedo-agouti) mice were less frequent than in litters born to mice not exposed to BPA.
Graph and photo adapted from Dolinoy et al.
In the photograph above, mice are arranged from left (yellow) to right (pseudo-agouti) showing the range of color variation produced by variation in methylation levels (low on left, high on right) of the Agouti metastable epiallele. The graph above that compares the distribution of color types in BPA-exposed vs control animals. The change in distribution is highly significant (p= 0.007).
BPA-exposure reduced the percentage of cells with methylation at the nine sites on the Agouti gene by 31%, from 39% methylated in controls to 27% methylated in BPA-exposed (p= 0.004). Using other statistical procedures, they were able to show that the effect of BPA on coat color was largely mediated by BPA's effect on methylation.
When they compared methylation patterns from a range of mouse tissue types (brain, kidney, liver and tail), they found that there was little variability in methylation within one animal. There was much greater methyaltion variability between animals. This means that the methylation patterns are likely to have been established early in embryonic development.
And when they looked at methylation patterns on another gene, CabpIAP, they found that BPA-exposed animals had lower methylation rates than control. From this they conclude that BPA can cause reduction in methylation on multiple mouse genes. |
When they repeated the first experiment, contaminating the food with BPA but also adding nutrients known to increase methylation, the effect of BPA was eliminated. Not only was the distribution of coat color the same as the control group, but methylation patterns of control and experimental animals were comparable.
What does it mean? Dolinoy et al. establish clearly that BPA alters methylation patterns early during fetal development and that the effect is sufficient to change the appearance of the animal. They recorded no adverse effects on reproductive outcome, litter size or offspring health, although given their methodology it is unlikely they would have detected many of the effects observed in animal experiments that have raised concerns about BPA following fetal exposure to low doses, including severe chromosomal aberrations, precancerous prostate lesions, breast cancer, etc.
The dose they used, approximately 10 mg/kg/day, is thought to be far beneath the level of common human exposure. This assumption may prove invalid, if new calculations of the exposures necessary to produce the levels of biologically-active BPA found in most people, 1-2 nanograms/milliliter, can be confirmed and extended: Vandenberg et al. estimate that daily human exposure necessary to produce serum levels within that range are at least 500 µg/kg/day (1/20th of Dolinoy's dose), and may be significantly higher if, as some data indicate, humans metabolize BPA more rapidly than rodents.
Does a diet rich in nutrients that promote methylation offer a prevention strategy for avoiding potential health effects of BPA? As noted above, this is unlikely. BPA works through multiple genetic mechanisms; it is highly unlikely that all are counterbalanced by nutrients promoting methylation. And excess methylation can produce adverse effects.
Resources:
Dolinoy, DC, J Wiedman, R Waterland and RL Jirtle. 2006. Maternal Genistein Alters Coat Color and Protects Avy Mouse Offspring from Obesity by Modifying the Fetal Epigenome. Environmental Health Perspectives 114:567-572.
Epigenetics. Wikipedia.
Murray, TJ, MV. Maffini, AA Ucci, C Sonnenschein
and AM. Soto. 2006. Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure. Reproductive Toxicology 23: 383-390.
Myers, J.P. 2006. Good genes gone bad. American Prospect.
Timms, BG, KL Howdeshell, L Barton, S Bradley, CA Richter and FS vom Saal. 2005. Estrogenic chemicals in plastic and oral contraceptives disrupt development of the fetal mouse prostate and urethra. Proceedings of the National Academy of Sciences, 10.1073/pnas.0502544102.
Vandenberg, LN, R Hauser, M Marcus, N Olea and WV Welshons. 2007. Human exposure to bisphenol A (BPA). Reproductive Toxicology, accepted for publication.
Watters, E. 2006. DNA is not destiny. Discover.
Wetherill, YB, BT Akingbemic, J Kannod, JA McLachlane, A Nadalf, C Sonnenscheing, CS Watson, RT Zoelleri and SM Belcher. 2007. In vitro molecular mechanisms of bisphenol A action. Reproductive Toxicology doi:10.1016/j.reprotox.2007.05.010.
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