The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are essential for normal growth and development of the fetus. Their bioavailability in utero depends on development of the fetal hypothalamic-pituitary-thyroid gland axis and the abundance of thyroid hormone transporters and deiodinases that influence tissue levels of bioactive hormone. Fetal T4 and T3 concentrations are also affected by gestational age, nutritional and endocrine conditions in utero, and placental permeability to maternal thyroid hormones, which varies among species with placental morphology. Thyroid hormones are required for the general accretion of fetal mass and to trigger discrete developmental events in the fetal brain and somatic tissues from early in gestation. They also promote terminal differentiation of fetal tissues closer to term and are important in mediating the prepartum maturational effects of the glucocorticoids that ensure neonatal viability. Thyroid hormones act directly through anabolic effects on fetal metabolism and the stimulation of fetal oxygen consumption. They also act indirectly by controlling the bioavailability and effectiveness of other hormones and growth factors that influence fetal development such as the catecholamines and insulin-like growth factors (IGFs). By regulating tissue accretion and differentiation near term, fetal thyroid hormones ensure activation of physiological processes essential for survival at birth such as pulmonary gas exchange, thermogenesis, hepatic glucogenesis, and cardiac adaptations. This review examines the developmental control of fetal T4 and T3 bioavailability and discusses the role of these hormones in fetal growth and development with particular emphasis on maturation of somatic tissues critical for survival immediately at birth.

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Thyroid hormones in fetal growth and prepartum maturation.

. Olegard, R., Sabel, K.-G., Aronsson, M., Sandin, B., Johansson, P. R. Carlsson, C., Kyllerman, M., Iversen, K. and Hrbek, A. (Departments of Paediatrics, East Hospital, University of Goteborg and Psychiatric Clinic II and Nordhem Alcoholic Clinic, Lillhagen Hospital, Goteborg, Sweden). Effect on the child of alcohol abuse during pregnancy. Retrospective and prospective studies. Retrospective and prospective investigations of children to alcoholic women gave an incidence of fetal alcohol lesion of one per 300 deliveries of whom half had the complete fetal alcohol syndrome. Perinatal and infant mortalities were increased seven to tenfold and low birth weight (<2500 g), preterm deliveries (<37 weeks) and smallness for gestational age (<-2 S.D.) were increased eightfold, threefold and twelvefold, respectively. Small size at birth correlated with reduced mental performance later in life, 58% had IQ below 85 and 19% below 70. 8% had cerebral palsy. The incidence of cerebral palsy associated with maternal inebriety was 1/5000 deliveries, i.e. every sixth case of cerebral palsy. Tracing of alcoholic women during pregnancy and treatment gave favourable effect on intrauterine growth when sobriety could be induced early in pregnancy but could not protect from functional brain disturbance measured by neurological performance and by evoked response electroencephalography. Damage to the fetus by alcohol is now the largest known health hazard by a noxious agent that is preventable.

Effects on the child of alcohol abuse during pregnancy. Retrospective and prospective studies.

Fetal alcohol exposure has multiple deleterious effects on brain development, and represents a leading known cause of mental retardation. This review of the effects of alcohol exposure on the developing brain evaluates results from human, animal andin vitro studies, but focuses on key research issues, including possible mechanisms of damage. Factors that affect the risk and severity of fetal alcohol damage also are considered.

Fetal alcohol syndrome: the vulnerability of the developing brain and possible mechanisms of damage

Dynamics of fetal circulatory responses to hypoxia and asphyxia.

Mental retardation, hydrocephalus, and agenesis of the corpus callosum are observed both in fetal alcohol syndrome (FAS) and in children with mutations in the gene for the cell adhesion molecule L1. We studied the effects of ethanol on cell-cell adhesion in mouse fibroblasts transfected with human L1. L1-transfected fibroblasts exhibited increased cell-cell adhesion compared with wild-type or vector-transfected controls. Ethanol potently and completely inhibited L1-mediated adhesion both in transfected L cells and NIH/3T3 cells. Half-maximal inhibition was observed at 7 mM ethanol, a concentration achieved in blood and brain after ingesting one alcoholic beverage. In contrast, ethanol did not inhibit the adhesion of fibroblasts transfected with vector alone or with N-CAM-140. L1-mediated cell-cell adhesion was inhibited with increasing potency by n-propanol and n-butanol, but was not inhibited at all by n-alcohols of 5 to 8 carbons, acetaldehyde, or acetate, suggesting that ethanol interacts directly with a small hydrophobic pocket within L1. Phenylalanine, teratogenic anticonvulsants, and high concentrations of glucose did not inhibit L1-mediated cell-cell adhesion. Ethanol also inhibited potently the heterotypic adhesion of rat cerebellar granule cells to a monolayer of L1-transfected NIH/3T3 cells, but had no effect on their adhesion to N-CAM-140 or vector-transfected NIH/3T3 cells. Because L1 plays a role in both neural development and learning, ethanol inhibition of L1-mediated cell-cell interactions could contribute to FAS and ethanol-associated memory disorders.

https://rupress.org/jcb/article-pdf/133/2/381/1265630/381.pdf

Maida Liu

Papers

Placental transport of alcohol and its effect on maternal and fetal acid-base balance.

Effect of alcohol on fetal cerebral function and metabolism.

The effect of umbilical vein occlusion on fetal oxygenation, cardiovascular parameters, and fetal electroencephalogram.

The effects of fetal thyroidectomy in the ovine fetus

The effect of methadone on fetal brain function.