Early-Life Exposure to Polycyclic Aromatic Hydrocarbons and ADHD Behavior Problems

Importance Polycyclic aromatic hydrocarbons are widespread urban air pollutants from combustion of fossil fuel and other organic material shown previously to be neurotoxic. Objective In a prospective cohort study, we evaluated the relationship between Attention Deficit Hyperactivity Disorder behavior problems and prenatal polycyclic aromatic hydrocarbon exposure, adjusting for postnatal exposure. Materials and Methods Children of nonsmoking African-American and Dominican women in New York City were followed from in utero to 9 years. Prenatal polycyclic aromatic hydrocarbon exposure was estimated by levels of polycyclic aromatic hydrocarbon- DNA adducts in maternal and cord blood collected at delivery. Postnatal exposure was estimated by the concentration of urinary polycyclic aromatic hydrocarbon metabolites at ages 3 or 5. Attention Deficit Hyperactivity Disorder behavior problems were assessed using the Child Behavior Checklist and the Conners Parent Rating Scale- Revised. Results High prenatal adduct exposure, measured by elevated maternal adducts was significantly associated with all Conners Parent Rating Scale-Revised subscales when the raw scores were analyzed continuously (N = 233). After dichotomizing at the threshold for moderately to markedly atypical symptoms, high maternal adducts were significantly associated with the Conners Parent Rating Scale-Revised DSM-IV Inattentive (OR = 5.06, 95% CI [1.43, 17.93]) and DSM-IV Total (OR = 3.37, 95% CI [1.10, 10.34]) subscales. High maternal adducts were positivity associated with the DSM-oriented Attention Deficit/Hyperactivity Problems scale on the Child Behavior Checklist, albeit not significant. In the smaller sample with cord adducts, the associations between outcomes and high cord adduct exposure were not statistically significant (N = 162). Conclusion The results suggest that exposure to polycyclic aromatic hydrocarbons encountered in New York City air may play a role in childhood Attention Deficit Hyperactivity Disorder behavior problems

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Depressed height gain of children associated with intrauterine exposure to polycyclic aromatic hydrocarbons (PAH) and heavy metals : the cohort prospective study

Fetal exposure to environmental toxicants may program the development of children and have long-lasting health impacts. The study tested the hypothesis that depressed height gain in childhood is associated with prenatal exposure to airborne polycyclic aromatic hydrocarbons (PAH) and heavy metals (lead and mercury). The study sample comprised 379 children born to non-smoking mothers among whom a total of 2011 height measurements were carried out over the 9-year follow-up period. Prenatal airborne PAH exposure was assessed by personal air monitoring of the mother in the second trimester of pregnancy and heavy metals were measured in cord blood. At the age of 3 residential air monitoring was done to evaluate the level of airborne PAH, and at the age 5 the levels of heavy metals were measured in capillary blood. The effect estimates of prenatal PAH exposure on height growth over the follow-up were adjusted in the General Estimated Equation (GEE) models for a wide set of relevant covariates. Prenatal exposure to airborne PAH showed a significant negative association with height growth, which was significantly decreased by 1.1 cm at PAH level above 34.7 ng/m(3) (coeff. = − 1.07, p = 0.040). While prenatal lead exposure was not significantly associated with height restriction, the effect of mercury was inversely related to cord blood mercury concentration above 1.2 ug/dL (coeff. = −1.21, p = 0.020), The observed negative impact of prenatal PAH exposure on height gain in childhood was mainly mediated by shorter birth length related to maternal PAH exposure during pregnancy. The height gain deficit associated with prenatal mercury exposure was not seen at birth, but the height growth was significantly slower at later age

Early-life exposure to polycyclic aromatic hydrocarbons and ADHD behavior problems.

IMPORTANCE: Polycyclic aromatic hydrocarbons are widespread urban air pollutants from combustion of fossil fuel and other organic material shown previously to be neurotoxic. OBJECTIVE: In a prospective cohort study, we evaluated the relationship between Attention Deficit Hyperactivity Disorder behavior problems and prenatal polycyclic aromatic hydrocarbon exposure, adjusting for postnatal exposure. MATERIALS AND METHODS: Children of nonsmoking African-American and Dominican women in New York City were followed from in utero to 9 years. Prenatal polycyclic aromatic hydrocarbon exposure was estimated by levels of polycyclic aromatic hydrocarbon- DNA adducts in maternal and cord blood collected at delivery. Postnatal exposure was estimated by the concentration of urinary polycyclic aromatic hydrocarbon metabolites at ages 3 or 5. Attention Deficit Hyperactivity Disorder behavior problems were assessed using the Child Behavior Checklist and the Conners Parent Rating Scale- Revised. RESULTS: High prenatal adduct exposure, measured by elevated maternal adducts was significantly associated with all Conners Parent Rating Scale-Revised subscales when the raw scores were analyzed continuously (N = 233). After dichotomizing at the threshold for moderately to markedly atypical symptoms, high maternal adducts were significantly associated with the Conners Parent Rating Scale-Revised DSM-IV Inattentive (OR = 5.06, 95% CI [1.43, 17.93]) and DSM-IV Total (OR = 3.37, 95% CI [1.10, 10.34]) subscales. High maternal adducts were positivity associated with the DSM-oriented Attention Deficit/Hyperactivity Problems scale on the Child Behavior Checklist, albeit not significant. In the smaller sample with cord adducts, the associations between outcomes and high cord adduct exposure were not statistically significant (N = 162). CONCLUSION: The results suggest that exposure to polycyclic aromatic hydrocarbons encountered in New York City air may play a role in childhood Attention Deficit Hyperactivity Disorder behavior problems

Prenatal polycyclic aromatic hydrocarbon (PAH) exposure, antioxidant levels and behavioral development of children ages 6-9

PURPOSE: Prenatal polycyclic aromatic hydrocarbon (PAH) exposure has been shown to increase DNA adduct levels and to affect neurodevelopment. Micronutrients may modify the adverse effect of PAH on neurodevelopment. Thus, we examined if micronutrient concentrations modified the association between PAH exposure and neurodevelopmental outcomes. METHODS: 151 children from a birth cohort who had micronutrient concentrations measured in cord blood and completed the Child Behavioral Checklist (CBCL), between the ages of 6 and 9 years, were evaluated. Prenatal airborne PAH exposure was measured by personal air monitoring. The betas and 95% CI for the associations of antioxidant concentrations and PAH exposure with each of the outcomes of CBCL raw score and dichotomized standardized T-score (based on clinical cutpoints) were estimated, respectively, by multivariable poisson and logistic models. RESULTS: Children below the median for alpha-tocopherol and gamma-tocopherol concentrations, compared to those above, were more likely to have thought problems, aggressive behavior and externalizing problems (p<0.05). Lower carotenoid concentration was associated with more thought problems (MVβ=0.60, p<0.001) and externalizing problems (MVβ=0.13, p<0.05) for the same contrast. No statistically significant associations were observed between retinol concentrations and neurodevelopmental symptoms. Overall, no consistent patterns were observed when we examined the interaction between antioxidants (e.g., alpha-tocopherol) and PAH in relation to CBCL symptoms (e.g., internalizing and externalizing problems, p<0.05). CONCLUSIONS: Lower alpha-tocopherol, gamma-tocopherol and carotenoid levels may adversely affect healthy neurodevelopment, even after accounting for PAH exposure. Future research to confirm these findings are warranted given the importance of identifying modifiable factors for reducing harmful PAH effects

Distribution of CBCL and CPRS Scores in children at age 9 (N = 250^a).

a<p>Children included in analysis with all covariates.</p>b<p>CBCL “borderline or clinical” defined as percentile ≥93^rd; CPRS “moderately to markedly atypical” defined as T-score >65.</p><p>Distribution of CBCL and CPRS Scores in children at age 9 (N = 250^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111670#nt117" target="_blank">a</a>}).</p

Number of children categorized as moderately to markedly atypical on the CPRS DSM-IV Hyperactive Impulsive and CPRS DSM-IV Inattentive Subscales^a.

<p>Number of children categorized as moderately to markedly atypical on the CPRS DSM-IV Hyperactive Impulsive and CPRS DSM-IV Inattentive Subscales^a.</p

Number of children scoring in the borderline or clinical range on the CBCL and in the moderately to markedly atypical range on the CPRS in the analyses with maternal adducts or cord adducts^a.

a<p>Children included in analysis with all covariates.</p>b<p>CBCL- Borderline or clinical defined as percentile ≥93^rd; CPRS- Moderately to markedly atypical defined as T-score >65.</p><p>Number of children scoring in the borderline or clinical range on the CBCL and in the moderately to markedly atypical range on the CPRS in the analyses with maternal adducts or cord adducts^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111670#nt119" target="_blank">a</a>}.</p

Associations between PAH Exposure and CBCL DSM-oriented Attention Deficit/Hyperactivity problems and ADHD Behavior Problems on the CPRS Subscales adjusting for postnatal exposure^a.

a<p>Adjusting for postnatal PAH exposure (measured by metabolites at ages 3 or 5, adjusted for specific gravity), prenatal ETS, child sex, maternal education, child ethnicity, gestational age, maternal demoralization, heating season, HOME caretaking environment, maternal intelligence, child age at assessment, maternal ADHD, child anxiety/depression at age 9.</p>b<p>OR stands for odds Ratio; CI stands for Confidence Interval.</p>c<p>CBCL- Borderline or clinical defined as percentile ≥93^rd; CPRS- Moderately to markedly atypical defined as T-score >65.</p><p>*p-value <0.05.</p><p>Associations between PAH Exposure and CBCL DSM-oriented Attention Deficit/Hyperactivity problems and ADHD Behavior Problems on the CPRS Subscales adjusting for postnatal exposure^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111670#nt121" target="_blank">a</a>}.</p