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The prenatal period of development is uniquely susceptible to lasting harmful health effects from exposure to environmental toxicants. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants which have a wide variety of associated health effects, including impaired neurodevelopment when exposure occurs in-utero. While a handful of mechanisms have been implicated in PAH neurodevelopmental toxicity, none fully resolve the intricate biological processes that contribute to these outcomes. Mitochondria are increasingly being studied as sensitive targets of many environmental toxicants including PAHs. Despite the known mitochondrial sensitivity to PAHs, and the role of mitochondrial functions in neurodevelopment, little research has been done to evaluate mitochondrial dysfunction as mechanism of PAH neurodevelopmental toxicity. The work of this dissertation seeks to investigate a number of questions on this topic using a wide variety of techniques. We study exposure sources of individual PAHs, the relationship between prenatal PAH exposure constituents and mitochondrial functional outcomes and mitochondrial DNA copy number (mtDNAcn) in multiple biospecimens, including windows of exposure. We employ both epidemiological and experimental techniques, leveraging the advantages of one approach against the weakness of another to draw robust conclusions. Chapter 2 begins by comprehensively studying the demographic and behavioral variables predictive of personal PAH exposure. We combined a significant amount of personal exposure data collected using silicone wristbands with prenatal questionnaires to identify variables most predictive of both exposure to individual PAH compounds and total exposure. This work revealed complex relationships between multiple parameters in the prediction of each individual PAH. We found demographic and socioeconomic variables to be the most common predictors of exposure, followed by behavior variables. This work provides the foundation to identify pathways to reduce exposure and protecting the most vulnerable populations. In chapter 3, we describe two epidemiological studies conducted in Northern Manhattan birth cohorts. The first study uses data from the Columbia Center for Children’s Environmental Health (CCCEH) Fair Start cohort. We measured mitochondrial DNA copy number (mtDNAcn) in umbilical cord tissue, a novel biospecimen with unique utility due to its ease of acquisition and homogenous cellular composition. We measured individual exposure to 63 PAH compounds using silicone wristband samplers and analyze this data using both individual models and quantile G computation to estimate the overall mixture effect. We identified three compounds associated with mtDNAcn in individual models, and a positive association between the mixture of 19 compounds and mtDNAcn. In the second study we expanded upon previous analyses in the CCCEH Mothers and Newborns cohort which had demonstrated an association between summed-total prenatal exposure to 8 carcinogenic PAHs and scores on the Bayley Scale of Infant Development-II at age 3. We used measures of mtDNAcn in umbilical cord blood to evaluate the role of mitochondrial toxicity in PAH neurodevelopment and improved upon prior studies by including adjustment for cell type composition. We utilized both traditional linear model approaches as well as quantile G computation to evaluate the mixture both as a sum-total and using newly developed mixture methods. We determined that while prenatal PAH exposure was negatively associated with umbilical cord blood mtDNAcn using mixtures methods mtDNAcn was not associated with neurodevelopment. The bidirectional effect of prenatal PAH exposure on mtDNAcn between these two studies reveals the complexity of mtDNAcn as a biomarker and the need for more direct measures of mitochondrial functions in the study of PAH neurodevelopmental toxicity. Chapter 4 seeks to complement the epidemiological research with an experimental system. Using mouse preimplantation embryos, we measured the effect of exposure to an environmentally relevant mixture of PAHs on morphological development, superoxide production, mitochondria membrane potential, and mtDNAcn. We found exposure to low levels of a PAH mixture from days 2.5-3.5 post fertilization caused a significant decrease in healthy embryo morphology and a reduction in mtDNAcn. PAH exposure increased mitochondrial membrane potential under several dosing regimens while the effect on superoxide levels was variable and potentially mediated by changes in mitochondrial mass. As a whole these results indicate mitochondrial dysfunction as a result of low-level PAH exposure during the earliest periods of development with a window of heightened susceptibility immediately prior to implantation. In chapter 5 we evaluate the relative mitochondrial potency of the 8 commonly studied carcinogenic PAHs and an environmental relevant mixture of those 8 compounds. Using human umbilical cord mesenchymal stem cells, we specifically study these effects in the context of prenatal development. Superoxide production, mitochondrial membrane potential, mitochondrial mass, cell death and mtDNAcn was quantified at 9 doses for each exposure. This data was used to fit dose response curves and determine relative potency of each exposure/outcome endpoint. We identified benzo[k]fluoranthene and chrysene among the most toxic compounds analyzed and noted differences between relative mitochondrial toxicity and carcinogenicity of these constituents emphasizing the need for continued research into the non-cancer endpoints of PAH exposure. With the intentional comparable exposures and outcomes utilized in these studies comes the opportunity to make connections and draw conclusions across chapters to arrive at four major conclusion: (1) Demographic variables, not behavior, are most predictive of exposure to many PAH compounds (2) prenatal PAH exposure affects multiple measures of mitochondrial functions, (3) there is variability in the susceptibility during early development, and (4) the developmental mitochondrial toxicity of previously studied PAH compounds does not follow the same patterns of relative potency seen in carcinogenesis. This work provides significant insight into the impact of prenatal PAH exposure on mitochondrial functions while highlighting critical areas for further research. More studies are needed to fully understand the mechanisms and long-term effects of PAH exposure on early development, as well as to identify effective interventions to mitigate these risks.

Made available in DSpace on 2016-08-19T18:16:02Z (GMT). No. of bitstreams: 1 NAIME DIANE SAUAIA HOLANDA SILVA.pdf: 2473346 bytes, checksum: 07e67a7f1132d9fe7f4754bac958aa45 (MD5) Previous issue date: 2010-09-24 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / Objective: To compare the results with the Scale of Alberta (Alberta Infant Motor Scale), applied at three months of corrected gestational age (IGC), with those Scale Bayley (Bayley Scales of Infant Development - 3rd edition) in premature infants, discharged from the Neonatal Intensive Care Unit-NICU of University Hospital Maternal Child Unit - UFMA. Methods: We studied 42 premature infants in the outpatient clinics ("Follow up") Unit, University Hospital Maternal Child Unit - UFMA between March and August 2009. In the study of concurrent validity and agreement of the 42 premature infants at 3 months of IGC were assessed by AIMS and the motor scale of the Bayley Scales of Infant Development, 3rd edition, using the correlation coefficient of Pearson and the concordance test Bland & Altman to analyze the results. Results: In the study of concurrent validity, correlation found between the two scales was high (r = 0.86) and statistically significant (p <0.01) in the total population of infants. In concordance analysis showed that most of the measures is in the range between ± 1.96 standard deviation is thus the two tests agree. Conclusion: The AIMS is a valid and consistent with the standard measures can be recommended for evaluation of motor development of premature infants in the population of public health in Brazil. / Objetivo: Comparar os resultados obtidos com a Escala de Alberta (Alberta Infant Motor Scale), aplicada com três meses de idade gestacional corrigida (IGC), com aqueles da Escala de Bayley (Bayley Scales of Infant Development - 3ª edição) em lactentes nascidos prematuros, egressos da UTIN do Hospital Universitário Unidade Materno Infantil - UFMA. Métodos: Foram avaliados 42 lactentes nascidos prematuros no do Ambulatório de Seguimento ( Follow up ) do Hospital Universitário Unidade Materno Infantil - UFMA entre Março e Agosto de 2009. No estudo de validade concorrente e concordância os 42 lactentes prematuros com 3 meses de IGC foram avaliados pela AIMS e pela escala motora da Bayley Scales of Infant Development- 3ª edição, utilizando-se o coeficiente de correlação de Pearson e o teste de concordância Bland & Altman para analise dos resultados. Resultados: No estudo de validade concorrente, a correlação encontrada entre as duas escalas foi alta (r = 0,86) e estatisticamente significativa (p < 0,01) na população total de lactentes. Na análise de concordância observou-se que a maioria das medidas está na faixa compreendida entre ± 1,96 desvio padrão sendo, portanto, os dois testes concordantes. Conclusão: A AIMS é uma escala válida e concordante com as medidas padrões podendo ser indicada para avaliação do desenvolvimento motor de lactentes prematuros na população da rede publicam de saúde brasileira.

Malgré les avancées médicales, la prédiction précoce du devenir développemental des enfants nés prématurément demeure un défi. Ces enfants sont à risque de séquelles plus ou moins sévères telles l'infirmité motrice d'origine cérébrale, les déficiences intellectuelles et sensorielles ainsi que les difficultés d'apprentissage. Afin de diminuer l’impact fonctionnel de ces séquelles, l’identification de marqueurs précoces devient un enjeu important. Dans le contexte actuel de ressources financières et humaines limitées, seuls les enfants nés avant 29 semaines de gestation ou avec un poids de naissance (PN) <1250g sont systématiquement suivis, laissant pour compte 95% des enfants prématurés. L’identification de marqueurs précoces permettrait de cibler les enfants nés après 28 semaines de gestation porteurs de séquelles. Le principal objectif des présents travaux visait à évaluer l’utilité de l’Évaluation neurologique d’Amiel-Tison (ENAT) dans l’identification et le suivi des enfants nés entre 29 et 37 semaines de gestation et qui présenteront des problèmes neurodéveloppementaux à l’âge corrigé (AC) de 24 mois. Plus précisément, la fidélité inter-examinateurs, la stabilité ainsi que la validité prédictive de l’ENAT ont été évaluées. La cohorte était composée initialement de 173 enfants nés entre 290/7 et 370/7 semaines de gestation, avec un PN<2500g et ayant passé au moins 24 heures à l’unité de soins néonatals du CHU Sainte-Justine. Les enfants étaient évalués avec l’ENAT à terme et aux AC de 4, 8, 12 et 24 mois. À l’AC de 24 mois, leur développement était évalué à l’aide du Bayley Scales of Infant Development–II. Les principaux résultats révèlent une excellente fidélité inter-examinateurs ainsi qu’une bonne stabilité au cours des deux premières années de vie du statut et des signes neurologiques. Des différences significatives à l’AC de deux ans ont été relevées aux performances développementales en fonction du statut neurologique à terme, qui constitue l’un des meilleurs facteurs prédictifs de ces performances. Les résultats encouragent l’intégration du statut neurologique tel que mesuré par l’ENAT comme marqueur précoce dans le cours d’une surveillance neurodéveloppementale des enfants les plus à risque. / Despite the progress in medicine, early prediction of neurodevelopmental outcome for infants born preterm still remains a challenge. Infants born preterm are at risk of mild to severe disabilities such as cerebral palsy, mental retardation, sensory impairments or learning disabilities. To reduce the functional impact of those disabilities, identification of valid early markers of neurodevelopmental disabilities becomes important. As financial and human resources are limited, only those infants with a gestational age (GA) <29 weeks and a birth weight (BW) <1250 are systematically followed, leaving 95% of the preterm population without surveillance. The identification of early markers would allow targeting infants born after 28 weeks of GA the more at risk. The main objective of the present work was to assess the use of the Amiel-Tison Neurological Assessments (ATNA) in the identification and the follow-up of infants with a GA between 29 and 37 weeks who will present neurodevelopmental problems at two years of corrected age (CA). Specifically, the inter-examiner reliability, the stability during the first two years of life and the predictive validity of the ATNA were assessed. The cohort was composed of 173 children born between 290/7 and 370/7 weeks of GA, with a BW<1250g and who stayed at least 24 hours in the neonatal intensive care unit at the CHU Sainte-Justine. The children were assessed with the ATNA at term age and at 4, 8, 12 and 24 months CA. At 24 months CA, their development was assessed with the Bayley Scales of Infant Development–II. The results revealed excellent inter-examiners reliability and good stability during the first two years of age of the neurological status and signs. Significant differences according to the neurological status at term age were observed at 24 months CA for developmental performance. Moreover, this status was one of the main predictive variables of developmental performance at two years CA. Results incite the integration of the neurological status as assessed by the ATNA as an early marker for the surveillance of infants the more at risk.

Malgré les avancées médicales, la prédiction précoce du devenir développemental des enfants nés prématurément demeure un défi. Ces enfants sont à risque de séquelles plus ou moins sévères telles l'infirmité motrice d'origine cérébrale, les déficiences intellectuelles et sensorielles ainsi que les difficultés d'apprentissage. Afin de diminuer l’impact fonctionnel de ces séquelles, l’identification de marqueurs précoces devient un enjeu important. Dans le contexte actuel de ressources financières et humaines limitées, seuls les enfants nés avant 29 semaines de gestation ou avec un poids de naissance (PN) <1250g sont systématiquement suivis, laissant pour compte 95% des enfants prématurés. L’identification de marqueurs précoces permettrait de cibler les enfants nés après 28 semaines de gestation porteurs de séquelles. Le principal objectif des présents travaux visait à évaluer l’utilité de l’Évaluation neurologique d’Amiel-Tison (ENAT) dans l’identification et le suivi des enfants nés entre 29 et 37 semaines de gestation et qui présenteront des problèmes neurodéveloppementaux à l’âge corrigé (AC) de 24 mois. Plus précisément, la fidélité inter-examinateurs, la stabilité ainsi que la validité prédictive de l’ENAT ont été évaluées. La cohorte était composée initialement de 173 enfants nés entre 290/7 et 370/7 semaines de gestation, avec un PN<2500g et ayant passé au moins 24 heures à l’unité de soins néonatals du CHU Sainte-Justine. Les enfants étaient évalués avec l’ENAT à terme et aux AC de 4, 8, 12 et 24 mois. À l’AC de 24 mois, leur développement était évalué à l’aide du Bayley Scales of Infant Development–II. Les principaux résultats révèlent une excellente fidélité inter-examinateurs ainsi qu’une bonne stabilité au cours des deux premières années de vie du statut et des signes neurologiques. Des différences significatives à l’AC de deux ans ont été relevées aux performances développementales en fonction du statut neurologique à terme, qui constitue l’un des meilleurs facteurs prédictifs de ces performances. Les résultats encouragent l’intégration du statut neurologique tel que mesuré par l’ENAT comme marqueur précoce dans le cours d’une surveillance neurodéveloppementale des enfants les plus à risque. / Despite the progress in medicine, early prediction of neurodevelopmental outcome for infants born preterm still remains a challenge. Infants born preterm are at risk of mild to severe disabilities such as cerebral palsy, mental retardation, sensory impairments or learning disabilities. To reduce the functional impact of those disabilities, identification of valid early markers of neurodevelopmental disabilities becomes important. As financial and human resources are limited, only those infants with a gestational age (GA) <29 weeks and a birth weight (BW) <1250 are systematically followed, leaving 95% of the preterm population without surveillance. The identification of early markers would allow targeting infants born after 28 weeks of GA the more at risk. The main objective of the present work was to assess the use of the Amiel-Tison Neurological Assessments (ATNA) in the identification and the follow-up of infants with a GA between 29 and 37 weeks who will present neurodevelopmental problems at two years of corrected age (CA). Specifically, the inter-examiner reliability, the stability during the first two years of life and the predictive validity of the ATNA were assessed. The cohort was composed of 173 children born between 290/7 and 370/7 weeks of GA, with a BW<1250g and who stayed at least 24 hours in the neonatal intensive care unit at the CHU Sainte-Justine. The children were assessed with the ATNA at term age and at 4, 8, 12 and 24 months CA. At 24 months CA, their development was assessed with the Bayley Scales of Infant Development–II. The results revealed excellent inter-examiners reliability and good stability during the first two years of age of the neurological status and signs. Significant differences according to the neurological status at term age were observed at 24 months CA for developmental performance. Moreover, this status was one of the main predictive variables of developmental performance at two years CA. Results incite the integration of the neurological status as assessed by the ATNA as an early marker for the surveillance of infants the more at risk.

Background: Oruro is a mining city in the Bolivian highlands. Most of its citizens are exposed to polymetalic cocktails. This study aims to determine whether the neuropsychological development of one year-old children can be associated with 1) polymetalic exposures and/or 2) growth patterns. Methods: The thesis builds from data collected by the ToxBol multidisciplinary project. The health task was centred on the follow-up of a birth-cohort that set to evaluate child development. Children were examined at 11 and 12 months of age using the Bayley Scale of Infant Development (BSID). Results: 1) Analyses revealed no high concentrations of metals in the blood of pregnant women. 2) No neuropsychological anomalies were observed in association with metal concentrations or growth patterns. 3) A positive association was observed between low lead values in blood and the neuropsychological development of children. 4) During the first 6 months of life, growth rate was negatively associated with weight at birth and positively associated with the BMI at 12 months of age. Conclusion: Although heavy metallic pollution was demonstrated by environmental studies, unexpected low levels of exposure were registered from pregnant women. Neither the level of exposure to metals nor the growth patterns appear to have an impact on child neuropsychological development. We argue that the positive effect that was observed in association to lead might be caused by factors such as diet. / Antecedentes: Oruro es una ciudad minera del altiplano boliviano. Muchos de sus habitantes están expuestos a un cóctel polimetálico. El objetivo principal es el de determinar si existe una asociación entre desarrollo neuropsicológico de los niños de un año y 1) la exposición polimetálica y/o 2) los patrones de crecimiento. Métodos: Esta tesis está basada en los datos recogidos del Proyecto multidisciplinario ToxBol. Se realizó el seguimiento de una cohorte de niños para evaluar su desarrollo. Para evaluar el desarrollo neuropsicológico de los niños se utilizaron las escalas de Bayley de desarrollo infantil (BSID). Resultados: 1) No se observaron altas concentraciones de metales en sangre de las mujeres embarazadas. 2) No se observaron anormalidades neuropsicológicas en relación con concentraciones de metales o patrones de crecimiento. 3) Se observó una asociación positiva entre exposiciones bajas de plomo y el desarrollo neuropsicológico del niño al año de vida. 4) La velocidad de crecimiento, desde el nacimiento hasta los 6 meses, se asoció negativamente con el peso al nacer y positivamente con el BMI a los 12 meses. Conclusión: A diferencia de lo demostrado en otros estudios epidemiológicos, se observó una inesperada baja exposición. No se observó una relación entre el grado de exposición a metales- o los patrones de crecimiento -y el desarrollo neuropsicológico del niño. El efecto positivo del plomo creemos que se debe a otros factores como la dieta. / Antecedents: Oruro es una ciutat minera del altiplà Bolivià. La població es troba es contacte amb fonts de contaminación polimetàlica. L’objectiu principal es el de determinar si existeix una associació entre el desenvolupament neuropsicològic dels nens d’un any i 1) la exposició polimetálica i/o 2) patrons de creixement. Mètodes: Esta tesi està basada en dades del Projecte multidisciplinari ToxBol. La tasca de salut es va centrar en el seguiment del desenvolupament d’una cohort de nens. El desenvolupament neuropsicològic infantil es va avaluar amb les escales de Baley de Desenvolupament infantil (BSID). Resultats: 1) No es van observar concentracions altes de metalls en sang de les dones embarassades. 2) No es va observar anormalitats neuropsicològiques en realció amb les concentracions de metalls o patrons de creixement. 3) Es va observar una associació positiva entre concentracions baixes de plom en sang i el desenvolupament neuropsicològic dels nens d’un any. 4) La velocitat de creixement, des del naixement fins els 6 mesos, es va associar negativament amb el pes al néixer i positivament amb el BMI als 12 mesos. Conclusió: A diferencia del que esperàvem, es van registrar baixes concentracions de metalls a les dones embarassades. Tampoc s’observa una relació entre el grau d’exposició a metalls, o patrons de creixement, i el desenvolupament neuropsicològic del nens. El efecte positiu que observem del plom, pensem que es deu a altres factors com la dieta.