Thirty years after PCBs (polychlorinated biphenyls) were banned in the U.S., UC Davis researchers have discovered how the class of toxic chemicals may cause behavioral disorders in some children, even at the low levels that people encounter now.
The series of three new studies together reveal that PCBs can disrupt cellular signals crucial for normal brain development and function.
Earlier studies linked PCBs to a range of neurological impairments such as autism, ADHD and seizure disorders.
The new studies provide a compelling explanation for this link and furthermore implicate the most abundant and least regulated PCBs – which were once thought to pose less threat to human health – as particularly harmful agents in the developing nervous system, the researchers said.
“Not all PCB forms will have this same effect, but the work represents a clear picture of the damage that these chemicals – and ones like it – can cause,” said Thomas Zoeller, a biology professor at University of Massachusetts, Amherst who was not involved in the studies.
PCBs were used in a wide variety of products such as electronic components, pesticides and flame retardants. They do not easily degrade and substantial amounts persist in the environment, accumulating in the air and in fish that people consume from hotspots like Chicago and the Great Lakes.
In the first study, published in Environmental Health Perspectives, researchers simulated in animals the type of PCB exposure that children might have in order to find out how the chemicals alter the way brain neurons (cells) develop.
The researchers exposed rat pups in utero and during weaning by feeding mother rats a mixture of PCBs similar to those found in the environment. Compared to their untainted counterparts, pups that had low levels of PCB exposure exhibited slower learning curves in a water maze exercise designed to stimulate patterns of neural growth associated with learning and memory.
In brain regions affected by developmental disorders, PCBs altered the plasticity (shape) of neurons, as well as the changes in neural growth and plasticity typically observed with water maze training. The researchers also noticed higher levels and activity of calcium channels in neurons known as ryanodine receptors (RR), which generate electric signals that influence plasticity.
“We think, in part, it’s because that the function of the RRs have been altered [by PCB exposure] over a long period of time [that we saw all these changes],” said Isaac Pessah, professor and chair of the department of molecular biosciences at the UC Davis School of Veterinary Medicine, who co-authored all three studies.
At higher doses, these effects are not seen because the PCBs trigger defensive mechanisms in the body that remove the chemicals before they reach the brain, he explained.
To get a clearer sense of the cause and effect relationship between PCBs and RR activity in the second study, which was published in Toxicology and Applied Pharmacology, the researchers exposed rat brain tissue slices to individual PCBs.
Although one was more potent than the other, both of the tested PCBs had excitatory effects on brain tissue at low doses, which could be dampened by adding a compound that blocks RR signaling.
Normal brain function depends on a fine balance between excitatory and inhibitory pathway signals in the nervous system, and we showed that PCBs can disrupt this balance through the RRs, Pessah explained.
“In kids with autism [and some other disorders], the inhibitory side seems to be not operating quite as well as it should be,” he said. “So these kids tend to start out being somewhat imbalanced,” a problem that can be intensified “…with compounds [like PCBs] that enhance the excitatory side preferentially over the inhibitory side.“
The researchers sealed their conclusion with their third and newest study, which was published in Public Library of Science – Biology. They captured high resolution snapshots of PCB molecules directly interacting with RRs and locking the channels in the open active form, which account for the PCB effects seen in the first two studies.
“We found out that it was only those [PCBs] which act at [and activate] the RR … that were causing these effects on neurotoxicity and excitability,” said Pamela Lein, lead author of the Environmental Health Perspectives animal study and an associate professor in the department of molecular biosciences at the UC Davis School of Veterinary Medicine.
Because certain populations may be at higher risk for PCB-linked developmental disorders, the researchers next plan to study PCB effects on mice that carry some of the same RR genetic variants that humans do.
“We would predict that people that have genetic mutations that target [signaling] balance in their neurons would be more at risk for developing PCB developmental neurotoxic effects,” Lein said. “So [this type of study] might be able to help us … eliminate or to protect and prevent some problems in people by minimizing their exposure to PCBs.“
The findings also raise speculations that chemicals similar to PCBs that are widely used today might target RR function and contribute to impaired brain development, the researchers said.
“Without this work, the scientific community and government regulatory agencies are stuck in a quagmire of ambiguity about the relationships between human disease and chemical exposures and the relative safety of our living conditions,” Zoeller said.
ELAINE HSIA can be reached at campus@theaggie.org.
