Study explores link between cholesterol metabolism and environmental toxicants
By Stella Child
In the last two decades, scientists have found increasing evidence for the contribution of environmental factors to neurodegenerative diseases. Organic solvents, heavy metals, and air pollutants are now all categorized as neurotoxicants, substances that affect the function of the nervous system. A subset of these is a group of substances called developmental neurotoxicants, which cause damage to the brain when it is developing.
Although it is relatively easy to identify potential neurotoxicants, it has been difficult to translate this knowledge into direct human health advice and assessments of environmental risk. Most investigations rely on either animal studies or epidemiological studies of human populations, but it can be difficult to identify the exact molecular target or interrupted pathway of the toxicant(s) in question.
A recent study from the laboratory of Ned Porter (Chemistry), published in Environmental Health Perspectives, takes a more direct look at the problem. In collaboration with Aaron Bowman (Pediatrics), Porter’s group studied the effect of potential toxicants on developing human neural tissue. They chose to focus on one aspect of cellular metabolism, the biosynthesis of cholesterol, given its essential role: as much as 25% of the total cholesterol in the body is in the brain, and it is critical for central nervous system function. Change to the cholesterol balance in neural cells is a common feature of many neurodegenerative disorders, including Huntington’s and Alzheimer’s diseases.
The researchers tested environmental chemicals to see if they could affect human neural development by disrupting cholesterol metabolism. They chose to focus on 7-dehydrocholesterol reductase (DHCR7), an enzyme that converts the precursor 7-dehydrocholesterol into cholesterol, as there is evidence that DHCR7 is inhibited by widely used drugs such as the commonly prescribed antipsychotic aripiprazole (sold under the brand name Abilify) and the antiseptic benzalkonium chloride.
Using ToxCastTM, a library of 1,851 different environmentally active chemicals, the researchers identified 29 compounds that affected cholesterol metabolism in mouse neuroblastoma cells. A number of criteria, including consistent increases to two metabolites in the same cholesterol synthesis pathway as DHCR7 and the likelihood of environmental exposure, were used to narrow in on 4 of the 29 initial compounds. They were then tested to see if they had the same effect on human cells as they had had in mouse cells. Of the four compounds, two agricultural pesticides, fenpropimorph and spiroxamine, demonstrated the same activity in immortalized human cell lines, suggesting that they inhibit DHCR7.
Through their work, Porter and colleagues demonstrated that about 1.5% of the ToxCastTM library interacts with enzymes involved in cholesterol metabolism in neural cells, and identified two commonly used agricultural pesticides that had not previously been linked to issues in cholesterol biosynthesis, opening the door to necessary future studies about the neural toxicity of both compounds.
In addition to the direct findings, the high-throughput methods developed in the paper will be useful in ongoing tests of chemicals affecting cholesterol metabolism. This study lays the groundwork for understanding the interruption of cholesterol biosynthesis as a possible mechanism of action of environmental neurotoxicants.
This work was supported by the National Institute of Environmental Health Sciences.