Common pesticide may increase risk of ADHD

Mice exposed to a commonly used pesticide in utero and through lactation exhibited several features of ADHD, including dysfunctional dopamine signaling in the brain, hyperactivity, working memory, attention deficits and impulsive-like behaviour.

A commonly used pesticide may alter the development of the brain's dopamine system, responsible for emotional expression and cognitive function, and increase the risk of attention deficit hyperactivity disorder in children, according to a new Rutgers study.

The research published Wednesday in the Journal of the Federation of American Societies for Experimental Biology (FASEB J.), by Rutgers scientists and colleagues from Emory University, the University of Rochester Medical Center, and Wake Forest University discovered that mice exposed to the pyrethroid pesticide deltamethrin in utero and through lactation exhibited several features of ADHD, including dysfunctional dopamine signaling in the brain, hyperactivity, working memory, attention deficits and impulsive-like behaviour.

Attention deficit hyperactivity disorder most often affects children, with an estimated 11 percent of children between the ages of 4-17, about 6.4 million, diagnosed as of 2011.

Boys are three to four times more likely to be diagnosed than girls. While early symptoms, including an inability to sit still, pay attention and follow directions, begin between the ages of 3 to 6, diagnosis is usually made after the child starts attending school full time.

Importantly, in this study, the male mice were affected more than the female mice, similar to what is observed in children with ADHD.

The ADHD-like behaviours persisted in the mice through adulthood, even though the pesticide, considered to be less toxic and used on golf courses, in the home, and on gardens, lawns and vegetable crops, was no longer detected in their system.

Although there is strong scientific evidence that genetics plays a role in susceptibility to the disorder, no specific gene has been found that causes ADHD and scientists believe that environmental factors may also contribute to the development of the behavioural condition.

Using data from the Centers for Disease Control, National Health and Nutrition Examination Survey (NHANES) the study analyzed health care questionnaires and urine samples of 2,123 children and adolescents.

Researchers asked parents whether a physician had ever diagnosed their child with ADHD and cross-referenced each child's prescription drug history to determine if any of the most common ADHD medications had been prescribed.

Children with higher pyrethroid pesticide metabolite levels in their urine were more than twice as likely to be diagnosed with ADHD.

These findings provide strong evidence, using data from animal models and humans, that exposure to pyrethroid pesticides, including deltamethrin, may be a risk factor for ADHD, says lead author Jason Richardson, associate professor in the Department and Environmental and Occupational Medicine at Rutgers Robert Wood Johnson Medical School and a member of the Environmental and Occupational Health Sciences Institute (EOHSI).

"Although we can't change genetic susceptibility to ADHD, there may be modifiable environmental factors, including exposures to pesticides that we should be examining in more detail," says Richardson.

Young children and pregnant women may be more susceptible to pesticide exposure because their bodies do not metabolize the chemicals as quickly.

This is why, Richardson says, human studies need to be conducted to determine how exposure affects the developing fetus and young children.

"We need to make sure these pesticides are being used correctly and not unduly expose those who may be at a higher risk," Richardson says.

More information: "Developmental pesticide exposure reproduces features of attention deficit hyperactivity disorder." FASEB J fj.14-260901; published ahead of print January 28, 2015, doi: 10.1096/fj.14-260901

Silencing the extra chromosome responsible for Down syndrome

Scientists at the University of Massachusetts Medical School are the first to establish that a naturally occurring X chromosome "off switch" can be rerouted to neutralize the extra chromosome responsible for trisomy 21, also known as Down syndrome, a genetic disorder characterised by cognitive impairment.

The discovery provides the first evidence that the underlying genetic defect responsible for Down syndrome can be suppressed in cells in culture (in vitro).

This paves the way for researchers to study the cell pathologies and identify genome-wide pathways implicated in the disorder, a goal that has so far proven elusive.

Doing so will improve scientist's understanding of the basic biology underlying Down syndrome and may one day help establish potential therapeutic targets for future therapies.

Details of the study by Jiang et al. were published online in Nature.

Jeanne B. Lawrence

"The last decade has seen great advances in efforts to correct single-gene disorders, beginning with cells in vitro and in several cases advancing to in vivo and clinical trials," said lead author Jeanne B. Lawrence, PhD, professor of cell & developmental biology at the University of Massachusetts Medical School.

"By contrast, genetic correction of hundreds of genes across an entire extra chromosome has remained outside the realm of possibility.

Our hope is that for individuals living with Down syndrome, this proof-of-principal opens up multiple exciting new avenues for studying the disorder now, and brings into the realm of consideration research on the concept of "chromosome therapy' in the future."

Humans are born with 23 pairs of chromosomes, including two sex chromosomes, for a total of 46 in each cell.

People with Down syndrome are born with three (rather than two) copies of chromosome 21, and this "trisomy 21" causes cognitive disability, early-onset Alzheimer's disease; and a greater risk of childhood leukemia, heart defects and immune and endocrine system dysfunction.

Unlike genetic disorders caused by a single gene, genetic correction of a whole chromosome in trisomic cells has been beyond the realm of possibility, even in cultured cells.

Harnessing the power of the RNA gene called XIST, which is normally responsible for "turning off" one of the two X chromosomes found in female mammals, UMass Medical School scientists have shown that the extra copy of chromosomes 21 responsible for Down syndrome can be silenced in the laboratory using patient-derived stem cells.

This finding opens multiple new avenues for translational scientists to study Down syndrome in ways not previously possible.

Determining the underlying cell pathologies and gene pathways responsible for the syndrome has previously proven difficult, because of the complexity of the disorder and the normal genetic and epigenetic variation between people and cells.

For example, some prior studies suggested that cell proliferation in Down syndrome patients may be impaired, but differences between people and cell lines made it difficult to conclude this definitively.

By controlling expression of the XIST gene, Lawrence and colleagues were able to compare otherwise identical cultures of the Down syndrome cells, with and without expression of the extra chromosome.

What they showed is that the Down syndrome cells have defects in cell proliferation and in neural cell differentiation, both of which are reversed by silencing one chromosome 21 by XIST.

"This highlights the potential of this new experimental model to study a host of different questions in different human cell-types, and in Down syndrome mouse models" said Lawrence.

"We now have a powerful tool for identifying and studying the cellular pathologies and pathways impacted directly due to over-expression of chromosome 21."

"Dr. Lawrence has harnessed the power of a natural process to target abnormal gene expression in cells that have an aberrant number of chromosomes," said Anthony Carter, PhD, of the National Institutes of Health's National Institute of General Medical Sciences, which partly supported the study.

"Her work provides a new tool that could yield novel insights into how genes are silenced on a chromosomal scale, and into the pathological processes associated with chromosome disorders such as Down syndrome."

More information: DOI: 10.1038/nature12394