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<p>The association between low birth weight at <em>term </em>birth and an increased risk for insulin resistance (IR) in adulthood is well established. Less is known about this association in those born markedly <em>preterm</em>. Lower birth weights are more prevalent among individuals born preterm. We compared and examined determinants of IR in adults born preterm with extremely low birth weight (ELBW; birth weight</p> / Master of Health Sciences (MSc)

The prepartum surge in fetal plasma cortisol, essential for the maturation of organs in mammals and the normal timing of parturition in some species, including sheep, may result from an increase in the molar ratio of adrenocorticotropin (ACTH) to pro-opiomelanocortin (POMC) in the fetal circulation. Related to this, the cleavage of POMC to ACTH by the enzyme, prohormone convertase 1 (PC1), may be influenced by corticotrophin releasing hormone (CRH) stimulation. Accumulating evidence suggests that the capacity of individual corticotrophs to process POMC to ACTH may vary and individual corticotrophs are differentially responsive to CRH. It is not known, however, if there are separate corticotroph subpopulations in the fetal sheep pituitary which can be identified by differential colocalisation of POMC, ACTH and the CRH receptor 1, CRHR₁, nor if changes in the relative proportions of such subpopulations play a role in the molecular mechanisms underlying the overall changes in pituitary function described previously during gestation and in response to suboptimal uterine environments. To investigate these hypotheses, it was first necessary to develop novel methods for the simultaneous immunohistochemical labelling of POMC, ACTH and CRHR₁ in individual cells on sections of fetal sheep pituitary. In addition, I developed and validated an automated method to categorise and count individual cells to increase the quantitative power of this study. Pituitary tissue was collected from control fetuses at 53-55 (n=6), 63-85 (n=6), 110 (n=4), 139-141 (n=4) and 144-145 (n=6) days gestation. Two animal models, known to alter pituitary function in the fetal sheep, were used to investigate corticotrophic adaptations to suboptimal uterine environments. For the maternal periconceptional undernutrition (PCUN) model, maternal feed was reduced to 70% of maintenance requirements from at least 45 days before to 7 days after mating and fetal tissues were collected at 53-55 days gestation (n=7). For the placental restriction (PR) model, the majority of the placental attachment sites were removed in five ewes before mating and fetal tissues were collected at 140 (n=4) and 144 (n=4) days gestation. Pituitary sections were simultaneously labelled with antisera raised against full length POMC, ACTH and CRHR₁ and the proportions of pituitary cells with combinations of antisera were quantified. Four subpopulations of corticotrophs were identified, which expressed either: POMC+ACTH+CRHR₁, ACTH+CRHR₁, POMC+ CRHR₁ or POMConly. There was a significant decrease in the proportion of pituitary cells expressing POMC+ACTH+CRHR₁ between 53-55 and 65-85 days gestation, before an increase at 110 days gestation and a further marked decrease between 139-141 and 144-145 days gestation. In fetuses from the PCUN group, the proportion of pituitary cells expressing POMC+ACTH+CRHR₁ in early gestation was reduced. PR resulted in a significantly higher proportion of corticotrophs expressing POMC+ACTH+CRHR₁ during the prepartum period. This work represents the discovery of the differential expression of POMC, ACTH and CRHR₁ in individual corticotrophs of the fetal sheep pituitary and the first insights into the pituitary adaptations to periconceptional nutrient restriction and placental restriction at the level of individual corticotrophs. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1337370 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2008

The prepartum surge in fetal plasma cortisol, essential for the maturation of organs in mammals and the normal timing of parturition in some species, including sheep, may result from an increase in the molar ratio of adrenocorticotropin (ACTH) to pro-opiomelanocortin (POMC) in the fetal circulation. Related to this, the cleavage of POMC to ACTH by the enzyme, prohormone convertase 1 (PC1), may be influenced by corticotrophin releasing hormone (CRH) stimulation. Accumulating evidence suggests that the capacity of individual corticotrophs to process POMC to ACTH may vary and individual corticotrophs are differentially responsive to CRH. It is not known, however, if there are separate corticotroph subpopulations in the fetal sheep pituitary which can be identified by differential colocalisation of POMC, ACTH and the CRH receptor 1, CRHR₁, nor if changes in the relative proportions of such subpopulations play a role in the molecular mechanisms underlying the overall changes in pituitary function described previously during gestation and in response to suboptimal uterine environments. To investigate these hypotheses, it was first necessary to develop novel methods for the simultaneous immunohistochemical labelling of POMC, ACTH and CRHR₁ in individual cells on sections of fetal sheep pituitary. In addition, I developed and validated an automated method to categorise and count individual cells to increase the quantitative power of this study. Pituitary tissue was collected from control fetuses at 53-55 (n=6), 63-85 (n=6), 110 (n=4), 139-141 (n=4) and 144-145 (n=6) days gestation. Two animal models, known to alter pituitary function in the fetal sheep, were used to investigate corticotrophic adaptations to suboptimal uterine environments. For the maternal periconceptional undernutrition (PCUN) model, maternal feed was reduced to 70% of maintenance requirements from at least 45 days before to 7 days after mating and fetal tissues were collected at 53-55 days gestation (n=7). For the placental restriction (PR) model, the majority of the placental attachment sites were removed in five ewes before mating and fetal tissues were collected at 140 (n=4) and 144 (n=4) days gestation. Pituitary sections were simultaneously labelled with antisera raised against full length POMC, ACTH and CRHR₁ and the proportions of pituitary cells with combinations of antisera were quantified. Four subpopulations of corticotrophs were identified, which expressed either: POMC+ACTH+CRHR₁, ACTH+CRHR₁, POMC+ CRHR₁ or POMConly. There was a significant decrease in the proportion of pituitary cells expressing POMC+ACTH+CRHR₁ between 53-55 and 65-85 days gestation, before an increase at 110 days gestation and a further marked decrease between 139-141 and 144-145 days gestation. In fetuses from the PCUN group, the proportion of pituitary cells expressing POMC+ACTH+CRHR₁ in early gestation was reduced. PR resulted in a significantly higher proportion of corticotrophs expressing POMC+ACTH+CRHR₁ during the prepartum period. This work represents the discovery of the differential expression of POMC, ACTH and CRHR₁ in individual corticotrophs of the fetal sheep pituitary and the first insights into the pituitary adaptations to periconceptional nutrient restriction and placental restriction at the level of individual corticotrophs. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1337370 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2008

The prepartum surge in fetal plasma cortisol, essential for the maturation of organs in mammals and the normal timing of parturition in some species, including sheep, may result from an increase in the molar ratio of adrenocorticotropin (ACTH) to pro-opiomelanocortin (POMC) in the fetal circulation. Related to this, the cleavage of POMC to ACTH by the enzyme, prohormone convertase 1 (PC1), may be influenced by corticotrophin releasing hormone (CRH) stimulation. Accumulating evidence suggests that the capacity of individual corticotrophs to process POMC to ACTH may vary and individual corticotrophs are differentially responsive to CRH. It is not known, however, if there are separate corticotroph subpopulations in the fetal sheep pituitary which can be identified by differential colocalisation of POMC, ACTH and the CRH receptor 1, CRHR₁, nor if changes in the relative proportions of such subpopulations play a role in the molecular mechanisms underlying the overall changes in pituitary function described previously during gestation and in response to suboptimal uterine environments. To investigate these hypotheses, it was first necessary to develop novel methods for the simultaneous immunohistochemical labelling of POMC, ACTH and CRHR₁ in individual cells on sections of fetal sheep pituitary. In addition, I developed and validated an automated method to categorise and count individual cells to increase the quantitative power of this study. Pituitary tissue was collected from control fetuses at 53-55 (n=6), 63-85 (n=6), 110 (n=4), 139-141 (n=4) and 144-145 (n=6) days gestation. Two animal models, known to alter pituitary function in the fetal sheep, were used to investigate corticotrophic adaptations to suboptimal uterine environments. For the maternal periconceptional undernutrition (PCUN) model, maternal feed was reduced to 70% of maintenance requirements from at least 45 days before to 7 days after mating and fetal tissues were collected at 53-55 days gestation (n=7). For the placental restriction (PR) model, the majority of the placental attachment sites were removed in five ewes before mating and fetal tissues were collected at 140 (n=4) and 144 (n=4) days gestation. Pituitary sections were simultaneously labelled with antisera raised against full length POMC, ACTH and CRHR₁ and the proportions of pituitary cells with combinations of antisera were quantified. Four subpopulations of corticotrophs were identified, which expressed either: POMC+ACTH+CRHR₁, ACTH+CRHR₁, POMC+ CRHR₁ or POMConly. There was a significant decrease in the proportion of pituitary cells expressing POMC+ACTH+CRHR₁ between 53-55 and 65-85 days gestation, before an increase at 110 days gestation and a further marked decrease between 139-141 and 144-145 days gestation. In fetuses from the PCUN group, the proportion of pituitary cells expressing POMC+ACTH+CRHR₁ in early gestation was reduced. PR resulted in a significantly higher proportion of corticotrophs expressing POMC+ACTH+CRHR₁ during the prepartum period. This work represents the discovery of the differential expression of POMC, ACTH and CRHR₁ in individual corticotrophs of the fetal sheep pituitary and the first insights into the pituitary adaptations to periconceptional nutrient restriction and placental restriction at the level of individual corticotrophs. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1337370 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2008

Introdução: Considerando-se a dificuldade e o elevado custo para o tratamento da obesidade, e seu papel como fator de risco para diversas patologias, sua prevenção mostra-se fundamental, por este motivo, a identificação precoce de fatores de risco evitáveis, como a inadequação do estado nutricional em períodos críticos para a gênese da obesidade, representa um interessante campo para investigação científica. Objetivo: Verificar a relação entre o excesso de peso corporal em adolescentes segundo estado nutricional ao nascer e excesso de peso durante o primeiro ano de vida e no período de repleção da adiposidade. Método: Participaram deste estudo alunos de ambos os sexos matriculados nos quintos e sextos anos de Unidades Escolares no Município de São José dos Campos-SP. A coleta de dados ocorreu em três etapas, a primeira consistiu na avaliação nutricional durante a adolescência, considerando-se as medidas de índice de massa corporal (IMC), circunferências abdominal e do braço e soma das pregas cutâneas triciptal e subescapular. Na segunda etapa foram coletadas informações referentes à escolaridade materna, aleitamento materno e estado nutricional ao nascer por meio de questionário respondido pelos pais. As crianças foram classificadas segundo os índices peso ao nascer por idade gestacional, índice ponderal ao nascer e peso ao nascer. Na última etapa foram obtidas informações de peso e estatura durante a infância nos prontuários de atendimento das Unidades Básicas de Saúde (UBS) do Município. Realizou-se análise de regressão logística para verificar associação entre excesso de peso aos 10 anos de idade, considerada variável dependente e, como variáveis independentes, estado nutricional ao nascer, excesso de peso corporal no primeiro ano de vida e no período de repleção da adiposidade (entre os 5 e 7 anos de idade). As análises foram ajustadas para demais variáveis. Resultados: Os estudantes apresentaram média (desvio-padrão) de 131,3 meses (10,99) de idade. Verificou-se elevada correlação entre o peso e comprimento ao nascer informado pelos responsáveis e registrado no prontuário das UBSs (coeficiente de correlação: 0,95 e 0,98, respectivamente). Com relação ao estado nutricional ao nascer, observou-se que o elevado peso ao nascer e o peso ao nascer pequeno para idade gestacional associaram-se ao excesso de peso corporal no início da adolescência. Foi identificado limiar de associação entre excesso de peso corporal no primeiro ano de vida e aos 10 anos de idade. Também foi encontrada associação entre excesso de peso corporal na adolescência e no período de repleção da adiposidade. Conclusão: Os achados mostram consistência com a hipótese de que períodos críticos do crescimento acarretariam em maior predisposição ao excesso de gordura corporal, identificada no presente estudo no início da adolescência / Introduction: Considering that obesity is a major risk for many diseases as well as the difficulties and elevated costs for its treatment, its prevention and the identification of early avoidable health risks, such as nutritional status in critical periods of life, represent important aspects for scientific investigation. Objective: Verify the relationship between excessive body weight during adolescence according to birth nutrition status and excessive body weight during the first year of life and at the period of adiposity rebound. Method: This study was conducted with schoolchildren of both sexes, enrolled in Public Schools in São José dos Campos - SP (SJC-SP). The data was collected in 3 phases, the first consisted of collecting anthropometric information during adolescence, considering body mass index (BMI), arm and abdominal circumferences and the sum of skin fold thickness (triceps and sub scapular). Information about mother´s education, breastfeeding and birth nutritional status was collected in the second phase through a survey which the parents answered. The children were classified according to birth weight for gestational age, ponderal index and birth weight. In the last phase, information about nutritional status during infancy was obtained from medical registers of primary health units in the city. Logistical regression analyses were made to investigate the association between excessive body weight at 10 years of age, considered as dependent variable and, as independent variables, the nutritional status at time of birth, the first year of age and during the period of adiposity rebound (between 5 and 7 years of age). The analyses were adjusted by other variables. Results: The students presented a mean of 131.3 months of age (10.99). An elevated correlation was observed between parents information about birth weight and length and the information registered at the medical documents of primary health units in the city (Correlation coefficient: 0.95 and 0.98, for weight and for length, respectively). An association between elevated birth weight and birth weight small for gestational age and excessive body weight during adolescence was observed. A weak association between excessive body weight during the first year of life and at 10 years of age was identified. It was also verified association in relation to adiposity during the period of adiposity rebound and excessive weight at 10 years of age. Conclusion: These results show consistency in the hypothesis that the critical period for growth development could predispose to future obesity, identified in the present study during early adolescence

Introdução: Considerando-se a dificuldade e o elevado custo para o tratamento da obesidade, e seu papel como fator de risco para diversas patologias, sua prevenção mostra-se fundamental, por este motivo, a identificação precoce de fatores de risco evitáveis, como a inadequação do estado nutricional em períodos críticos para a gênese da obesidade, representa um interessante campo para investigação científica. Objetivo: Verificar a relação entre o excesso de peso corporal em adolescentes segundo estado nutricional ao nascer e excesso de peso durante o primeiro ano de vida e no período de repleção da adiposidade. Método: Participaram deste estudo alunos de ambos os sexos matriculados nos quintos e sextos anos de Unidades Escolares no Município de São José dos Campos-SP. A coleta de dados ocorreu em três etapas, a primeira consistiu na avaliação nutricional durante a adolescência, considerando-se as medidas de índice de massa corporal (IMC), circunferências abdominal e do braço e soma das pregas cutâneas triciptal e subescapular. Na segunda etapa foram coletadas informações referentes à escolaridade materna, aleitamento materno e estado nutricional ao nascer por meio de questionário respondido pelos pais. As crianças foram classificadas segundo os índices peso ao nascer por idade gestacional, índice ponderal ao nascer e peso ao nascer. Na última etapa foram obtidas informações de peso e estatura durante a infância nos prontuários de atendimento das Unidades Básicas de Saúde (UBS) do Município. Realizou-se análise de regressão logística para verificar associação entre excesso de peso aos 10 anos de idade, considerada variável dependente e, como variáveis independentes, estado nutricional ao nascer, excesso de peso corporal no primeiro ano de vida e no período de repleção da adiposidade (entre os 5 e 7 anos de idade). As análises foram ajustadas para demais variáveis. Resultados: Os estudantes apresentaram média (desvio-padrão) de 131,3 meses (10,99) de idade. Verificou-se elevada correlação entre o peso e comprimento ao nascer informado pelos responsáveis e registrado no prontuário das UBSs (coeficiente de correlação: 0,95 e 0,98, respectivamente). Com relação ao estado nutricional ao nascer, observou-se que o elevado peso ao nascer e o peso ao nascer pequeno para idade gestacional associaram-se ao excesso de peso corporal no início da adolescência. Foi identificado limiar de associação entre excesso de peso corporal no primeiro ano de vida e aos 10 anos de idade. Também foi encontrada associação entre excesso de peso corporal na adolescência e no período de repleção da adiposidade. Conclusão: Os achados mostram consistência com a hipótese de que períodos críticos do crescimento acarretariam em maior predisposição ao excesso de gordura corporal, identificada no presente estudo no início da adolescência / Introduction: Considering that obesity is a major risk for many diseases as well as the difficulties and elevated costs for its treatment, its prevention and the identification of early avoidable health risks, such as nutritional status in critical periods of life, represent important aspects for scientific investigation. Objective: Verify the relationship between excessive body weight during adolescence according to birth nutrition status and excessive body weight during the first year of life and at the period of adiposity rebound. Method: This study was conducted with schoolchildren of both sexes, enrolled in Public Schools in São José dos Campos - SP (SJC-SP). The data was collected in 3 phases, the first consisted of collecting anthropometric information during adolescence, considering body mass index (BMI), arm and abdominal circumferences and the sum of skin fold thickness (triceps and sub scapular). Information about mother´s education, breastfeeding and birth nutritional status was collected in the second phase through a survey which the parents answered. The children were classified according to birth weight for gestational age, ponderal index and birth weight. In the last phase, information about nutritional status during infancy was obtained from medical registers of primary health units in the city. Logistical regression analyses were made to investigate the association between excessive body weight at 10 years of age, considered as dependent variable and, as independent variables, the nutritional status at time of birth, the first year of age and during the period of adiposity rebound (between 5 and 7 years of age). The analyses were adjusted by other variables. Results: The students presented a mean of 131.3 months of age (10.99). An elevated correlation was observed between parents information about birth weight and length and the information registered at the medical documents of primary health units in the city (Correlation coefficient: 0.95 and 0.98, for weight and for length, respectively). An association between elevated birth weight and birth weight small for gestational age and excessive body weight during adolescence was observed. A weak association between excessive body weight during the first year of life and at 10 years of age was identified. It was also verified association in relation to adiposity during the period of adiposity rebound and excessive weight at 10 years of age. Conclusion: These results show consistency in the hypothesis that the critical period for growth development could predispose to future obesity, identified in the present study during early adolescence

Background In some cross-sectional epidemiologic studies the shape of the association between serum concentrations of perfluoroalkyl acids (PFAAs) and lipids suggests departures from linearity. Objectives We used statistical approaches allowing for non-linearity to determine associations of prenatal exposures of perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) with lipid concentrations. Methods PFAAs were measured in serum from pregnant women collected in 1991–1992 at enrollment in the Avon Longitudinal Study of Parents and Children and lipids in serum from their daughters at ages 7 (n = 111) and 15 (n = 88). The associations of PFAAs with lipids were first explored by cubic splines, followed by piecewise linear regressions by tertiles to obtain regression coefficients (β) and their 95% confidence limits (95% CL) (in mg/dL per 1 ng/mL). Results At age 7, total cholesterol was positively associated with prenatal PFOA concentrations in the lower tertile (β = 15.01; 95% CL = 2.34, 27.69) but not with PFOA concentrations in the middle (β = − 3.63; 95% CL = − 17.43, 10.16) and upper (β = − 1.58; 95% CL = − 4.58, 1.42) tertiles. At age 15, a similar pattern was noted as well. Positive associations between LDL-C and prenatal PFOA concentration in the lower tertile were observed in daughters at ages 7 (β = 14.91; 95% CL = 3.53, 28.12) and 15 (β = 13.93; 95% CL = 0.60, 27.26). LDL-C was not associated with PFOA concentrations in the middle or upper tertile at any age. Neither HDL-C nor triglycerides was associated with prenatal PFOA exposure. Non-linear patterns of association of total cholesterol and LDL-C with prenatal PFOS were less consistently noted. Conclusion Exposure to low levels of PFOA during prenatal development may alter lipid metabolism later in life. Given the small sample size further replication of the association in large independent cohorts is important.