Research | Children’s Health Associations of Prenatal Exposure to Organophosphate Pesticide Metabolites with Gestational Age and Birth Weight Stephen A. Rauch,1 Joe M. Braun,2 Dana Boyd Barr,3 Antonia M. Calafat,4 Jane Khoury,5 M. Angela Montesano,4 Kimberly Yolton,5 and Bruce P. Lanphear 1,5,6 1Child & Family Research Institute, BC Children’s Hospital, Vancouver, British Columbia, Canada; 2Department of Environmental Health, Harvard University, Boston, Massachusetts, USA; 3Rollins School of Public Health, Emory University, Atlanta, Georgia, USA; 4National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA; 5Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA; 6Simon Fraser University, Vancouver, British Columbia, Canada Background : Prenatal exposure to organophosphate (OP) insecticides, a widely used class of pesticides, may be associated with decreased gestational age and lower birth weight. Single nucleo­ tide polymorphisms in paroxanase (PON1) enzyme genotypes may modify the relationships between OP exposure and perinatal outcomes. o Bjectiv : We examined the relationship of prenatal OP insecticide exposure, measured using urinary dialkyl phosphate (DAP) metabolite concentrations, with gestational age and birth weight. Methods : We measured the concentrations of six nonspecific DAP metabolites of OP insecticides in two maternal spot urine samples collected in a prospective birth cohort. We performed multi­ variable regression to examine associations between the sum of six DAP concentrations (ΣDAP) with gestational age and birth weight. We also examined whether these associations differed accord­ ing to infant PON1192 and PON1–108 genotypes. r tluse : Among 306 mother–infant dyads, a 10f­old increase in ΣDAP concentrations was associ­ ated with a decrease in covariatea­djusted gestational age [–0.5 weeks; 95% confidence interval (CI): –0.8, –0.1] and birth weight (–151 g; CI: –287, –16); the decrements in birth weight were attenu­ ated after adjusting for gestational age. hTe relationship between ΣDAP concentrations and gesta­ tional age was stronger for white (–0.7 weeks; CI: –1.1, –0.3) than for black (–0.1 weeks; 95% CI: –0.9, 0.6) newborns. In contrast, there was a greater decrease in birth weight with increasing urinary ΣDAP concentrations for black (–188 g; CI: –395, 19) than for white (–118 g; CI: –296, 60) new­ borns. Decrements in birth weight and gestational age associated with ΣDAP concentrations were greatest among infants with PON1192QR and PON–108CT genotypes. c onclusi : Prenatal urinary ΣDAP concentrations were associated with shortened gestation and reduced birth weight in this cohort, but the effects differed by race/ethnicity and PON1192/108 genotypes. k ey words : birth weight, DAPs, fetal growth, gestational age, OPs, organophosphate, paraoxanase, pesticide, PON, prenatal, toxicity. Environ Health Perspect 120:1055–1060 (2012). http://dx.doi. org/10.1289/ehp.1104615 [Online 5 April 2012] Fifty years ago, Rachel Carson warned about the toxicity of pesticides, including organo- phosphate (OP) insecticides, in her book Silent Spring (Carson 1962). In particular, Carson warned that pesticides were toxic. Despite these warnings, there have been few attempts to study the consequences of fetal exposures to organophosphate insecticides until recently, when several epidemiologic studies using uri- nary pesticide metabolites have begun to raise concerns about adverse health effects of expo- sure (Bouchard et al. 2011; Engel et al. 2007, 2011; Eskenazi et al. 2004; Marks et al. 2010; Rauh et al. 2011). Although OP insecticide use in the United States has declined, the vast majority of people in the United States, including pregnant women and children, are routinely exposed (Bouchard et al. 2010; Woodruff et al. 2011). The developing fetus may be especially vul- nerable to OP pesticides because of its small size, rapid growth and development, and lim- ited ability to detoxify harmful substances (Eskenazi et al. 1999). Animal studies sug- gest that prenatal OP insecticide exposure at levels higher than those typically encountered by humans reduces fetal growth (Spyker and Avery 1977; Srivastava and Raizada 1996). However, results from several epidemiologic studies that sampled from different racial and ethnic populations have been inconclusive. Among African-American and Dominican mothers living in New York City, Whyatt et al. (2004) reported an inverse association between cord blood concentrations of chlorpy- rifos, an OP insecticide, with birth length and birth weight. In a cohort of primarily Mexican- American mothers, Eskenazi et al. (2004) reported an association between prenatal uri- nary dialkyl phosphate (DAP) concentrations, which are metabolites of OP insecticides, and shortened gestation, but not gestation-adjusted birth weight. Paraoxonase (PON) is an enzyme that detoxifies several OP pesticides, including chlorpyrifos, parathion, and diazinon (Costa et al. 2003). Several polymorphisms in the PON1 gene affect the function, production, and efficiency of PON in the body; recent studies have focused on two alleles: PON1192 Environmental Health Perspectives • volume 120 | number 7 | July 2012 and PON1–108 (Costa et al. 2003; Deakin et al. 2003). Briefly, a change in the promoter region of PON1–108 from the C allele to the T allele causes decreased PON production, and a change in the coding region of PON1192 from the R to the Q allele decreases PON’s efficiency at detoxifying certain pesticides (Costa et al. 2003). In epidemiologic studies, results have been inconclusive: Harley et al. (2011) found larger DAP-associated reduc- tions in birth weight and gestational age in infants with PON1–108TT genotype (vs. PON1–108CC); for PON1192, they found DAP- associated reductions in gestational age for QQ infants, and weaker associations for the RR or QR groups. However, Wolff et al. (2007) identified PON1192RR as the more susceptible group, reporting stronger negative associa- tions between diethyl alkyl phosphate (DEAP) metabolites and birth weight, and between dimethyl alkyl phosphate (DMAP) metabo- lites and birth length, in mothers with the PON1192RR genotype (compared with those with QQ genotype). Berkowitz et al. (2004) found no overall relationship between a urinary chlorpyrifos metabolite (3,5,6-trichloropyri- dinol) and gestational age, birth weight, and birth length, but they found an inverse associa- tion with head circumference when stratifying by tertiles of maternal paraoxonase activity. In the United States, black children are more likely than white children to be born preterm (gestation < 37 weeks) and to be low birth weight (< 2,500 g), both of which place Address correspondence to B.P. Lanphear, 3415 Ash St., Vancouver, BC V5Z3E5 Canada. Telephone: (778) 387-3939. Email: blanphear@sfu.ca Supplemental Material is available online (http:// dx.doi.org/10.1289/ehp.1104615). We acknowledge the technical assistance of C. Chambers, C. Fernandez, D.G. Kim, M. Odetokun, P. Olive, T. Bernert, and K. Caldwell [Centers for Disease Control and Prevention (CDC)] in measuring the urinary concentrations of DAP metabolites and creatinine, serum cotinine, and blood lead. This work was partially supported by grants from the National Institute of Environmental Health Sciences (R01 ES015517, P01 ES11261, T32 ES007069). The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the CDC. The authors declare they have no actual or potential competing financial interests. Received 12 October 2011; accepted 20 March 2012. 1055