PCBs affect learning by stunting brain nerve development.

Nov 06, 2008

Yang, D, KH Kim, A Phimister, AD, Bachstetter, TR Ward, RW Stackman, RF Mervis,  AB Wisniewski, SL Klein, PRS Kodavanti, KA Anderson, G Wayman, IN Pessah and PJ Lein. 2008. Developmental exposure to polychlorinated biphenyls interferes with experience-dependent dendritic plasticity and ryanodine receptor expression in weanling rats. Environmental Health Perspectives doi: 10.1289/ehp.11771 .



Synopsis by Heather Hamlin and Wendy Hessler

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In a unique study, researchers show that exposure to PCBs in rats interferes with learning by stopping the brain from forming complex nerve networks essential for memory and intellect. In essence, the exposure prevented nerves in the rats' brains from changing as a result of experience.

This effect could underpin some of the impacts that PCBs have on children's ability to learn.

 
 
 
 

Context

Polychlorinated biphenyls, or PCBs, refers to a group of chemically related compounds that were used extensively in coolants, pesticide extenders, caulking sealants, carbonless copy paper, wood floor finishes and many other products. Although PCBs were banned in the United States in the 1970s, and most other industrialized countries since then, they are extremely stable chemicals and do not readily break down in the environment.

Although it has been decades since their extensive use, PCBs are still found at sometimes extremely high concentrations in animals and humans around the world. Since PCBs tend to accumulate in fatty tissues, they are a common contaminant in human breast milk (Barr 1992). Disturbingly, environmental PCBs represent only a fraction of the world’s PCB supply. The lion’s share is still in use and could eventually enter the environment. Today, the primary sources of PCBs are food, particularly animal fats.

There is a strong link with PCB exposure and neurological disorders in children, including impaired memory and a reduced ability to learn. Newborns exposed to PCBs through their mother’s milk have abnormal reflexes and exposed children show poor mental development (Ribas-Fito et al. 2001). It is not clear, however, why PCBs cause negative changes in mental ability and cognitive development.

Researchers test for cognition, the ability to think and learn, in many different ways. One method, the Morris water maze, is commonly used to test learning and memory in rodents. Typically, a rat or mouse is placed into a pool of water that contains a single escape platform. Visual cues, such as colored markings or shapes, are placed at various locations around the pool, or on the platform, to orient the rat to its location.

When released into the pool, the rat searches for an exit and eventually finds the escape platform. The time it spends looking for the escape platform and its travel patterns are recorded, and compared to subsequent trials. With practice, a healthy rat can swim directly to the platform, no matter where along the pool's edge it is released.

What did they do?

The authors were trying to determine if PCBs change the growth of neural cell projections called dendrites and thus alter brain and nerve development in ways that might interfere with learning and memory. Rat pups were exposed to a PCB mixture called Aroclor 1254 through their mothers during gestation and lactation. The mother rats were fed one of two different concentrations (1 and 6 mg/kg/day) of the PCB mixture, beginning 2 weeks prior to their pregnancy and for several weeks after their pups were born.

Various brain and reproductive aspects were measured in the rat pups to determine effects of the exposure. The researchers examined body weight, male to female sex ratios of the litters, prostate size in males, sperm count, size of reproductive organs, genes known to be affected by PCB exposure and several other endpoints. Thyroid and estrogen hormone levels were also measured because previous studies show that PCBs can interfere with thyroid function and estrogen production.

To assess spatial learning and memory, the rat pups swam a series of Morris water maze challenges for 7 days. The nerves in the brain increase in length and complexity after significant or memorable experiences. To the rats, the water maze is a memorable experience, and will cause the nerves in the brain of healthy rats to become detectably longer and more complex. The part of the nerve in the brain that is affected is called the dendrite, and the phenomenon of lengthening and increased complexity is called experience-dependent dendritic growth. Following the maze challenges, the rat’s brains were evaluated for changes in their dendrites.

What did they find?

The rat mothers exposed to the PCB maintained normal weights, gestation of the pups, litter sizes and milk production. The rat pups also gained a normal amount of weight during lactation.

The rat pups had an initial decrease in the thyroid hormones T3 and T4. However, the pups in the lower exposure group recovered and had normal T3 and T4 concentrations, while the pups exposed to the higher concentration continued to have lower thyroid hormone concentrations.

Mother rats exposed to the higher PCB concentration had twice as many males as females. Males had significantly enlarged prostates at the low, but not the high PCB dose. Some endpoints that were not affected include size of reproductive organs (excluding the prostate), sperm counts and estrogen and testosterone hormone concentrations.

The pups exposed to the lower PCB dose took significantly longer to complete the maze and a lower percentage of them found the platform in the given period of time than those exposed to the higher PCB dose or those not exposed at all. This and other results show that the young rats were not as proficient at spacial learning than either unexposed or highly exposed animals. However, with additional daily training, the rats in the lower exposed group were able to finally learn the task, but it took more time and training than rats in the other groups. 

Visual cues and swimming speed did not differ among the three groups, which suggests the slower learning and memory abilities observed in the lower-dosed animals were not tied to poor eyesight, less motivation or an inability to swim fast.

Brain nerve growth differed among the three groups. The rats not exposed to PCBs had significant increases in the lengths of their dendrites. Rats exposed to the high PCB concentration had no change in dendrite length. Rats exposed to the low PCB dose experienced significant dendritic retraction, meaning their dendrites actually got shorter.

The developmental exposure to the PCB increased the expression of a gene called RyR. Three types of the RyR gene are found in the rat brain. These genes influenced the changes in dendrite growth that were associated with the rats' learning and training. The Arochlor 1254 exposure altered differently the expression of two of these genes, when compared to controls, and more so in the 1 mg/kg/day group than in the 6 mg/kg/day group. The results suggest that these genes could be largely responsible for the effects of PCB on dendritic growth.

What does it mean?

Exposure to constant levels of PCBs during development and nursing can lead to memory and learning impairments. These effects may be worse with low exposures than either high or no exposure conditions. The study shows another example of lower doses producing greater effects than higher doses and further supports the growing body of evidence for low-dose effects.

This is the first study to show a change in gene expression that controls memory dependent nerve growth (rather than hormone changes associated with endocrine disurption) as a possible cause for the previously unexplained correlation of PCBs and impaired cognitive development in children. Impaired cognition can have significant biological and social costs for those affected.

The results have significant implications for humans, who are often exposed to low and chronic concentrations of PCBs through food. Learning impairment in children exposed to PCBs is described as subtle but with significant consequences. This study found similar results as the human studies: subtle but significant impairments in the ability of the rats to learn the water maze.

Importantly, the deficits are likely caused by the inability of the nerves in the brain to respond by growing and changing. In fact, PCB exposure in this study caused delays in learning that correlated with shortened dendrite lengths. The dendrites of the unexposed rats got longer, which is normal and critical for successful learning. The ability of the nerves to respond to experiences is the cornerstone of learning and memory. When the nerves in the brain cannot respond appropriately, learning cannot occur.

Exposure to PCBs caused an increase in the expression of the gene called RyR, which in turn alters calcium signaling in the brain. Calcium is critical for normal brain function and assists in the communication of one nerve to another. Understanding the genes involved could be critical to developing therapies to combat its negative effects.

This study also found temporary decreases in thyroid hormones in the low exposure group and a persistent decrease in thyroid hormones in the highly exposed group. Changes in thyroid function could have significant impacts on an animal’s metabolism and energy level. The thyroid and its hormones influence virtually every organ system in the body, and thyroid disorders are a growing epidemic in the United States. About 13 million Americans are affected by thyroid disorders, which can lead to obesity, miscarriage, infertility and many other serious health consequences.

Of further importance, this study noted a skewed sex ratio, in that the mothers exposed to the higher PCB level had twice as many males as females. Both males and females showed some sort of reproductive disorder. PCB exposed males for example, had enlarged prostates. Prostate inflammation affects approximately 9% of men and more than $84 billion are spent annually in the US on prostate inflammation diagnosis and management.

Resources

Barr M. 1992. Environmental contamination of human breast milk. American Journal of Public Health, 71: 124-126.

Carpenter, DO. 2006. Polychlorinated biphenyls (PCBs): routes of exposure and effects on human health. Reviews on Environmental Health 21: 1-23.

Poirrier, JE. 2007. Morris Water Maze: Movie of a rat that finds the platform. YouTube.com.

Ribas-Fito N, M Sala, M Kogevinas and J Sunyer. 2001. Polychlorinated biphenyls (PCBs) and neurological development in children: a systematic review. Journal of Epidemiological Community Health. 55: 537-546.

PCBs and cognition

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