Genes change message after newborn rats given BPA.
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Doshi, T, SS Mehta, V Dighe, N Balasinor and G Vanage. 2011. Hypermethylation of estrogen receptor promoter region in adult testis of rats exposed neonatally to bisphenol A. Toxicology http://dx.doi.org/10.1016/j.tox.2011.07.011. |
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| The lining inside most food and beverage cans contains bisphenol A that is is a source of exposure for people of all ages. |
The findings add to a growing body of research showing that BPA can impact the way genes are coded and then interpreted later in life during sexual maturity. Such changes have been documented in the brain, prostate and uterus.
The early-life exposures added chemical groups to two important genes on the DNA in the testes and increased the levels of enzymes that control these epigenetic additions. Due to the broader impact on these enzyme levels, newborn BPA exposure may affect more genes and levels of control than identified in the current study.
Context
Bisphenol A (BPA) is one of the most produced chemicals in the world. Its biggest uses are in the production of polycarbonate plastics that are used to make some drinking bottles, food packages and compact disks, and in epoxy resins that line food and drink cans. Some dental sealants and thermal paper receipts also contain BPA.
BPA's wide use and ubiquitous presence in consumer products and packaging results in nearly universal human exposure in developed countries. People can ingest, absorb or inhale BPA. Multiple studies find that more than 90 percent of the U.S. population has detectable levels of BPA in their urine.
Associated with this pervasive level of BPA exposure is a body of evidence showing health impacts from BPA exposure, especially during development in the womb and in early life. Mounting experimental and human studies link exposure to a wide range of health issues, including reproductive cancers (breast and prostate), behavior, infertility, obesity and diabetes.
Animal studies document a variety of health effects of BPA due to its ability to disrupt hormonal activity. BPA is a weak estrogen, and as such, can change gene expression patterns in several different tissues to alter development. Males seem particularly vulnerable.
Early-life exposure to BPA may result in male reproductive deficiencies later in life at sexual maturity. These can include impaired testicular development and altered sperm production. However, the way early-life exposure may alter male reproductive effects is not known.
Epigenetics refers to biological changes to DNA structure that do not alter the DNA's basic code sequence. These structural changes then lead to changes in how the affected genes function. The modifications are permanent and can be passed to future generations.
Often, adding a chemical methyl group to the DNA – known as methylation – makes epigenetic changes. DNA methylation often prevents the altered gene from being read and thus, reduces the amount of the chemical product made by the gene, which alters its function.
What did they do?
The researchers injected newborn male rat pups with 2.4 micrograms of BPA in sesame oil per day for the first five days after birth. Experimental control pups received only the oil injection during this period.
This BPA dose was chosen because it is the lowest dose previously found to impair male fertility. Further, this dose is relevant to human exposures. It is within the range of documented children's and adult occupational exposures.
After treatment, pups were raised to adults. Genetic material – DNA and RNA – and proteins in the testes tissues were analyzed. The researchers measured the degree of epigenetic modification of the DNA, the amount of RNA coding that produce the estrogen receptors and the amount of proteins in the testes that are responsible for methylating DNA.
Estrogen hormones play an important role in male reproduction. The molecular signals sent by estrogen hormones alter the estrogen receptors in the testes in ways that change gene expression levels. In this way, estrogen signaling plays an important role in maintaining male reproductive health.
What did they find?
BPA treatments of male rat pups during the first five days after birth resulted in epigenetic changes to the structure of DNA in the adult testes. These were coupled with changes in testicular gene activity in the sexually mature adults.
The DNA epigenetic marks were altered on certain genes in the adult rats. Specifically, two genes that provide directions to build two forms of estrogen receptors – a process called encoding – were affected. The BPA treatment increased the frequency of methyl groups – known as hypermethylation – attached to specific DNA codes in the promoter regions of the two genes. Promoter regions control the rate at which the genes are read. These epigenetic changes were associated with decreased expression levels of the two estrogen receptors.
Further, early-life treatment increased testicular levels of two enzymes that regulate the production and maintenance of epigenetic methylation markers. These enzymes methylate the DNA over a broad range of genes.
Therefore, the observed BPA-induced hypermethylation may not be limited to only the two specific estrogen signaling genes focused on in this study but may impact a far broader range of testicular genes and impact multiple levels of reproductive control.
What does it mean?
In this study, BPA permanently modified genetic markers in the testes of exposed rat pups that control expression of the genes and dictate their long-term function. The DNA markers are called epigenetic controls.
These results strongly demonstrate that developmental BPA exposure has the ability to alter the regulation of reproductive function much later in life, long after the BPA treatment has left the animal’s body. The findings advance understanding by honing in on the molecular cues and signals that BPA exposure affects.
The study identified two key ways that BPA impacted the male rats' epigenetic controls. First, chemical markers were added to key parts of the DNA responsible for estrogen signals. The markers – called methylation – alter how the estrogen-related genes function. In this case, they reduced gene expression in the sexually mature rats. Since estrogen hormones are necessary for normal development and function of the male reproductive system – including testes development and sperm production – hormone level changes can lead to abnormalities and infertility.
Second, early-life exposure to BPA increased the levels of enzymes that make and add the methyl groups to the DNA. This finding aligns with prior studies that show estrogen increases the action of these enzymes. As a weak estrogen, BPA could affect them as well. Affecting methylation rates may impact more genes than were identified in this study.
Overall, the study details a specific and powerful biological mechanism – epigenetic modifications – through which a limited, post-birth BPA exposure altered testicular control mechanisms past the age of sexual maturity. Because of the health implications of these changes, the authors suggest "the need for toxicological assessment of endocrine disruptors at epigenetic level and analysis of genome-wide DNA methylation pattern to be taken into consideration for risk assessment."
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