Paraoxonase Polymorphisms, Haplotypes, and Enzyme Activity in Latino Mothers and Newborns
Holland, Nina, Furlong, Clement, Bastaki, Maria, Richter, Rebecca, Bradman, Asa, Huen, Karen, Beckman, Kenneth, Eskenazi, Brenda, Environmental Health Perspectives
Recent studies have demonstrated widespread pesticide exposures in pregnant women and in children. Plasma paraoxonase 1 (PON1) plays an important role in detoxification of various organophosphates. The goals of this study were to examine in the Center for Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort of Latina mothers and their newborns living in the Salinas Valley, California, the frequencies of five PON1 polymorphisms in the coding region ([192.sub.QR] and [55.sub.LM]) and the promoter region (-[162.sub.AG], -[909.sub.CG], and -[108.sub.CT]) and to determine their associations with PON1 plasma levels [phenylacetate arylesterase (AREase)] and enzyme activities of paraoxonase (POase) and chlorpyrifos oxonase (CPOase). Additionally, we report results of PON1 linkage analysis and estimate the predictive value of haplotypes for PON1 plasma levels. We found that PON[1.sub.-909], PON[1.sub.-108], and PON[1.sub.192] had an equal frequency (0.5) of both alleles, whereas PON[1.sub.-162] and PON[1.sub.55] had lower variant allele frequencies (0.2). Nearly complete linkage disequilibrium was observed among coding and promoter polymorphisms (p < 0.001), except PON[1.sub.192] and PON[1.sub.-162] (p > 0.4). Children's PON1 plasma levels (AREase ranged from 4.3 to 110.7 U/mL) were 4-fold lower than their mothers' (19.8 to 281.4 U/mL). POase and CPOase activities were approximately 3-fold lower in newborns than in mothers. The genetic contribution to PON1 enzyme variability was higher in newborns ([R.sup.2] = 25.1% by genotype and 26.3% by haplotype) than in mothers ([R.sup.2] = 8.1 and 8.8%, respectively). However, haplotypes and genotypes were comparable in predicting PON1 plasma levels in mothers and newborns. Most of the newborn children and some pregnant women in this Latino cohort may have elevated susceptibility to organophosphate toxicity because of their PON[1.sub.192] genotype and low PON1 plasma levels. Key words: chlorpyrifos, cord blood, haplotypes, Latino cohort, linkage disequilibrium, organophosphate, paraoxonase 1 (PON1) genotype, paraoxonase activity, pesticides, PON1 polymorphisms, pregnancy. Environ Health Perspect 114:985-991 (2006). doi:10.1289/ehp.8540 available via http://dx.doi.org/ [Online 27 February 2006]
Organophosphate (OP) pesticide exposure remains widespread in the United States (Barr et al. 2004; Bradman et al. 2005; Hill et al. 1995; Loewenherz et al. 1997; Simcox et al. 1999). Pregnant women, fetuses, and children in both urban (Berkowitz et al. 2003; Whyatt et al. 2003) and rural agricultural populations (Eskenazi et al. 2004; Fenske et al. 2002) are directly exposed to pesticides, and in some cases these exposures may exceed health-based reference doses (Bradman et al. 2005; Castorina et al. 2003). OP pesticide metabolites have also been detected in meconium (Whyatt and Barr 2001) and amniotic fluid (Bradman et al. 2003). OP exposure at high doses has profound effects, primarily on the central nervous system (Eskenazi et al. 1999), and there is growing information in animals and humans suggesting that low-level chronic exposure may affect neurodevelopment (Eskenazi et al. 1999; Young et al. 2005).
The unique physiologic and behavioral characteristics of children may increase their exposures to environmental contaminants compared with adults (National Research Council 1993). Young children eat, drink, and breathe more per unit of body weight than do adults, and they also explore their environment orally, engaging in extensive hand-to-mouth behavior (National Research Council 1993). In addition, young children may be more susceptible to the adverse effects of OP exposure than are adults, because of their lower ability to metabolize and detoxify OP pesticides (Padilla et al. 2000; Sheets 2000).
The human paraoxonase 1 (PON1) enzyme (43 kDa, composed of 354 amino acids) is a polymorphic, high-density lipoprotein-associated esterase that metabolizes many different substrates, including OP compounds (Davies et al. …