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Neurobehavioral Effects of Hypothyroidism in Children from Antenatal and Childhood Exposure
NBTS 2011 Abstracts
Health and Nutrition Examination Survey (NHANES). Although levels were sufficient some populations are at a level that needs supplementation. In North America all women who are planning a pregnancy, are pregnant or breastfeeding, should take a daily oral supplement that contains 150 μg of iodine (250 μg in pregnancy), optimally in the form of potassium iodide. Elsewhere, strategies vary according to regional dietary patterns and iodized salt availability. doi:10.1016/j.ntt.2011.05.040
NBTS 29 Thyroid Function and Clinical Hypothyroidism from a Clinician's Perspective Alex Stagnaro-Green George Washington University, Washington, DC, USA Approximately 2.5% of all women who become pregnant have subclinical hypothyroidism and another 0.5% of women have overt hypothyroidism. Furthermore, euthyroid women with borderline thyroid reserve pre-pregnancy, will frequently develop hypothyroidism during pregnancy as the maternal thyroid needs to increase hormonal production by 50%. Although well known that overt hypothyroidism is associated with multiple adverse maternal and fetal effects research over the last twenty years has demonstrated the negative impact of subclinical hypothyroidism. Specifically, subclinical hypothyroidism has been associated with spontaneous miscarriage, preterm delivery and decreased intelligence quotient in the unborn child. A study published in 2010 performed in southern Italy demonstrated that treatment of thyroid antibody positive women who have TSH levels above 2.5 mIU/lwith levothyroxine decreased maternal/fetal complications. The present talk will focus on the following issues: 1) changes in thyroid function tests during pregnancy, 2) the incidence of overt and subclinical hypothyroidism during pregnancy, 3) the association of miscarriage, preterm delivery and decreased intelligence quotient with hypothyroidism, 4) intervention trials, both completed and ongoing, evaluating the impact of levothyroxine treatment of hypothyroidism during pregnancy on the mother and fetus, and 5) the present status of the debate of universal screening for thyroid disease during pregnancy. doi:10.1016/j.ntt.2011.05.041
NBTS 30 Neurodevelopmental Consequences of Low-Level Thyroid Hormone Disruption Induced by Environmental Contaminants Mary Gilbert US EPA, Research Triangle Park, NC, USA Inadequate levels of thyroid hormone during critical developmental periods lead to stunted growth, mental retardation, and neurological ‘cretinism’. Animal models of developmental thyroid hormone deficiency mirror well the impact of severe insults to the thyroid system. However, it has become clear from studies in humans that even modest perturbations of the thyroid axis may not be benign. A number of environmental contaminants reduce circulating levels of thyroid hormone, and do so by their interaction with a variety of target sites. The degree of thyroid hormone insufficiency induced by environmental contaminants is typically not severe, yet impact of modest fluctuations in hormone has not been adequately addressed in animal models. We have investigated the dose-response relationships of thyroid hormone disruption induced during pregnancy and lactation in rats exposed to a thyroid hormone synthesis inhibitor, propylthiouracil (PTU), dietary
503
iodine deficiency, and the environmental contaminant, ammonium perchlorate. These treatments were delivered to produce graded levels of hormone reduction and offspring were examined on a number of cognitive endpoints, neuroanatomical, genomic, and neurophysiological parameters. We found that severe hormone depletion is not necessary to alter brain development. Gene expression changes in cortex and hippocampus in PTU- and perchlorate-exposed pups were associated with mild alterations in serum hormones. Our work and others has demonstrated cell fate specificity and neuronal migration are disrupted by PTU, a related synthesis inhibitor, methimazole, and iodine deficiency. Electrophysiological impairments in hippocampal synaptic transmission in adult offspring were evident in all three models, and in our hands, were the most reliable in identifying brain dysfunction. Simple behavioral tasks (Morris water maze and fear conditioning) have not proven very sensitive in identifying neurodevelopmental insults at low levels of hormone insufficiency. In some cases, dam serum hormone levels were more predictive of neurophysiological and molecular deficits than hormones measured in pups. We conclude that long-term functional deficits accompany moderate levels of thyroid hormone insufficiency induced by a number of means. It is likely that the negative impact of a xenobiotic-induced perturbation in thyroid hormone status will be exacerbated under conditions of iodine deficiency and this is currently under study. Does not reflect EPA policy. doi:10.1016/j.ntt.2011.05.042
NBTS 31 Neurobehavioral Effects of Hypothyroidism in Children from Antenatal and Childhood Exposure Joann Rovet Sick Childrens' Hospital, Toronto, Ontario, Canada Thyroid hormone (TH) is essential for early brain development and if insufficient, will lead to significant brain abnormalities and neurobehavioral effects. In the human, demand for TH extends throughout gestation but since the fetal thyroid system matures late and does not achieve full function until term, the fetus has to rely on the mother for its supply of TH. During the latter part of gestation, the fetal thyroid system is maturing to assume full function at term. If either the maternal or child's own thyroid supplies are inadequate due to maternal hypothyroidism (MH) or congenital hypothyroidism (CH), early brain development may be compromised and specific effects reflect timing of TH insufficiency. In this presentation, I will review recent studies of child neurodevelopment following MH or CH and will describe behavioral findings from my lab on the specific sensory and cognitive sequelae associated with both conditions. For both groups, I will examine effects by severity of each condition. In addition, I will describe preliminary neuroimaging results showing how varying degrees of TH insufficiency at specific times during gestation and/or early life affect later brain development. I will present findings from structural and functional MRI studies, with special emphasis on the hippocampus. I will conclude by discussing the real-world implications of these findings for everyday functioning in both populations. doi:10.1016/j.ntt.2011.05.043
NBTS 32 Prenatal Cocaine Exposure and Embryonic Cortical Development Pradeep Bhide Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Health and Nutrition Examination Survey (NHANES). Although levels were sufficient some populations are at a level that needs supplementation. In North America all women who are planning a pregnancy, are pregnant or breastfeeding, should take a daily oral supplement that contains 150 μg of iodine (250 μg in pregnancy), optimally in the form of potassium iodide. Elsewhere, strategies vary according to regional dietary patterns and iodized salt availability. doi:10.1016/j.ntt.2011.05.040
NBTS 29 Thyroid Function and Clinical Hypothyroidism from a Clinician's Perspective Alex Stagnaro-Green George Washington University, Washington, DC, USA Approximately 2.5% of all women who become pregnant have subclinical hypothyroidism and another 0.5% of women have overt hypothyroidism. Furthermore, euthyroid women with borderline thyroid reserve pre-pregnancy, will frequently develop hypothyroidism during pregnancy as the maternal thyroid needs to increase hormonal production by 50%. Although well known that overt hypothyroidism is associated with multiple adverse maternal and fetal effects research over the last twenty years has demonstrated the negative impact of subclinical hypothyroidism. Specifically, subclinical hypothyroidism has been associated with spontaneous miscarriage, preterm delivery and decreased intelligence quotient in the unborn child. A study published in 2010 performed in southern Italy demonstrated that treatment of thyroid antibody positive women who have TSH levels above 2.5 mIU/lwith levothyroxine decreased maternal/fetal complications. The present talk will focus on the following issues: 1) changes in thyroid function tests during pregnancy, 2) the incidence of overt and subclinical hypothyroidism during pregnancy, 3) the association of miscarriage, preterm delivery and decreased intelligence quotient with hypothyroidism, 4) intervention trials, both completed and ongoing, evaluating the impact of levothyroxine treatment of hypothyroidism during pregnancy on the mother and fetus, and 5) the present status of the debate of universal screening for thyroid disease during pregnancy. doi:10.1016/j.ntt.2011.05.041
NBTS 30 Neurodevelopmental Consequences of Low-Level Thyroid Hormone Disruption Induced by Environmental Contaminants Mary Gilbert US EPA, Research Triangle Park, NC, USA Inadequate levels of thyroid hormone during critical developmental periods lead to stunted growth, mental retardation, and neurological ‘cretinism’. Animal models of developmental thyroid hormone deficiency mirror well the impact of severe insults to the thyroid system. However, it has become clear from studies in humans that even modest perturbations of the thyroid axis may not be benign. A number of environmental contaminants reduce circulating levels of thyroid hormone, and do so by their interaction with a variety of target sites. The degree of thyroid hormone insufficiency induced by environmental contaminants is typically not severe, yet impact of modest fluctuations in hormone has not been adequately addressed in animal models. We have investigated the dose-response relationships of thyroid hormone disruption induced during pregnancy and lactation in rats exposed to a thyroid hormone synthesis inhibitor, propylthiouracil (PTU), dietary
503
iodine deficiency, and the environmental contaminant, ammonium perchlorate. These treatments were delivered to produce graded levels of hormone reduction and offspring were examined on a number of cognitive endpoints, neuroanatomical, genomic, and neurophysiological parameters. We found that severe hormone depletion is not necessary to alter brain development. Gene expression changes in cortex and hippocampus in PTU- and perchlorate-exposed pups were associated with mild alterations in serum hormones. Our work and others has demonstrated cell fate specificity and neuronal migration are disrupted by PTU, a related synthesis inhibitor, methimazole, and iodine deficiency. Electrophysiological impairments in hippocampal synaptic transmission in adult offspring were evident in all three models, and in our hands, were the most reliable in identifying brain dysfunction. Simple behavioral tasks (Morris water maze and fear conditioning) have not proven very sensitive in identifying neurodevelopmental insults at low levels of hormone insufficiency. In some cases, dam serum hormone levels were more predictive of neurophysiological and molecular deficits than hormones measured in pups. We conclude that long-term functional deficits accompany moderate levels of thyroid hormone insufficiency induced by a number of means. It is likely that the negative impact of a xenobiotic-induced perturbation in thyroid hormone status will be exacerbated under conditions of iodine deficiency and this is currently under study. Does not reflect EPA policy. doi:10.1016/j.ntt.2011.05.042
NBTS 31 Neurobehavioral Effects of Hypothyroidism in Children from Antenatal and Childhood Exposure Joann Rovet Sick Childrens' Hospital, Toronto, Ontario, Canada Thyroid hormone (TH) is essential for early brain development and if insufficient, will lead to significant brain abnormalities and neurobehavioral effects. In the human, demand for TH extends throughout gestation but since the fetal thyroid system matures late and does not achieve full function until term, the fetus has to rely on the mother for its supply of TH. During the latter part of gestation, the fetal thyroid system is maturing to assume full function at term. If either the maternal or child's own thyroid supplies are inadequate due to maternal hypothyroidism (MH) or congenital hypothyroidism (CH), early brain development may be compromised and specific effects reflect timing of TH insufficiency. In this presentation, I will review recent studies of child neurodevelopment following MH or CH and will describe behavioral findings from my lab on the specific sensory and cognitive sequelae associated with both conditions. For both groups, I will examine effects by severity of each condition. In addition, I will describe preliminary neuroimaging results showing how varying degrees of TH insufficiency at specific times during gestation and/or early life affect later brain development. I will present findings from structural and functional MRI studies, with special emphasis on the hippocampus. I will conclude by discussing the real-world implications of these findings for everyday functioning in both populations. doi:10.1016/j.ntt.2011.05.043
NBTS 32 Prenatal Cocaine Exposure and Embryonic Cortical Development Pradeep Bhide Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA