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Original Investigation |

Effects of Prenatal Exposure to Air Pollutants (Polycyclic Aromatic Hydrocarbons) on the Development of Brain White Matter, Cognition, and Behavior in Later Childhood

Bradley S. Peterson, MD1,2; Virginia A. Rauh, ScD3,4; Ravi Bansal, PhD1,2; Xuejun Hao, PhD5,6; Zachary Toth, BA5,6; Giancarlo Nati, BA1,2; Kirwan Walsh, BA5,6; Rachel L. Miller, MD4,7; Franchesca Arias, MS4; David Semanek, BA5,6; Frederica Perera, DrPH, PhD4
[+] Author Affiliations
1Institute for the Developing Mind, Children’s Hospital Los Angeles, Los Angeles, California
2Keck School of Medicine, University of Southern California, Los Angeles
3Heilbrunn Department of Population and Family Health, Mailman School of Public Health, Columbia University, New York, New York
4Columbia Center for Children’s Environmental Health, Mailman School of Public Health, Columbia University, New York, New York
5Department of Psychiatry, Columbia College of Physicians and Surgeons, New York, New York
6New York State Psychiatric Institute, New York
7Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Columbia College of Physicians and Surgeons, New York, New York
JAMA Psychiatry. 2015;72(6):531-540. doi:10.1001/jamapsychiatry.2015.57.
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Published online

Importance  Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous and neurotoxic environmental contaminants. Prenatal PAH exposure is associated with subsequent cognitive and behavioral disturbances in childhood.

Objectives  To identify the effects of prenatal PAH exposure on brain structure and to assess the cognitive and behavioral correlates of those abnormalities in school-age children.

Design, Setting, and Participants  Cross-sectional imaging study in a representative community-based cohort followed up prospectively from the fetal period to ages 7 to 9 years. The setting was urban community residences and an academic imaging center. Participants included a sample of 40 minority urban youth born to Latina (Dominican) or African American women. They were recruited between February 2, 1998, and March 17, 2006.

Main Outcomes and Measures  Morphological measures that index local volumes of the surface of the brain and of the white matter surface after cortical gray matter was removed.

Results  We detected a dose-response relationship between increased prenatal PAH exposure (measured in the third trimester but thought to index exposure for all of gestation) and reductions of the white matter surface in later childhood that were confined almost exclusively to the left hemisphere of the brain and that involved almost its entire surface. Reduced left hemisphere white matter was associated with slower information processing speed during intelligence testing and with more severe externalizing behavioral problems, including attention-deficit/hyperactivity disorder symptoms and conduct disorder problems. The magnitude of left hemisphere white matter disturbances mediated the significant association of PAH exposure with slower processing speed. In addition, measures of postnatal PAH exposure correlated with white matter surface measures in dorsal prefrontal regions bilaterally when controlling for prenatal PAH.

Conclusions and Relevance  Our findings suggest that prenatal exposure to PAH air pollutants contributes to slower processing speed, attention-deficit/hyperactivity disorder symptoms, and externalizing problems in urban youth by disrupting the development of left hemisphere white matter, whereas postnatal PAH exposure contributes to additional disturbances in the development of white matter in dorsal prefrontal regions.

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Figure 1.
Correlations of Prenatal Polycyclic Aromatic Hydrocarbon Levels With Cerebral Surface Measures

At each point on the cerebral surface is shown the statistical significance (probability values) for correlations of total prenatal polycyclic aromatic hydrocarbon levels with measures of the cerebral surface, either cortical thickness or distance from the surface of the template brain (see the eMethods in the Supplement for detailed descriptions of each of these measures). The distance at each point of the cerebral surface in each participant from the corresponding point of the surface of the template brain provides a continuous measure that, when strictly defined, assesses the degree of indentation or protrusion at that point on the surface relative to the template brain, which can be more loosely considered an index of local volume at that point. This index of local volume can derive from either the underlying cortical gray matter, white matter, or both. Both cortical thickness and distance measures were rescaled for overall brain size, and the statistical models accounted for the age and sex of all children. The color bar indicates the color coding of P values for testing of statistical significance at each point on the surface. P values were thresholded at P < .05 after correction for multiple comparisons using the false discovery rate. Warm colors (yellow, orange, and red) represent significant positive correlations, and cool colors (blue and purple) represent inverse correlations. Sea green indicates correlations that are not statistically significant. The boundaries of major gyri are outlined in white. A, Correlations are shown for total prenatal polycyclic aromatic hydrocarbon levels with distances of the cerebral surface of each participant brain from the corresponding point on the template surface. Correlations are more statistically significant and more spatially extensive in the left hemisphere than in the right hemisphere. The gyri containing statistically significant correlations are labeled. B, These images are correlations of total prenatal polycyclic aromatic hydrocarbon levels with distances of the white matter surface of each participant from the corresponding point on the surface of white matter in the template brain. Regions with statistically significant correlations are much more extensive than those in A, covering almost the entire extent of the white matter surface in the left hemisphere. Correlations with cortical thickness were not statistically significant. Together, these findings suggest that correlations detected at the cerebral surface in A derived primarily from the underlying white matter. CG indicates cingulate gyrus; Cu, cuneus; GR, gyrus rectus; IFG, inferior frontal gyrus; ITG, inferior temporal gyrus; MFG, middle frontal gyrus; MOF, medial orbitofrontal gyrus; MTG, middle temporal gyrus; PoG, postcentral gyrus; PreC, precuneus; PrG, precentral gyrus; SFG, superior frontal gyrus; SMG, supramarginal gyrus; SPG, superior parietal gyrus; and STG, superior temporal gyrus.

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Figure 2.
Correlations of Polycyclic Aromatic Hydrocarbon (PAH) Levels With White Matter Surface Measures

Scatterplots show that the significant correlations derive from the entire range of prenatal and postnatal PAH levels and are not driven by outliers. White matter measures are adjusted for age and sex of each participant. A, Maps for these correlations are as described for Figure 1. The white circles indicate where in the brain the data set was sampled to generate the scatters. The Pearson product moment correlation coefficients from left to right are −0.57 (95% CI, −0.75 to −0.30), −0.51 (95% CI, −0.71 to −0.23), −0.50 (95% CI, −0.71 to −0.22), and −0.56 (95% CI, −0.75 to −0.30). B, Maps for these correlations are as described for Figure 1 except that the regressions are for postnatal PAH exposure levels measured at age 5 years. The analyses covaried for age, sex, and prenatal PAH levels. The values for postnatal PAH metabolite levels have been natural log transformed. The Pearson product moment correlation coefficients from left to right are −0.47 (95% CI, −0.69 to −0.18) and −0.52 (95% CI, −0.72 to −0.25). In(PAH) indicates the natural logarithm of PAH levels.

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Figure 3.
Prenatal Polycyclic Aromatic Hydrocarbon (PAH) Effects on Processing Speed

A, P values that are false discovery rate–corrected for multiple comparisons are plotted for partial correlations of processing speed with distances at each point on the white matter surface from the corresponding point on the white matter surface of the template brain, while covarying for age and sex. Warm colors (yellow, orange, and red) represent significant positive correlations in which white matter reductions associate with lower indexes for processing speed. Sea green indicates correlations that are not statistically significant. B, P values are plotted for regression models that test whether white matter surface distances mediate the association of prenatal PAH levels with processing speed from the Wechsler Intelligence Scale for Children IV (WISC-IV) assessed at ages 7 to 9 years. We tested the significance of the mediation effect at each voxel on the surface of white matter using a Sobel test z score, which was large and typically exceeded 90. We then plotted the associated P values for this mediation pathway on the template brain, corrected them for multiple statistical comparisons using the false discovery rate, and color coded the corrected P values to identify voxels where partial mediation was statistically significant. These voxels were detected throughout all lobes on the white surfaces of the left hemisphere.

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Figure 4.
Scatterplots for Correlations of White Matter Surface Measures With Processing Speed, Child Behavior Checklist (CBCL) Externalizing Problems, and CBCL DSM Attention-Deficit/Hyperactivity Disorder (ADHD) Symptoms

The maps were sampled at the locations indicated by white circles. The y-axis shows distances at those points for the white matter surface of each participant from the corresponding point on the white matter surface of the template brain, adjusted for age and sex of each participant. The scatterplots show that the significant findings were not driven by outliers. The Externalizing Composite Scale included only the rule-breaking behavior and aggressive behavior subscales. The Pearson product moment correlation coefficients that follow are from left to right. For processing speed, they are 0.62 (95% CI, 0.39-0.79), 0.56 (95% CI, 0.29-0.74), and 0.43 (95% CI, 0.13-0.66). For externalizing symptoms, they are −0.52 (95% CI, −0.72 to −0.24), −0.49 (95% CI, −0.70 to −0.20), and −0.50 (95% CI, −0.71 to −0.21). For DSM ADHD, they are −0.53 (95% CI, −0.72 to −0.25), −0.57 (95% CI, −0.75 to −0.31), and −0.48 (95% CI, −0.69 to −0.18). WISC-IV indicates Wechsler Intelligence Scale for Children IV.

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