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Troublesome Chemical

By Karl Hill

Jeffrey Arterburn

Chemist Jeffrey Arterburn, left, cell biologist Charles Shuster, center, and biology doctoral student Olivia George teamed up to inves- tigate the mechanism by which bisphenol A disrupts cell division.

Bisphenol A disrupts cell division by targeting key protein, NMSU researchers find

A chemical widely used in plastic beverage and food containers can disrupt cell division by interfering with a protein that is critical to the process, a team of New Mexico State University researchers has found.

The recently published results of a study led by Charles “Brad” Shuster, an assistant professor in NMSU’s Department of Biology, and Jeffrey Arterburn, a professor in the Department of Chemistry and Biochemistry, add a dramatic new dimension to the controversy over bisphenol A, also known as BPA.

BPA is used in polycarbonate plastic bottles, food can liners and even some dental sealants and surgical implants. The compound, which acts as a synthetic estrogen, can leach from these plastics, and there is growing concern about the effects it can have on living organisms.

“A lot of animal studies have shown that it causes reproductive abnormalities,” Arterburn said. “It’s really problematic.”

The risk of BPA exposure in humans remains a subject of debate, although the chemical is found in low concentrations in most people who live in developed countries. Recent government-sponsored studies have come to essentially opposite conclusions, with some scientists saying there is no evidence of human health risks from exposure to low levels of BPA while others warn of potential links to cancer, reproductive abnormalities and neurological disorders in humans.

Strong evidence of the chemical’s ability to affect cell division turned up about four years ago, when a geneticist at Case Western Reserve University in Cleveland discovered a sudden, dramatic increase in chromosome abnormalities in the university’s mouse colony.

“She did some detective work and found that the animal care facility had changed the detergent that they cleaned the plastic cages and water bottles with,” Shuster said.

The harsher detergent had caused bisphenol A to leach from the plastics, accidentally exposing the mice to the chemical. To confirm the link, the Case Western scientists deliberately exposed mice to low levels of BPA; again, the mice’s developing eggs showed greatly increased rates of chromosome abnormalities.

“This is where Jeff (Arterburn) and I got interested in it,” Shuster said. “Jeff is interested in the connections between estrogen and breast cancer. I’m interested in the basic mechanics of cell division. We wanted to understand better how this process was occurring, because chromosome segregation errors are important not only during early development – they are also a huge aggravating factor in cancer.”

Cell division

During normal cell division, microtubules are organized into a bipolar mitotic spindle, with two poles on opposite sides of the cell.The chromosomes are attached to microtubules originating from the spindle poles so that each daughter cell gets identical genetic material when the cell divides.

In normal cell division, whether it’s an egg splitting when fertilized (meiosis) or another type of cell dividing into two identical daughter cells (mitosis), the chromosomes line up so that each of the new cells gets the correct number of chromosomes. Critical to this process is a cellular scaffold made of microtubules, which contain a protein called tubulin.

The abnormality seen in the Case Western mouse eggs, in which cells end up with too few or too many chromosomes, is known as aneuploidy. The link between bisphenol A and aneuploidy in the mice seemed conclusive, but the molecular mechanism by which BPA caused the abnormalities remained unknown.

Arterburn and Shuster, working with doctoral biology student Olivia George and other NMSU graduate students, exposed different types of cells – including human cells and sea urchin cells – to BPA and to BPA molecules that had been modified in ways designed to help them identify BPA’s cellular targets. Their study was the first to investigate the mechanism by which BPA interferes with cell division.

“What we have found is that bisphenol A can directly bind to tubulin and actually alter how the microtubules are organized during cell division,” Shuster said.

During normal cell divisions, microtubules are organized into a bipolar mitotic spindle, with two poles on opposite sides of the cell. The chromosomes are attached to microtubules originating from the spindle poles so that each daughter cell gets identical genetic material when the cell divides. Cells exposed to BPA are likely to form three or four poles, so the genetic division “is a random scramble,” Shuster said. “It’s really quite stunning.”

Significantly, Arterburn and Shuster also found that BPA’s effect on cell division has nothing to do with its estrogenic properties. They discovered this by exposing cells to a BPA derivative modified by Arterburn to block the compound’s estrogen activity.

“Those have no estrogenic activity at all, but they are just as potent in affecting and disrupting cell division,” Arterburn said.

So bisphenol A is worrisome from two standpoints, Shuster added – its ability to activate estrogen receptors when they shouldn’t be activated, and its ability to alter the microtubule cytoskeleton during cell division.

Cell exposed to bisphenol

In this cell exposed to bisphenol A, three spindle poles are forming prior to cell division, causing a misalignment of the chromosomes. The daughter cells that result will have too few or too many chromosomes, a condition called aneuploidy.

“Most of us have been thinking about bisphenol A in terms of its possible effects on male reproductive development and other endocrine issues,” he said. “We’re saying there is a new reason to be concerned about this substance and it has to do with chromosome segregation. And these two issues appear to be separate.”

The NMSU researchers intend to seek funding to continue their investigation.

“We’ve got the tools now and we’ve got the foundation,” Shuster said. “Now we can start to ask how exactly do those extra spindle poles form. We know what the target is, but we can’t quite make an absolute connection about how this little molecule interacting with this protein leads to these extra spindle poles.”

Arterburn and Shuster are cautious about drawing conclusions regarding BPA’s potential effects on human health, but they note that the implications are far-reaching.

“For instance, we know that in humans the incidence of chromosome segregation errors during egg maturation increases as women age, leading to an increased incidence of Down syndrome,” Shuster said. “The persistence of this stuff (BPA) in our bodies may be a contributing factor – it could be building on top of what is already a problem.”

A problem in evaluating BPA’s potential for disrupting hormone functions in humans, Arterburn said, “is that these compounds that disrupt the endocrine system can operate at two different levels of concentration. At very low concentrations they initiate one sort of effect; at high concentrations they elicit other biological effects. Most of the toxicity classification that our country uses is based on high dose, but the biology is so complicated.”

While the debate over BPA risks contin- ues, the NMSU study “adds to the literature suggesting we have to take these kinds of compounds more seriously – especially when talking about infants and children, who are developing and have much more cell division going on in their bodies than the average adult does,” Shuster said.


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