Research | Children’s Health Prenatal Exposure to Organophosphates, Paraoxonase 1, and Cognitive Development in Childhood Stephanie M. Engel,1 James Wetmur,2,3 Jia Chen,1 Chenbo Zhu,1 Dana Boyd Barr,4 Richard L. Canfield,5 and Mary S. Wolff 1 1Department of Preventive Medicine, 2Department of Microbiology, and 3Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA; 4School of Public Health, Emory University, Atlanta, Georgia, USA; 5Division of Nutritional Sciences, College of Human Ecology, Cornell University, Ithaca, New York, USA Background : Prenatal exposure to organophosphate pesticides has been shown to negatively affect child neurobehavioral development. Paraoxonase 1 (PON1) is a key enzyme in the metabolism of organophosphates. o Bjectiv : We examined the relationship between biomarkers of organophosphate exposure, PON1, and cognitive development at ages 12 and 24 months and 6–9 years. Methods : hTe Mount Sinai Children’s Environmental Health Study enrolled a multiethnic prena - tal population in New York City between 1998 and 2002 (n = 404). hTird- trimester maternal urine samples were collected and analyzed for organophosphate metabolites (n = 360). Prenatal maternal blood was analyzed for PON1 activity and genotype. Children returned for neurodevelopment assessments ages 12 months (n = 200), 24 months (n = 276), and 6–9 (n = 169) years of age. r esult : Prenatal total dialkylphosphate metabolite level was associated with a decrement in mental development at 12 months among blacks and Hispanics. hTese associations appeared to be enhanced among children of mothers who carried the PON1 Q192R QR/RR genotype. In later childhood, increasing prenatal total dialkyl- and dimethylphosphate metabolites were associated with decrements in perceptual reasoning in the maternal PON1 Q192R QQ genotype, which imparts slow catalytic activity for chlorpyrifos oxon, with a monotonic trend consistent with greater decrements with increasing prenatal exposure. words c onclusion : Our findings suggest that prenatal exposure to organophosphates is negatively associated with cognitive development, particularly perceptual reasoning, with evidence of effects beginning at 12 months and continuing through early childhood. PON1 may be an important sus- ceptibility factor for these deleterious effects. k ey : environmental exposures, IQ, mental development, organophosphates, pesticides. Environ Health Perspect 119:1182–1188 (2011). doi:10.1289/ehp.1003183 [Online 21 April 2011] Before 2001, residential exposure to organo- phosphate pesticides, including chlorpyri- fos and diazinon, was common, even in an urban setting. Insecticides are used in mul- tiunit, inner-city dwellings to control insect and rodent infestations within apartments, in common spaces, and around building exte- riors. Despite the voluntary cancellation of residential use registrations of chlorpyrifos and diazinon in 2001 and 2004, respectively, between June 2005 and March 2006, 78% of randomly selected nationally representative U.S. homes had measurable levels of chlorpy- rifos, and 35% had measurable levels of diazi- non, suggesting ongoing residential exposure (Stout et al. 2009). Additionally, exposure to organophosphate pesticides or their residues may occur via consumption of conventionally grown fruits and vegetables (Lu et al. 2008). Neurodevelopmental consequences of human exposure to organophosphate pes- ticides have been demonstrated in urban (Bouchard et al. 2010; Engel et al. 2007; Rauh et al. 2006), rural (Eskenazi et al. 2007, 2010; Young et al. 2005), and occupational settings (Handal et al. 2008; Roldan-Tapia et al. 2006), some of which specifically involve prenatal exposure (Engel et al. 2007; Eskenazi et al. 2007, 2010; Marks et al. 2010; 1182 Rauh et al. 2006; Young et al. 2005). We have previously reported that prenatal pes- ticide exposure was associated with smaller head circumference (Berkowitz et al. 2004) and more abnormal primitive reflexes (Engel et al. 2007), particularly among children of mothers with low paraoxonase 1 (PON1) activity. PON1 is a key enzyme in the metab- olism of organophosphate pesticides (Costa et al. 1999) and has been shown to be a bio- marker of susceptibility to the toxic effects of organophophate pesticides, both in animals (Costa et al. 2003) and in humans (Engel et al. 2007; Eskenazi et al. 2010; Lee et al. 2003; Nielsen et al. 2010). We undertook an investigation of the impact of prenatal organophosphate metabo- lite biomarker levels in relation to cognitive development at multiple times in childhood, while considering the modifying influence of maternal and child PON1 genotype and enzymatic activity. Methods The Mount Sinai Children’s Environmental Health Cohort study is a prospective multieth- nic cohort that enrolled primiparous women who presented for prenatal care with single- ton pregnancies at the Mount Sinai prenatal clinic and two private practices and were sub- sequently delivered at Mount Sinai Hospital between May 1998 and July 2001. The target population was healthy, first-born infants with no underlying health conditions that might independently result in serious neurodevelop- mental impairment. Therefore, women were considered eligible if they were primiparous with singleton pregnancies, had no underlying health conditions that might predispose them to have serious complications of pregnancy that might result in an at-risk infant, and ultimately delivered infants that were neither extremely preterm nor very low birth weight. (Berkowitz et al. 2003, 2004). Mother–infant pairs were recruited early in pregnancy (n = 479). In brief, subsequent to delivery, 75 women were excluded because of medical complications, very premature births (delivery before 32 com- pleted weeks or birth weight < 1,500 g), deliv- ery of an infant with a birth defect, inability to collect biologic specimens before birth, change of hospital or residence outside New York City, or refusal to continue to participate, leav- ing 404 women–infant pairs in the final cohort (Berkowitz et al. 2004). We administered a questionnaire to par- ticipants during their third trimester of preg- nancy to obtain information on environmental exposures, sociodemographic characteristics, Address correspondence to S. Engel, Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina–Chapel Hill, 2104C McGavran-Greenberg, Box 7435, Chapel Hill, NC 27599-7435 USA. Telephone: (919) 966- 7435. Fax: (919) 966-2089. E-mail: Stephanie. Engel@unc.edu Supplemental Material is available online (doi:10.1289/ehp.1003183 via http://dx.doi.org/). We gratefully acknowledge the tremendous contri- butions of G. Berkowitz in developing the New York Children’s Environmental Health cohort. We also thank M. Lievano, S. Meisel, K. Ireland, Z. Liu, and K. Nichols for valuable assistance. This research was supported by National Institute for Environmental Health Sciences/U.S. Environmental Protection Agency Children’s Center grants ES09584 and R827039, the New York Community Trust, and the Agency for Toxic Substances and Disease Registry/ Centers for Disease Control and Prevention (CDC)/ Association of Teachers of Preventive Medicine. 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 7 November 2010; accepted 5 April 2011. ovlume 119 | number 8 | August 2011 • Environmental Health Perspectives