NEW YORK, New York, June 5, 2013 (ENS) – For the first time, an experiment on animals shows that exposure to the environmental toxin lead could cause people to develop the severe mental disorder schizophrenia.

Scientists at Columbia University’s Mailman School of Public Health and the Johns Hopkins University School of Medicine engineered mice with a human gene for schizophrenia and exposed them to lead early in their lives. The mice showed behaviors and structural changes in their brains consistent with schizophrenia.

Their findings appear online in the current issue of the journal “Schizophrenia Bulletin” in an article entitled, “Chronic Exposure of Mutant DISC1 Mice to Lead Produces Sex-Dependent Abnormalities Consistent With Schizophrenia and Related Mental Disorders: A Gene-Environment Interaction Study.”

Tomas Guilarte

Dr. Tomas Guilarte (Photo courtesy Columbia University)

“The animal model provides a way forward to answer important questions about the physiological processes underlying schizophrenia,” says Tomas Guilarte, PhD, senior author of the new study and professor and chair of the department of Environmental Health Sciences at the Mailman School.

The researchers say their findings suggest a combined effect of lead exposure and a genetic risk factor produces symptoms of the mental disorder.

They say their findings open an avenue to better understanding of the complex gene-environment interactions that put people at risk for schizophrenia and other mental illnesses.

Schizophrenia is a chronic, severe, and disabling brain disorder that has affected people throughout history. About one percent of Americans have this illness.

Common symptoms include auditory hallucinations, paranoid or bizarre delusions, disorganized speech or thinking, and social or occupational dysfunction. The onset of symptoms typically occurs in young adulthood.

Back in 2004, work by Dr. Guilarte and other scientists at the Mailman School suggested a connection between prenatal lead exposure in humans and increased risk for schizophrenia later in life. But the scientists still wondered how lead exposure could trigger the disease.

Dr. Guilarte believed the answer was in the direct inhibitory effect of lead on the N-methyl-D-aspartate receptor, NMDAR, a connection point in the brain important to brain development, learning, and memory.

His research in rodents found that exposure to lead blunted the function of the NMDAR.

In the new study, Dr. Guilarte and his co-investigators focused on mice engineered to carry the mutant form of Disrupted-in-Schizophrenia-1, or DISC1, a gene that is a risk factor for the disease in humans.

schizophrenia

One young man’s depiction of schizophrenia (Photo by Timplosion)

Beginning before birth, half of the mutant DISC1 mice were fed a diet containing lead, while half were given a normal diet that did not contain lead.

A second group of normal mice not expressing the mutant DISC1 gene were also split into the two feeding groups. All mice were put through a battery of behavioral tests and their brains were examined using magnetic resonance imaging, MRI.

The genetically engineered mutant mice exposed to lead and given a psychostimulant showed elevated levels of hyperactivity and were less able to suppress a startle in response to a loud noise after being given an acoustic warning.

The brains of the mutant mice also had markedly larger lateral ventricles – empty spaces containing cerebrospinal fluid – compared with other mice.

“These results mirror what is known about schizophrenia in humans,” the researchers say.

Starting in 1973, the U.S. government began a gradual phase-down of lead content in gasoline, and by 1996, banned the sale of leaded gas completely. However, lead from car exhausts mixed with soil near roads and is still there today, according to the New York State Department of Health. Homes near busy streets may have higher levels of lead in the soil.

Lead still comes from metal smelting, battery manufacturing, and other factories that use lead. This lead gets into the air and then mixes with the soil near homes, especially if the home is near one of these sources, says the New York State Health Department. Flaking lead-based paint on the outside of buildings can also mix with the soil close to buildings. Lead-based paint mixing with soil is a problem during home remodeling if workers are not careful. Once the soil has lead in it, wind can stir up lead dust, and blow it into homes and yards.

While the role of genes in schizophrenia and mental disorders is well established, the effect of toxic chemicals in the environment is only just beginning to emerge. This study’s results focus on schizophrenia, but implications could be broader.

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One young woman’s college photo project showing schizophrenia (Photo by Amy Cosford)

“We’re just scratching the surface,” says Dr. Guilarte. “We used lead in this study, but there are other environmental toxins that disrupt the function of the NMDAR.”

Another set of possible culprits is a family of chemicals in air pollution called polycyclic aromatic hydrocarbons or PAHs. PAHs occur in oil, coal, and tar deposits, and are produced as byproducts of fuel burning, whether fossil fuel or biomass. Studies have shown that high levels of PAHs are found in meat cooked at high temperatures such as grilling or barbecuing, and in smoked fish.

PAHs are of concern because some compounds have been identified as carcinogenic and mutagenic. PAHs also are known to cause physical defects in a developing embryo.

“Similarly, any number of genes could be in play,” says Dr. Guilarte, noting that DISC1 is among many genes implicated in schizophrenia.

Future research may reveal to what extent schizophrenia is determined by environmental factors as distinct from genetic factors or their interactions, and what other mental problems might be in the mix.

An ongoing study by Dr. Guilarte is looking at whether lead exposure alone can contribute to deficits of one specialized type of neuron called parvalbumin-positive GABAergic interneuron that is known to be affected in the brain of schizophrenia patients.

Scientists are also interested to establish the critical window for exposure, whether it is before the fetus is born or after birth, or both.

The study’s first author is Bagrat Abazyan, MD, a post-doctoral fellow in the Behavioral Neurobiology and Neuroimmunology Lab, Department of Psychiatry and Behavioral Sciences at Johns Hopkins School of Medicine, which is led by Mikhail Pletnikov, MD, PhD, senior co-author of the paper and principal developer of the DISC1 mouse model. Neuroimaging studies were led by Susumu Mori, PhD, Department of Radiology, also of Johns Hopkins.

Funding for the study was provided by the National Institute of Environmental Health Sciences of the National Institutes of Health.

Copyright Environment News Service (ENS) 2013. All rights reserved.

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