The National Institute of Environmental Health Sciences (NIEHS), the National Toxicology Program (NTP), the Food and Drug Administration and NIEHS-funded University researchers are working together in a collaborative venture to assess the toxicity of BPA following whole-life oral exposure in a rodent model.
Five years after the collaboration--the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA)--launched, results are beginning to come in that will allow researchers to compare the effects of a wide range of BPA doses on a variety of endpoints related to multiple health concerns. Researchers across the country are considering whether this chemical affects a variety of organ systems, including the brain, various behaviors, reproduction and fertility, accumulation of fat tissue, heart disease, the immune system, and several types of cancers.
“The idea of this Consortium is to examine the potential systems that have been previously suggested to be affected by BPA,” said Cheryl Rosenfeld, an associate professor of biomedical sciences at the University of Missouri and heads one of thirteen academic research groups involved in the project.
Recent results from this partnership looked at spatial navigation learning and memory. Rosenfeld found that BPA could potentially hinder the ability of female rats to solve the maze, suggestive of cognitive changes. The effects varied by sex and BPA dose.
Approved by the FDA in the early 1960s, BPA can be found in a wide variety of products, including plastic food and drink containers with recycle codes 3 or 7, toys, and the linings of metal cans and water pipes. BPA has structural similarities to estrogen and has been shown to act as a weak estrogen. It may also potentially act by other pathways.
In Rosenfeld’s experiment, researchers at the FDA’s National Center for Toxicological Research (NCTR) dosed pregnant rats orally with one of three doses of BPA (2.5, 25, and 2500 mg/kg body weight/day) on a daily basis. After the baby rats were born, researchers continued to provide the same dose of BPA to them as their mothers had received.
When the rats were three months old, they were tested in a circular maze with twenty possible exit holes, one of which was randomly chosen to be escape hole. Researchers tested the rats daily and determined whether they could solve the maze in 5 minutes and, if so, how long it took them to do so.
“Rats can solve the maze in three ways,” Rosenfeld said. “They can run around the maze in a spiral pattern, hugging the outer walls, and work their way in until they find the correct escape hole, in what is called a serial search strategy. Or they might move aimlessly in the maze, and that's called an indirect search strategy,” Rosenfeld added. “In this case, the rats seemingly find the correct escape hole by random chance.”
Lastly, the rats “can travel directly from the center of the maze to the correct escape hole”, Rosenfeld said. The third strategy is considered the most efficient method because the rats rapidly enter the correct hole.
Sarah Johnson, a graduate student and first author on the paper, assessed each rat’s performance in the maze using a three-point tracking program that recognizes the rat’s nose, body, and tail.
By using this program, Johnson measured their performances in terms of the total distance traveled, the speed at which the rat ran the maze, how long it took the rats to solve the maze (latency), and how often the rat sniffed at an incorrect hole.
The last two parameters are considered the best gauges of spatial navigation learning and memory.
“What you expect to see is that they should start learning where that correct escape hole is” Rosenfeld said. Thus, their latency and sniffing incorrect holes should decrease over time.
Rosenfeld’s group found that female rats that were exposed to the highest dose of BPA since fetal development were less likely to find the escape hole than controls.
As for how this study may translate to people, “the same brain regions control identical behaviors in rodents and humans,” Rosenfeld said. She considered it a starting point for setting up experiments that take into consideration sex differences in cognitive behaviors and neurological responses to BPA.
Meanwhile, immediate next steps for the Rosenfeld group include analyzing tissue collected from the brains of rats that had been tested in these experiments. They will measure DNA methylation and expression of genes that may be required for these cognitive behaviors. The overarching goal is to determine whether molecular changes in the brain may lead to the observed behavioral alterations.
NIEHS grant U01 ES020929 supported this research. Additional coauthors include Mark R. Ellersieck, Michelle S. Painter, and Angela B. Javurek of the University of Missouri, Thomas H. Welsh Jr. of Texas A&M University, and Luísa Camacho, Sherry A. Ferguson, Sherry M. Lewis, and Michelle M. Vanlandingham of the Food and Drug Administration/National Center of Toxicological Research. Read the full study on the Hormones and Behavior website and browse the supplementary data for this work.
Hormones and Behavior