Showing papers by "Frederica P. Perera published in 2013"

Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure

Abstract: Bisphenol A (BPA) is an estrogenic endocrine disruptor widely used in the production of plastics. Increasing evidence indicates that in utero BPA exposure affects sexual differentiation and behavior; however, the mechanisms underlying these effects are unknown. We hypothesized that BPA may disrupt epigenetic programming of gene expression in the brain. Here, we provide evidence that maternal exposure during pregnancy to environmentally relevant doses of BPA (2, 20, and 200 µg/kg/d) in mice induces sex-specific, dose-dependent (linear and curvilinear), and brain region-specific changes in expression of genes encoding estrogen receptors (ERs; ERα and ERβ) and estrogen-related receptor-γ in juvenile offspring. Concomitantly, BPA altered mRNA levels of epigenetic regulators DNA methyltransferase (DNMT) 1 and DNMT3A in the juvenile cortex and hypothalamus, paralleling changes in estrogen-related receptors. Importantly, changes in ERα and DNMT expression in the cortex (males) and hypothalamus (females) were associated with DNA methylation changes in the ERα gene. BPA exposure induced persistent, largely sex-specific effects on social and anxiety-like behavior, leading to disruption of sexually dimorphic behaviors. Although postnatal maternal care was altered in mothers treated with BPA during pregnancy, the effects of in utero BPA were not found to be mediated by maternal care. However, our data suggest that increased maternal care may partially attenuate the effects of in utero BPA on DNA methylation. Overall, we demonstrate that low-dose prenatal BPA exposure induces lasting epigenetic disruption in the brain that possibly underlie enduring effects of BPA on brain function and behavior, especially regarding sexually dimorphic phenotypes.

Urban Tree Canopy and Asthma, Wheeze, Rhinitis, and Allergic Sensitization to Tree Pollen in a New York City Birth Cohort

Abstract: Background: Urban landscape elements, particularly trees, have the potential to affect airflow, air quality, and production of aeroallergens Several large-scale urban tree planting projects have sought to promote respiratory health, yet evidence linking tree cover to human health is limited Objectives: We sought to investigate the association of tree canopy cover with subsequent development of childhood asthma, wheeze, rhinitis, and allergic sensitization Methods: Birth cohort study data were linked to detailed geographic information systems data characterizing 2001 tree canopy coverage based on LiDAR (light detection and ranging) and multispectral imagery within 025 km of the prenatal address A total of 549 Dominican or African-American children born in 1998–2006 had outcome data assessed by validated questionnaire or based on IgE antibody response to specific allergens, including a tree pollen mix Results: Tree canopy coverage did not significantly predict outcomes at 5 years of age, but was positively associated with asthma and allergic sensitization at 7 years Adjusted risk ratios (RRs) per standard deviation of tree canopy coverage were 117 for asthma (95% CI: 102, 133), 120 for any specific allergic sensitization (95% CI: 105, 137), and 143 for tree pollen allergic sensitization (95% CI: 119, 172) Conclusions: Results did not support the hypothesized protective association of urban tree canopy coverage with asthma or allergy-related outcomes Tree canopy cover near the prenatal address was associated with higher prevalence of allergic sensitization to tree pollen Information was not available on sensitization to specific tree species or individual pollen exposures, and results may not be generalizable to other populations or geographic areas

Prenatal and postnatal bisphenol A exposure and asthma development among inner-city children

Abstract: Background Bisphenol A (BPA) is used widely to manufacture food container linings. Mouse models suggest exposure to BPA might increase allergic inflammation. Objectives We hypothesized that BPA exposure, as assessed based on urinary BPA concentrations, would be associated with increased odds of wheeze and asthma and increased fraction of exhaled nitric oxide (Feno) values in children. Methods The Columbia Center for Children's Environmental Health recruited pregnant women for a prospective birth cohort study (n = 568). Mothers during the third trimester and children at ages 3, 5, and 7 years provided spot urine samples. Total urinary BPA concentrations were measured by using online solid-phase extraction, high-performance liquid chromatography, isotope-dilution tandem mass spectrometry. Wheeze in the last 12 months was measured by using questionnaires at ages 5, 6, and 7 years. Asthma was determined by a physician once between ages 5 and 12 years. Feno values were measured at ages 7 to 11 years. Results Prenatal urinary BPA concentrations were associated inversely with wheeze at age 5 years (odds ratio [OR], 0.7; 95% CI, 0.5-0.9; P = .02). Urinary BPA concentrations at age 3 years were associated positively with wheeze at ages 5 years (OR, 1.4; 95% CI, 1.1-1.8; P = .02) and 6 years (OR, 1.4; 95% CI, 1.0-1.9; P = .03). BPA concentrations at age 7 years were associated with wheeze at age 7 years (OR, 1.4; 95% CI, 1.0-1.9; P = .04) and Feno values (β = 0.1; 95% CI, 0.02-0.2; P = .02). BPA concentrations at ages 3, 5, and 7 years were associated with asthma (OR, 1.5 [95% CI, 1.1-2.0], P = .005; OR, 1.4 [95% CI, 1.0-1.9], P = .03; and OR, 1.5 [95% CI, 1.0-2.1], P = .04, respectively). Conclusions This is the first report of an association between postnatal urinary BPA concentrations and asthma in children.

Early-life cockroach allergen and polycyclic aromatic hydrocarbon exposures predict cockroach sensitization among inner-city children

Abstract: Background Sensitization to cockroach is one of the strongest identified risk factors for greater asthma morbidity in low-income urban communities; however, the timing of exposures relevant to the development of sensitization has not been elucidated fully. Furthermore, exposure to combustion byproducts, including polycyclic aromatic hydrocarbons (PAHs), can augment the development of allergic sensitization. Objective We sought to test the hypotheses that domestic cockroach allergen measured prenatally would predict cockroach sensitization in early childhood and that this association would be greater for children exposed to higher PAH concentrations. Methods Dominican and African American pregnant women living in New York City were enrolled. In the third trimester expectant mothers wore personal air samplers for measurement of 8 nonvolatile PAHs and the semivolatile PAH pyrene, and dust was collected from homes for allergen measurement. Glutathione-S-transferase μ 1 (GSTM1) gene polymorphisms were measured in children. Allergen-specific IgE levels were measured from the children at ages 2, 3, 5, and 7 years. Results Bla g 2 in prenatal kitchen dust predicted cockroach sensitization at the ages of 5 to 7 years (adjusted relative risk [RR], 1.15; P = .001; n = 349). The association was observed only among children with greater than (RR, 1.22; P = .001) but not less than (RR, 1.07; P = .24) the median sum of 8 nonvolatile PAH levels. The association was most pronounced among children with higher PAH levels and null for the GSTM1 gene (RR, 1.54; P = .001). Conclusions Prenatal exposure to cockroach allergen was associated with a greater risk of allergic sensitization. This risk was increased by exposure to nonvolatile PAHs, with children null for the GSTM1 mutation particularly vulnerable.

Predictors and Consequences of Global DNA Methylation in Cord Blood and at Three Years

Abstract: DNA methylation changes have been implicated in many common chronic diseases leading to the hypothesis that environmental and age-related DNA methylation changes within individuals are involved in disease etiology. Few studies have examined DNA methylation changes within an individual over time and all of these studies have been conducted in adults. Here, we aim to characterize how global DNA methylation changes from birth to age three within a longitudinal birth cohort study and to determine whether there are consistent predictors of DNA methylation levels measured three years apart. We measured global DNA methylation in the same children at birth (cord blood) and again at three years of age among 165 children, using an immunoassay. We found that on average, DNA methylation was significantly higher in blood at age 3-years than in cord blood (p<0.01). However, for any individual child, the difference was less than would be expected by chance. We found that pre-pregnancy BMI was negatively predictive of both cord and three-year DNA methylation, even after statistical adjustment to account for the correlation between cord blood and three-year DNA methylation. The biologic implications of small changes in global DNA methylation are unknown. However, the observation that global DNA methylation levels persist within an individual from birth to age three supports the belief that factors that influence global DNA methylation, including pre-pregnancy BMI, may confer long-term effects.

Prenatal Exposure to Air Pollution, Maternal Psychological Distress, and Child Behavior

Abstract: BACKGROUND: Airborne polycyclic aromatic hydrocarbons (PAHs) are pollutants generated by combustion of fossil fuel and other organic material. Both prenatal PAH exposure and maternal psychological distress during pregnancy have each been associated with neurodevelopmental problems in children. The goal was to evaluate potential interactions between prenatal exposure to airborne PAHs and maternal psychological distress during pregnancy on subsequent behavioral problems in children. METHODS: In a longitudinal birth cohort study, 248 children of nonsmoking white women in the coal-burning region of Krakow, Poland, were followed from in utero until age 9. Prenatal PAH exposure was measured by personal air monitoring during pregnancy, maternal demoralization during pregnancy by the Psychiatric Epidemiology Research Instrument–Demoralization, and child behavior by the Child Behavior Checklist. RESULTS: Significant interactions between maternal demoralization and PAH exposure (high versus low) were identified for symptoms of anxious/depressed, withdrawn/depressed, social problems, aggressive behavior, internalizing problems, and externalizing problems. The effects of demoralization on syndromes of anxious/depressed, withdrawn/depressed, rule-breaking, aggressive behavior, and the composite internalizing and externalizing scores were seen only in conjunction with high PAH exposure. Fewer significant effects with weaker effect sizes were observed in the low-PAH-exposure group. CONCLUSIONS: Maternal demoralization during pregnancy appears to have a greater effect on child neurobehavioral development among children who experienced high prenatal PAH exposure. The results provide the first evidence of an interaction between prenatal exposure to maternal demoralization and air pollution on child neurobehavioral development, indicating the need for a multifaceted approach to the prevention of developmental problems in children.

The relationship between prenatal exposure to airborne polycyclic aromatic hydrocarbons (PAHs) and PAH-DNA adducts in cord blood.

Abstract: In a birth cohort study, we have assessed the dose-response relationship between individual measurements of prenatal airborne polycyclic aromatic hydrocarbon (PAH) exposure and specific PAH–DNA adducts in cord blood adjusted for maternal blood adducts and season of birth. The study uses data from an earlier established birth cohort of children in Krakow. The final analysis included 362 pregnant women who gave birth to term babies and had complete data on personal exposure in the second trimester of pregnancy to eight airborne PAHs including benzo[a]pyrene (B[a]P), as well as DNA adducts, both in maternal and cord blood. The relation between cord blood PAH–DNA adducts and airborne prenatal PAH exposure was non-linear. Although cord blood PAH–DNA adducts were significantly associated with the B[a]P exposure categorized by tertiles (non-parametric trend z=3.50, P<0.001), the relationship between B[a]P and maternal blood adducts was insignificant (z=1.63, P=0.103). Based on the multivariable linear regression model, we estimated the effect of the prenatal airborne B[a]P on the level of cord blood adducts. In total, 14.8% of cord blood adducts variance was attributed to the level of maternal adducts and 3% to a higher prenatal B[a] exposure above 5.70 ng/m3. The calculated fetal/maternal blood adduct ratio (FMR) linearly increased with B[a]P exposure (z=1.99, P=0.047) and was highest at B[a]P concentrations exceeding 5.70 ng/m3. In conclusion, the results support other findings that transplacental exposure to B[a]P from maternal inhalation produces DNA damage in the developing fetus. It also confirms the heightened fetal susceptibility to prenatal PAH exposure that should be a matter of public health concern, particularly in the highly polluted areas, because DNA adducts represent a pro-carcinogenic alteration in DNA. The continuation of this birth cohort study will assess the possible health effects of fetal DNA damage on the health of children and help in establishing new protective guidelines for newborns.

Circulating pro-surfactant protein B as a risk biomarker for lung cancer

Abstract: Background: Our prior studies of lung cancer suggested that a novel biomarker (pro- surfactant protein B or pro-SFTPB) might serve as a predictive marker for this disease. We aimed to determine the potential utility of pro-SFTPB for distinguishing lung cancer cases from matched controls as a risk marker. Methods: Study subjects were drawn from the longitudinal Physicians' Health Study (PHS). Cases (n = 188) included individuals who were cancer-free at study enrollment but developed lung cancer during follow-up. Controls (n = 337) were subjects who did not develop lung cancer. Cases and controls were matched on date of study enrollment, age at enrollment, and smoking status and amount. Baseline plasma samples drawn at enrollment were analyzed for pro-SFTPB using ELISA to detect differences in protein expression levels for cases and controls. Results: Pro-SFTPB-non-detectable status was significantly associated with lung cancer risk (OR = 5.88, 95% CI 1.24, 27.48). Among subjects with detectable levels of the protein, increasing plasma concentration of pro-SFTPB was associated with higher lung cancer risk (OR = 1.41 per unit increase in log pro-SFTPB, 95% CI 1.08, 1.84). Conclusion: These results suggest a non-linear, J- shaped association between plasma pro-SFTPB levels and lung cancer risk, with both non-detectable and higher levels of the marker being associated with lung cancer. Impact: These results show promise of a risk marker that could contribute to predicting risk for lung cancer development and to narrowing the high risk population for low-dose computed tomography (LDCT) screening.

Prenatal and postnatal polycyclic aromatic hydrocarbon exposure, airway hyperreactivity, and Beta-2 adrenergic receptor function in sensitized mouse offspring.

Abstract: Despite data associating exposure to traffic-related polycyclic aromatic hydrocarbons (PAH) in asthma, mechanistic support has been limited. We hypothesized that both prenatal and early postnatal exposure to PAH would increase airway hyperreactivity (AHR) and that the resulting AHR may be insensitive to treatment with a β2AR agonist drug, procaterol. Further, we hypothesized that these exposures would be associated with altered β2AR gene expression and DNA methylation in mouse lungs. Mice were exposed prenatally or postnatally to a nebulized PAH mixture versus negative control aerosol 5 days a week. Double knockout β2AR mice were exposed postnatally only. Prenatal exposure to PAH was associated with reduced β2AR gene expression among nonsensitized mice offspring, but not increases in DNA methylation or AHR. Postnatal exposure to PAH was borderline associated with increased AHR among sensitized wildtype, but not knockout mice. In the first study that delivers PAH aerosols to mice in a relatively physiological manner, small effects on AHR and β2AR gene expression, but not β2AR agonist drug activity, were observed. If confirmed, the results may suggest that exposure to PAH, common ambient urban pollutants, affects β2AR function, although the impact on the efficacy of β2AR agonist drugs used in treating asthma remains uncertain.

Exercise-induced wheeze, urgent medical visits, and neighborhood asthma prevalence.

Abstract: OBJECTIVE: Exercise-induced wheeze (EIW) may identify a distinct population among asthmatics and give insight into asthma morbidity etiology The prevalence of pediatric asthma and associated urgent medical visits varies greatly by neighborhood in New York City and is highest in low-income neighborhoods Although increased asthma severity might contribute to the disparities in urgent medical visits, when controlling for health insurance coverage, we previously observed no differences in clinical measures of severity between asthmatic children living in neighborhoods with lower (3%–9%) versus higher (11%–19%) asthma prevalence Among these asthmatics, we hypothesized that EIW would be associated with urgent medical visits and a child’s neighborhood asthma prevalence METHODS: Families of 7- to 8-year-old children were recruited into a case-control study of asthma through an employer-based health insurance provider Among the asthmatics ( n = 195), prevalence ratios (PRs) for EIW were estimated Final models included children with valid measures of lung function, seroatopy, and waist circumference ( n = 140) RESULTS: EIW was associated with urgent medical visits for asthma (PR, 229; P = 021), independent of frequent wheeze symptoms In contrast to frequent wheeze, EIW was not associated with seroatopy or exhaled NO, suggesting a distinct mechanism EIW prevalence among asthmatics increased with increasing neighborhood asthma prevalence (PR, 109; P = 012), after adjustment for race, ethnicity, maternal asthma, environmental tobacco smoke, household income, and neighborhood income CONCLUSIONS: EIW may contribute to the disparities in urgent medical visits for asthma between high- and low-income neighborhoods Physicians caring for asthmatics should consider EIW an indicator of risk for urgent medical visits

Predictors and consequences of global DNA methylation in cord blood and at three years

Abstract: Background: DNA methylation changes have been implicated in many common chronic diseases leading to the hypothesis that environmental and age-related methylation changes within individuals are invo...

Prenatal Bisphenol A and Birth Weight in an Urban Minority Birth Cohort

Abstract: Background: Prenatal exposure to the endocrine disruptor bisphenol A (BPA), a suspected obesogen, may have a role in the developmental origins of adult disease hypothesis. Objectives: We studied wh...