New thyroid theory: how maternal hormone affects developing brains. (NIEHS News).

When does a fetus's developing brain become sensitive to thyroid hormone? What developmental processes are affected by thyroid hormone, and how do these effects occur? How can toxicologists use these insights to evaluate environmental contaminants that affect the thyroid system? These are the questions that clinicians, basic researchers, and toxicologists addressed at a recent conference, "Thyroid Hormone and Brain Development: Translating Molecular Mechanisms to Population Risk," held 23-25 September 2002 in Research Triangle Park, North Carolina. The international conference was sponsored by the NIEHS, the U.S. Environmental Protection Agency, the NIH Office of Rare Diseases, the Agency for Toxic Substances and Disease Registry, the American Chemistry Council, and the Center for Neuroendocrine Studies at the University of Massachusetts, Amherst.

Neonatal thyroid hormone plays a major role in brain development. It is widely known that a lack of thyroid hormone late in pregnancy and the first months of a child's life results in congenital hypothyroidism. If untreated, this condition results in moderate to severe mental retardation, growth failure, deafness, and neurological problems. Those symptoms can be ameliorated by administering synthetic thyroid hormone before the child is three months old. After that, it's too late--the defects are permanent.

Until recently, endocrinologists believed thyroid hormone did not play a significant role in brain development before late pregnancy, says conference cochair Tom Zoeller, a biologist from the University of Massachusetts, Amherst. But a growing number of research scientists and clinicians are starting to recognize earlier windows during which thyroid hormone plays critical roles in fetal brain development. This controversial idea means that maternal thyroid hormone may play a direct role in fetal brain development--it may, in fact, act directly on the developing brain before the fetus begins making its own thyroid hormone. "We're seeing a paradigm shift to say that prenatal effects from thyroid hormone occur earlier during development than previously thought," says Zoeller.

Evidence supporting the direct impact of a mother's thyroid hormone on her child's brain development comes from epidemiological studies, patient reports, and, most recently, from basic research that uses experiments with mice to understand the molecular mechanisms for thyroid hormone action on the brain.

The best-known epidemiological study of maternal thyroid hormone and fetal effects was published by James E. Haddow and colleagues in the 19 August 1999 issue of the New England Journal of Medicine. The findings of this study suggested that untreated mild thyroid failure in a mother may reduce her child's IQ scores and other measurements of intelligence, aptitude, and visual-motor skills.

Neuropsychologist Joanne Rovet of Toronto's Hospital for Sick Children looks for windows of vulnerability by studying mothers and children with thyroid disorders. After more than a decade of study, she finds that maternal thyroid hormone deficiency early in fetal development is correlated with later problems with visual attention and gross motor skills. Hormone deficiency later in pregnancy increases the risk of fine motor deficits.

Recent experimental studies have begun to explore a complex molecular mechanism that regulates concentration of active thyroid hormone and the control of gene expression in the brain. But basic science still has a long way to go to fully understand thyroid hormone action during development. For example, mice in which thyroid hormone receptors have been knocked out do not show the effects of congenital hypothyroidism, according to Fred Wondisford, chief of the University of Chicago's thyroid unit. These mice have fairly normal central nervous systems except for having profound deafness and smaller cerebellums.

Current understanding of the molecular mechanisms for thyroid hormone action suggest a hypothesis that may help to explain this apparent contradiction. Thyroid hormone receptors, in the absence of thyroid hormone, repress gene expression, according to Juan Bernal, a molecular endocrinologist at the Instituto de Investigaciones Biomedicas in Madrid, Spain. In the presence of thyroid hormone, the receptors activate gene expression. When there are no receptors, the genes are expressed at an intermediate baseline level. So knockout mice reap some of the benefits of gene expression whereas hypothyroidal mice don't. "The main role of thyroid hormone may be to amplify signals already coming from the genes," said Bernal.

The deaf knockout mice also illustrate that timing is crucial for any attempts to evaluate how thyroid hormone affects brain development. Experimental geneticist Douglas Forrest of the Mount Sinai School of Medicine in New York City explained that one must consider timing to understand why those knockout mice couldn't hear. In normal mice, early after birth, the cells that translate vibration into sound in the inner ear respond rapidly to sound. In knockout mice the early response isn't so fast. Eventually the response catches up, but by then it's too late, and this contributes to a permanent deficit in hearing. "At this meeting progress was made because people were identifying molecular mechanisms that reproduce some of the clinical data," said David Armstrong, leader of the faculty of neuroscience and membrane signaling group in the NIEHS Laboratory of Signal Transduction.

This growing understanding presents toxicologists with a challenge. They must find end points that are indicative of a transient thyroid hormone imbalance. To do this they need to "validate known end points of thyroid hormone action in the brain, such as the rate of cell division or cell death at specific times in cerebellar development, for use ih toxicological studies," says Zoeller.

There are also practical implications to this growing understanding and changing perspective. Based on these results, learning disability advocacy groups are preparing to recommend preconception screening for hypothyroidism for women, according to activist Audrey McMahon of the Learning Disability Association (although some scientists question whether such screening is indicated by the science). In addition, in parts of the world where subtle iodine deficiencies affect a mother's thyroid hormone status, iodine supplementation may be more important than currently realized, according to Bernal.