Increased influence of genetic variation on PON1 activity in neonates.

Abstract

PON1 (paraoxonase-1) detoxifies organophosphates by cleavage of active oxons before they have a chance to inhibit cholinesterases. The corresponding gene PON1 has common polymorphisms in both the promoter (-909, -162, -108) and the coding region (L55M, Q192R). The five PON1 genotypes were determined for maternal blood (n = 402) and cord blood (n = 229) as part of a study of the effects of organophosphate pesticide exposure on infant growth and neurodevelopment. PON1 enzymatic activities were determined for a majority of subjects. The population contained Caucasians, Caribbean Hispanics, and African Americans. PON1 activity was strongly dependent upon the promoter alleles in both maternal and cord blood. For example, PON1 activities for position -108CC, CT, and TT mothers were 146, 128, and 109 arylesterase U/mL (analysis of variance, p < 0.0001), whereas the same PON1 activities for the respective cord bloods were 49.0, 32.4, and 23.2 U/mL (p < 0.0001). Compared with adults, neonates had lower PON1 activity, implying reduced capacity to detoxify organophosphates. In addition there was a larger difference in activity between genotype groups in neonates than in adults. Because the five polymorphisms in PON1 occur in a short stretch of DNA, they were tested for linkage disequilibrium (LD). Significant LD was found among all three promoter polymorphisms as well as between promoter polymorphisms and L55M, with the strongest LD for Caucasians and the weakest for African Americans. The Caribbean Hispanics fall between these two groups. Surprisingly, significant LD also was observed between the promoter polymorphisms and C311S in PON2. LD between the promoter polymorphisms and Q192R was not significant.

Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene–environment interactions

“…27,41 These phenotypic correlates of PON1 genotypes are even more prominent in neonates than in adults, and this trend may likely extend into prenatal life. 43 Hence, although we cannot exclude the existence of mutations in noncoding regions of PON1 or in nearby loci, the most parsimonious explanation for our findings is that a reduction in paraoxonase activity and/or amount produced by these SNPs may by itself confer autism vulnerability in one ethnic group only. PON1 encodes the human HDL-associated paraoxonase, which, in addition to hydrolyzing OP compounds, physiologically reduces LDL and HDL oxidation, and hydrolyzes platelet-activating factor (PAF).…”

Prenatal Pesticide and PCB Exposures and Birth Outcomes

“…Concentrations were imputed for missing values (5); metabolites were then summed (as nm/L) to obtain ⌺DEP (DEDP, diethylphosphate, diethylthiophosphate), ⌺DMP (DMDP, dimethylphosphate DMTP), and ⌺DAP (⌺DEP ϩ ⌺DMP). PON1 activity was determined as previously reported in plasma (mol/min/ mL) using phenylacetate as substrate (15). BuChe activity (mol/min/mL) was determined by the method of Ellman et al (16) using 1 mmol/L butyrylthiocholine as substrate in 50 mmol/L phosphate buffer, pH 8.0, at 25°C, following absorbance at 412 nm.…”

“…PONQ192R was genotyped (n ϭ 389) as reported (17). This PON1 variant was chosen because its maternal phenotypic variability exhibits a range of PON1 expression different from other PON1 variants (15,18). PCBs were defined as the sum of congeners 118, 153, 138, and 180 (7).…”

Harbingers of Neonatal Birth Weight: The PON1 Arylesterase and Lactonase Activities

“…Some studies have shown that the level of PON1 in newborns is 3-4fold lower than the adults [18,19]. But as per our knowledge no study has been conducted so far showing the relation between birth weight and cord blood arylesterase and lactonase activity.…”