Hertz-Picciotto Uncovers Environmental Clues to Autism

Photo: Irva Hertz-Picciotto
Irva Hertz-Picciotto

Autism rose roughly six hundred percent in California among children up to five years of age from 1990 to 2001, a seven-fold increase.1 Scientists now estimate it affects one in 88 eight year olds in the United States, with boys up to five times more vulnerable than girls.2 Diagnosis at younger ages, the inclusion of milder cases in the definition of the disorder, and improved diagnostics account for approximately a third of the growth,3 but other explanations remain elusive.4 Recently, however, researchers from UC Davis have successfully zeroed in on several modifiable factors that may influence autism susceptibility, namely, parental exposure to occupational chemicals, living near a freeway during late pregnancy, and folic acid intake before and during the first month of pregnancy.

These breakthrough studies come from a team of scientists led by COEH member Irva Hertz-Picciotto, the principal investigator and director of the UC Davis Center for Childhood Autism Risks from Genetics and the Environment, or CHARGE. Launched in 2003, CHARGE is the first comprehensive study of environmental causes and risk factors for autism and developmental delay.

A globally renowned scientist, Hertz-Picciotto has published over 200 papers identifying environmental exposures—metals, pesticides, air pollutants, and endocrine disruptors—and their effect on pregnancy, the newborn, and child development. In 2011, Hertz-Picciotto received the Goldsmith Lifetime Achievement Award by the International Society for Environmental Epidemiology. She is a professor of Epidemiology at UC Davis and chief of the Division of Environmental and Occupational Health in addition to the director of CHARGE.

Autism spectrum disorder (ASD) is a group of developmental conditions that include full syndrome autism, Asperger’s syndrome, and pervasive developmental disorder—not otherwise specified. Children with autism or ASD exhibit repetitive behaviors as well as measurable deficits in both social interaction and communication.

We now know that twenty or more genes contribute to autism, according to David Amaral, research director of the MIND Institute at UC Davis.5 But only a small percent of autism cases are purely genetic. Susceptibility genes may include common polymorphisms that, in combination with an environmental insult, can cause autism risk to increase substantially.

“I think for many years people have labored under the assumption that, because there is a pretty high heritability factor, autism is primarily genetic and that is where National Institutes of Health dollars should go,” says Hertz-Picciotto. “It was clear all along there were environmental contributions, even strong ones. In the 1970’s data showed mothers who had rubella infections during pregnancy had a 50 fold higher risk that their child would develop autism. Certainly, there was reason to think that the environment could play a role 40 years ago. People are finally starting to realize that genetics doesn’t preclude environment.”

Hertz-Picciotto and her team just published one of the first studies in several decades to evaluate occupational risks and their association with ASD. Based on a pilot sample of 174 families enrolled in CHARGE, lead author Erin McCanlies found that parental exposure to toxins may have lifelong consequences for their children.

As part of the study, parents of children with ASD, and a control group of unaffected children, reported their occupational exposure to 49 chemical agents suspected or have been found to be associated with adverse pregnancy outcomes, neurologic or physical malformation, or disturbances of the central nervous system. The study’s authors discovered parents of ASD children were more likely to have had occupational exposure to lacquer, varnish, and xylene. Asphalt and solvents exposures were also strongly linked with ASD.

Hertz-Picciotto believes paternal exposures are producing genetic variants—not because they are inherited, but because of insults from the environment. “Some recent data coming out of the genetic side is related to copy number variations (CNVs),” she explains. CNVs are alterations of the DNA of a genome, which results in the cell having an abnormal number of copies of one or more sections of the DNA.6

“Children with autism have more of these CNVs in certain regions of the chromosome. They are de novo, meaning they are not necessarily in the parents. They may happen during the period when the sperm is produced, a couple of months before conception. More of these de novo CNVs are coming from the father’s side, but they are not in the father meaning the damage is in the cells that give rise to sperm. ”

CHARGE received funding to expand this pilot into a much larger assessment using occupational data collected from over 1,000 participants enrolled in CHARGE, reports Hertz-Picciotto.

Photo: Dr. Hertz-Picciotto speaks with a mom about her participation in the study

Dr. Hertz-Picciotto speaks with a mom about her participation in the study

In a separate case-control study published in the July issue of the American Journal of Clinical Nutrition, CHARGE scientists showed folic acid may reduce ASD risk in mothers with inefficient folate metabolism. Women in the study who consumed 600 micrograms of folic acid per day were afforded protection compared to women who took less than 600 micrograms a day during the first month of pregnancy. “What’s critical here—this is before many women know they are pregnant,” notes Hertz-Picciotto.

The study found elevated risks of ASD among mothers and children with MTHFR 677 C>T variant genotype, and risk estimates decreased with increased folic acid.7 This gene plays a role in metabolism of folic acid. “Taking the prenatal supplements will, for those mothers or children with the high risk genotype, dramatically reduce the likelihood that their child will develop ASD,” says Hertz-Picciotto.

CHARGE scientists were also the first to report a two-fold increase in autism risk for children living within 300 meters of a freeway at birth.8 “We recognize living close to a freeway is usually not the most desirable neighborhood. Often these are families of lower socio-economic means. We controlled for these factors and still saw this association,” adds Hertz-Picciotto. “We want to look at the gene-environment interaction to see whether there might be certain groups that are more susceptible to air pollution with regard to child development.”

Traffic-related air pollutants induce inflammation and oxidative stress in toxicological and human studies. Emerging evidence that oxidative stress and inflammation are involved in the pathogenesis of autism supports the findings from Irva Hertz-Picciotto and her collaborators.9

After a decade of research, CHARGE scientists are producing positive scientific evidence that environmental changes–at both the individual and population level—may significantly reduce autism risk; whether it is better protection on the job, dietary education, or regulations for motor vehicle exhaust that protect vulnerable populations.

“At this point we have to keep casting a pretty wide net,” adds Hertz-Picciotto. “The good news is that there are things people can do. While the rates of autism keep going up, I would like to see them plateau and start coming down. That is what our research is aimed at,” says Hertz-Picciotto.

1,3Hertz-Picciotto I, Delwiche L. The rise in autism and the role of age at diagnosis. Epidemiology. 2009 Jan;20(1):84-90.
2http://www.cdc.gov/NCBDDD/autism/data.html
4McCanlies EC, Fekedulegn D, Mnatsakanova A, Burchfiel CM, Sanderson WT, Charles LE, Hertz-Picciotto I. Parental Occupational Exposures and Autism Spectrum Disorder. J Autism Dev Disord. 2012 Mar 8. [Epub ahead of print].
5PBS NEWSHOUR transcript with Dr. David Amaral, research director at the MIND Institute at the University of California, Davis, on the causes of autism.
6http://en.wikipedia.org/wiki/Copy_number_variation.
7Schmidt RJ, Tancredi DJ, Ozonoff S, Hansen RL, Hartiala J, Allayee H, Schmidt LC, Tassone F, Hertz-Picciotto I. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (Childhood Autism Risks from Genetics and Environment) case-control study. Am J Clin Nutr. 2012 Jul;96(1):80-9.
8Volk HE, Hertz-Picciotto I, Delwiche L, Lurmann F, McConnell R. Residential proximity to freeways and autism in the CHARGE study. Environ Health Perspect. 2011 Jun;119(6):873-7. PMID: 21156395.
9http://www.ucdmc.ucdavis.edu/newsroom/newsdetail.html?key=4888&keyword=autism&svr=http://www.ucdmc.
ucdavis.edu&table=archived.


Occupational Safety Training Prepares Workers with Special Needs

Approximately 4.5 million individuals in the United States have developmental disabilities such as autism. And an estimated 30 percent of working-age adults in this population are employed, according to a report from the Labor Occupational Health Program (LOHP) commissioned by the National Institute for Occupational Safety and Health (http://www.lohp.org/docs/projects/workerswithdisabilities/nioshfinalreport.pdf).

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LOHP’s curriculum, Staying Safe at Work: Teaching Workers with Disabilities about Health and Safety on the Job, offers training uniquely designed for workers with special developmental or intellectual challenges.

Created with employment agencies, job development programs, and high school transition programs in mind, Staying Safe at Work uses fun, interactive tools to teach job safety techniques and requires no literary skills for learning success.

LOHP also offers training for trainers and employers of individuals with disabilities. For more information contact Robin Dewey: rdewey@berkeley.edu. You can also view information about the curriculum on the following webpage: http://www.lohp.org/publications/workers_with_disabilities.html.

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