Research | Children’s Health Prenatal Exposure to Residential Air Pollution and Infant Mental Development: Modulation by Antioxidants and Detoxification Factors Mònica Guxens,1,2,3 Inmaculada Aguilera,1,2,3 Ferran Ballester,3,4,5 Marisa Estarlich,3,4 Ana Fernández-Somoano3,6 Aitana Lertxundi,7,8 Nerea Lertxundi,8,9 Michelle A. Mendez,1,2,3 Adonina Tardón,3,6 Martine Vrijheid,1,2,3 and Jordi Sunyer,1,2,3,10 on behalf of the INMA (INfancia y Medio Ambiente) Project 1Center for Research in Environmental Epidemiology (CREAL), Barcelona, Catalonia, Spain; 2Hospital del Mar Research Institute (IMIM), Barcelona, Catalonia, Spain; 3CIBER Epidemiologia y Salud Pública (CIBERESP), Spain; 4Division of Environment and Health, Center for Public Health Research-CSISP, Valencia, Spain; 5School of Nursing, University of Valencia, Valencia, Spain; 6University of Oviedo, Oviedo, Spain; 7Campus de Bizkaia, Universidad del País Vasco Leioa, Basque Country, Spain; 8Instituto de Investigación Sanitaria de Euskadi (BIODONOSTIA), Donostia, Basque Country, Spain; 9Campus de Gipuzkoa, Universidad del País Vasco, Donostia, Basque Country, Spain; 10Pompeu Fabra University, Barcelona, Catalonia, Spain Background : Air pollution effects on children’s neurodevelopment have recently been suggested to occur most likely through the oxidative stress pathway. o Bjectiv : We aimed to assess whether prenatal exposure to residential air pollution is associated with impaired infant mental development, and whether antioxidant/detoxification factors modulate this association. Methods : In the Spanish INfancia y Medio Ambiente (INMA; Environment and Childhood) Project, 2,644 pregnant women were recruited during their first trimester. Nitrogen dioxide (NO2) and benzene were measured with passive samplers covering the study areas. Land use regression models were developed for each pollutant to predict average outdoor air pollution levels for the entire pregnancy at each residential address. Maternal diet was obtained at first trimester through a validated food frequency questionnaire. Around 14 months, infant mental development was assessed using Bayley Scales of Infant Development. r esult : Among the 1,889 children included in the analysis, mean exposure during pregnancy was 29.0 μg/m 3 for NO2 and 1.5 μg/m 3 for benzene. Exposure to NO2 and benzene showed an inverse association with mental development, although not statistically significant, after adjusting for potential confounders [β (95% confidence interval) = –0.95 (–3.90, 1.89) and –1.57 (–3.69, 0.56), respectively, for a doubling of each compound]. Stronger inverse associations were estimated for both pollutants among infants whose mothers reported low intakes of fruits/vegetables during pregnancy [–4.13 (–7.06, –1.21) and –4.37 (–6.89, –1.86) for NO2 and benzene, respectively], with little evidence of associations in the high-intake group (interaction p-values of 0.073 and 0.047). Inverse associations were also stronger in non-breast-fed infants and infants with low maternal vita- min D, but effect estimates and interactions were not significant. c onclusion : Our findings suggest that prenatal exposure to residential air pollutants may adversely affect infant mental development, but potential effects may be limited to infants whose mothers report low antioxidant intakes. words k ey : aromatic hydrocarbons, breast-feeding, child development, cognition, environmental pollution, fruit, intelligence, nitrogen dioxide, vegetables, vitamin D. Environ Health Perspect 120:144–149 (2012). http://dx.doi.org/10.1289/ehp.1103469 [Online 25 August 2011] related to health disadvantage and vulnerabil- ity, high intakes of antioxidant nutrients has been proposed as an important potential modi- fier of air pollution impairment (Romieu et al. 2008; Villarreal-Calderon et al. 2010). Thus, we hypothesized that levels of different anti- oxidants and detoxification factors during preg- nancy and the first year of life may modulate the potential negative effect of air pollutants on mental development. Fruits and vegeta- bles are a rich source of antioxidant nutrients (Balsano and Alisi 2009), and breast milk has a high content of long-chain polyunsaturated fatty acids and other micronutrients that may reduce inflammation and oxidative stress (Rodriguez-Palmero et al. 1999). Moreover, a beneficial role of vitamin D in the develop- ing brain through antioxidant and detoxifica- tion mechanisms has recently been postulated (Buell and Dawson-Hughes 2008). Therefore, the purpose of the present study was to assess whether residential air pol- lution exposure during pregnancy adversely Address correspondence to M. Guxens, Centre for Research in Environmental Epidemiology (CREAL), Carrer Dr. Aiguader 88, 08003 Barcelona, Spain. Telephone: 34 932147331. Fax: 34 932147302. E-mail: mguxens@creal.cat Supplemental Material is available online (http:// dx.doi.org/10.1289/ehp.1103469). We particularly thank all the participants for their generous collaboration. This study was funded by grants from the Spanish Ministry of Health-Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041, FIS-PI041436, FIS- PI081151, FIS-PI042018, FIS-PI09/02311, FIS- PI06/0867, FIS-PS09/00090, FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, and 09/02647), Generalitat de Catalunya-CIRIT (Consell Interdepartamental de Recerca i Innovació Tecnològica) (1999SGR 00241), Conselleria de Sanitat Generalitat Valenciana, Universidad de Oviedo, Obra social Cajastur, Department of Health of the Basque Government (2005111093 and 2009111069), the Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001), and Fundación Roger Torné. A full roster of the INMA Project investigators can be found at http://www.proyectoinma.org/ presentacion-inma/listado-investigadores/en_listado- nvestigadores.html The authors declare they have no actual or poten- tial competing financial interests. Received 20 January 2011; accepted 25 August 2011. ovlume 120 | number 1 | January 2012 • Environmental Health Perspectives Ambient air pollution is a global public health threat. Cardiorespiratory effects and related mechanisms have been extensively investi- gated (Götschi et al. 2008; Sun et al. 2010). However, little is known about possible neu- rological effects, because preliminary evidence is limited (Sunyer 2008). Animal studies have shown that air pollutants might reach the brain directly via the olfactory bulb and may themselves be proinflammatory (Block and Calderon-Garciduenas 2009). Moreover, air pollutants seem to induce oxidative stress in the lung and cause chronic respiratory tract and systemic inflammation that may lead to brain inflammation by increasing levels of circulating cytokines (Block and Calderon- Garciduenas 2009). Maturation of the cortex during the first years of life is intensive (Grandjean and Landrigan 2006). This period of life is considered an important window for brain 144 development, because the brain’s plastic- ity decreases with age, and susceptibility to environmental insults is elevated (Grandjean and Landrigan 2006). Nine studies concern- ing neuropsychological effects of air pollu- tion on children have been published to date (Calderon-Garciduenas et al. 2008; Edwards et al. 2010; Freire et al. 2010; Perera et al. 2006, 2008, 2009; Siddique et al. 2011; Suglia et al. 2008; Tang et al. 2008; Volk et al. 2011; Wang et al. 2009). However, larger and more detailed research is needed given the potential worldwide impact of these findings. Furthermore, some researchers have pointed out that, at least in some countries, disadvantaged groups are more likely to live in areas of greater air pollution (Brulle and Pellow 2006). Consequently, health effects of air pollution exposure should be carefully sepa- rated from the potential confounding role of socioeconomic inequalities. Among the factors