Class of PCBs causes developmental abnormalities in rat pups

Scientists have determined that a specific class of PCB causes significant developmental abnormalities in rat pups whose mothers were exposed to the toxicant in their food during pregnancy and during the early weeks when the pups were nursing.

This class of PCB traditionally has not been considered particularly hazardous.

The pups were estimated to have levels of the toxicant in their blood that were roughly equivalent to those found in the blood of breast fed babies of mothers exposed to extremely high levels of the toxicant from contaminated fish, soil, water and air in high-risk environments.

The study, reported in the on line, Early Edition of Proceedings of the National Academy of Sciences the week of April 23-27, showed that the toxicant altered the rat pups’ auditory cortex, the part of the brain that processes sound. The neural circuitry of this region was disorganized and the nerve cells had a decreased capacity to change, or “learn,” in response to sound. The capacity of the brain’s cortex to change in response to stimuli contributes to the progressive development of cognitive function.

In children with a variety of developmental disorders, including language impairments and autism, the auditory cortex responds abnormally to sound. Some scientists believe this is the basis of the conditions.

While the scientists emphasized that their finding did not demonstrate that the toxicant causes developmental disorders, they said that, given its severe impact in the rat pups and the prevalence of this class of PCB in the environment - known as non-coplanar PCBs—and related chemicals warrant serious attention.

“The study indicates that there are chemicals out there, this being just one example, that could profoundly affect development,” says Tal Kenet, PhD, who led the research while a postdoctoral fellow in the lab of senior author Michael Merzenich, PhD, UCSF Francis A. Sooy Professor of Otolaryngology and a member of the Keck Center for Integrative Neuroscience at University of California, San Francisco.

“This is a red flag,” says Merzenich. “The impact of this class of chemicals, whose toxicity has been under-appreciated, must be studied in human populations, and fast.”

The finding builds on recent cell culture studies by co-author Isaac Pessah, PhD, professor of molecular biosciences at University of California, Davis, showing that non-coplanar PCBs significantly influence chemical and electrical signaling between neurons that affects brain development and learning.

While developmental disorders have a strong genetic component, many scientists, including the authors, believe that, in some circumstances the disorders are only expressed when environmental factors act upon inherited mutated genes.

“We know that some environmental risk applies in the early developmental history of the brain in the fetus and baby,” says Merzenich, a pioneer of studies on the neural basis of learning and memory and the neural origin of developmental disorders.

“People have struggled with what kinds of factors these might be. I think environmental poisons, including the chemical we’ve examined in this study, are very good candidates.”

Given that the rat pups in the study did not have a genetic susceptibility to a developmental disorder, the scientists suspect that the vulnerability might be greater in genetically susceptible human populations.

The study did not attempt to distinguish whether the PCB affected the rat pups’ developing brains while they were gestating or while they were nursing, but scientists reported in 2003 that infants who were breast fed for more than three months had 6.6 times higher levels of PCBs in their blood plasma than infants who did not breast feed.

This finding, coupled with other factors—particularly an increase in the rate and duration of breast feeding in the United States, epidemiologic evidence of negative effects on cognitive function in children, and lab evidence in rats, following PCB exposure in high-risk environments - is noteworthy, says Kenet, who is now a junior faculty member at Harvard Medical School and Massachusetts General Hospital.

“Breast feeding is by far the optimal choice for the vast majority of infants, given its indisputable nutritional and immunological benefits,” says Kenet, “and our findings, conducted in rats, by no means suggest women should alter their nursing practice. The finding does suggest the need for studies in human populations to determine whether there are possible risks associated with breast feeding in cases of extreme exposure to this class of chemicals, in particular in infants who may have a genetic predisposition to developmental disorders based on their family history.”

Polychlorinated biphenyls (PCBs), used mostly as coolants and lubricants beginning in the 1930s, were banned in 1977. Early toxicology studies focused mostly on a subset of PCBs known as coplanar PCBs, which were shown in cell culture and animal models to pose a serious health risk. Recent studies, however, have shown that non-coplanar PCBs are particularly stable, are less susceptible to degradation by organisms in the environment, and predominate in environmental and human tissue samples over their counterparts.

In the current study, the scientists focused on a non-coplanar PCB known as PCB95, which is exemplary of a type of PCB prevalent in the environment, and has qualities that could make it among the more hazardous.

In the primary experiment, one set of adult rats was exposed to the toxicant in their food during pregnancy and during the first three weeks after giving birth, when they nursed
their pups. Another group was fed normally. After both sets of pups had been weaned, the researchers recorded the electrical activity of neurons in their primary auditory cortex, the first sensory region to develop in the cortex.

The results were dramatic, says Kenet. While the brain region of the pups raised without exposure to the toxicant was developing typically, the brain region in the pups exposed to the toxicant in utero and while nursing was profoundly altered.

“The animals could hear, but their brain’s representation of what they heard was grossly disturbed,” says Merzenich.

In one pronounced change, the balance of inhibitory and excitatory signaling between nerve cells, which contributes to the appropriately controlled responses of the brain to stimuli, was disrupted. Strong evidence indicates that there is imbalance in signaling throughout the brain of children with some developmental disorders, such as autism, says Merzenich.

In a secondary experiment, the toxicant-exposed pups were raised in a modified sound environment in which they were exposed to continuous tone or noise pulses. It was here that the auditory cortex’s decreased capacity to change in response to sound was revealed.  “This activity is crucial in the developing brain,” says Merzenich. “Interruptions in these early-learning progressions contribute to learning-related challenges.”

As the auditory cortex is the first sensory region to develop, its abnormal development in the rat pups could be just a hint of more pervasive effects of exposure, the scientists say.

PCB95 is closely related in its chemical structure to polybrominated diphenyl ether (PBDE), which is difficult to study and has only begun to receive attention for its environmental effects, says Kenet. It has been used in large quantities in the last 25 years, mostly in fire retardation in home and office furniture and electronics.

“We’ve done as yet unpublished studies with PDBEs,” says Pessah, director of the UC Davis Center for Children’s Environmental Health and an autism researcher with the UC Davis M.I.N.D Institute. “The current finding could be just the tip of the iceberg.”

Other co-authors of the study were Robert Froemke, PhD, and Christoph Schreiner, MD, PhD, both of the Keck Center for Integrative Neuroscience at UCSF.

The study was funded by Cure Autism Now, the UC Davis M.I.N.D. Institute, the Jane Coffin Childs Foundation for Medical Research, the Sandler Program in Basic Sciences, the National Institutes of Health and the U.S. Environmental Protection Agency. 

UCSF is a leading university that advances health worldwide by conducting advanced biomedical research, educating graduate students in the life sciences and health professions, and providing complex patient care.

For more information:

Kenet:
http://www.nmr.mgh.harvard.edu/martinos/people/showPerson.php?people_id=667

Merzenich laboratory:
http://keck.ucsf.edu/neurograd/faculty/merzenich.html

UCSF Magazine, Dec. 2004, “Grasping Autism” http://pub.ucsf.edu/magazine/200412/autism.html

UCSF Magazine, 2003, “Faculty Entrepreneur”
http://pub.ucsf.edu/magazine/200305/learningcurve.html

Pessah:
http://www.ucdmc.ucdavis.edu/mindinstitute/ourteam/faculty_staff/

UC Davis Mind Institute:
http://www.ucdmc.ucdavis.edu/mindinstitute/

UC Davis School of Veterinary Medicine - Center for Children’s Environmental Health:
http://www.vetmed.ucdavis.edu/cceh