Effect of SNPs on Ops: age and race variations explored.

Newborns produce substantially less of the enzyme paraoxonase-1 (PON1)--which detoxifies organophosphate pesticides--than do adults, potentially leaving them more vulnerable to organophosphate exposures. Genetic differences in PON1 activity are also more pronounced in newborns than in adults, according to recent research by Jia Chen and colleagues at the Mount Sinai School of Medicine [EHP 111:1403-1409]. By helping to determine which groups are most susceptible based on age and genetic factors, these results may have implications for setting exposure standards.

Metabolites of organophosphates damage the nervous systems of insects and humans by reducing the ability of the enzyme cholinesterase to regulate the electrochemical signals between neurons. When cholinesterase levels drop, neurons become overstimulated and send repeat signals that can eventually cause muscle weakness, paralysis, and death. PON1 breaks down organophosphates before they can cause nerve damage.

The current study is part of ongoing research on the neurodevelopmental risks posed by exposure to the organophosphate pesticide chlorpyrifos among an inner-city population in New York City. Once among the most commonly used insecticides, chlorpyrifos was banned in 2000 for many residential uses in the United States because of concern over children's health. Like other organophosphates, chlorpyrifos and its toxic metabolite chlorpyrifos oxon can cross the placenta. Therefore, exposures by pregnant women can affect their unborn children. However, little is known about the effects of low-level exposures on children's development, including their ability to learn later in life. Chlorpyrifos is still approved for many agricultural uses, and children in rural areas continue to be exposed.

Researchers have identified five single-nucleotide polymorphisms that affect PON1 production, three in the promoter region of the PON1 gene (-909, -162, -108) and two in the coding region (L55M, Q192R). PON1 has also been linked to, or tends to be inherited along with, two other genes, PON2 and PON3.

From March 1998 through March 2002, the Mount Sinai researchers genotyped and measured PON1 activity in the blood of an ethnically diverse group of 402 expectant mothers and 229 newborns. Participants identified themselves, or were identified by their parents, as Caucasian (82 mothers, 56 newborns), African American (117 mothers, 66 newborns), or Caribbean Hispanic (203 mothers, 107 newborns). Blood samples were genotyped for the five PON1 polymorphisms. Because the researchers are also studying the linkage of PON genes, samples were also genotyped for a common PON2 polymorphism (C311S). The level of PON 1 activity in each blood sample was determined by an assay that measures hydrolysis of phenylacetate.

As expected, the results showed that PON1 activity of newborns was less than that of adults, and so newborns are potentially more susceptible to the effects of chlorpyrifos exposure. In addition, the Mount Sinai researchers found that some groups of newborns may be more vulnerable than others. The presence of PON1 polymorphisms and PON1 activity varied among racial/ethnic groups. PON 1 activity in the blood of the expectant mothers was 4.6, 3.6, and 2.6 times greater than in that of newborns for Caucasians, Caribbean Hispanics, and African Americans, respectively. In addition, the impact of genetic variability was greater in the newborns than in the adults. None of the polymorphisms affected PON1 activity in the women by more than 35%. However, among the newborns, several of the polymorphisms affected PON1 activity by as much as 200%. For example, Caucasian infants with the CC polymorphism of the -108 PON1 promoter had, on average, more than twice the PON 1 activity of infants with the TT polymorphism.

The researchers further found that the polymorphisms tended to be inherited in predictable patterns, a phenomenon referred to as "linkage disequilibrium." There was significant linkage disequilibrium among the three promoter polymorphisms, and among the promoter polymorphisms and the coding polymorphism L55M. These relationships were strongest for Caucasian participants and weakest for African-American participants. In addition, there was significant linkage disequilibrium among the PON1 promoter polymorphisms and the PON2 polymorphism C311S. These results may contribute to a better understanding of rates of recombination in genes, as well as provide a basis for future epidemiological studies.