# Congenital abnormalities resulting from fetal thyrotoxicosis

> **NIH NIH R21** · MAINEHEALTH · 2020 · $215,000

## Abstract

ABSTRACT
 Mammalian development involves a number of finely-tuned, time-sensitive molecular and
cellular processes essential to ensure normal physiology and health later in life. Disruptions during
this critical period may lead to impaired viability, congenital abnormalities and associated morbidities.
In humans, the causes of many congenital abnormalities remain unidentified, hampering efforts for
their prevention. These may include most cases of cardiomyopathies, hydrocephalus, Chiari
malformations, cleft palate, choanal atresia and other cranio-encephalic dysmorphisms. We propose
that transient, unidentified fetal thyrotoxicosis (i.e., thyroid hormone excess) causes some of these
abnormalities. Fetal thyrotoxicosis may occur as a result of exposure to chemicals that act as
endocrine disruptors, secondary to maternal thyroid disease before clinical treatment is initiated, or as
a consequence of environmentally-driven epigenetic disregulation in the gene (Dio3) that maintains
developmental levels of thyroid hormone levels much lower than those in the maternal circulation in
order to prevent untimely exposure.
 Using a highly suitable mouse model of fetal thyrotoxicosis based on a genetic or epigenetic
deficiency in DIO3, we propose to characterize the extent and ontogeny of cranio-encephalic and
cardiac abnormalities that arise as a consequence of thyroid hormone excess during development
(Aim 1). We also propose to identify the molecular mechanisms underlying the generation of those
congenital abnormalities (Aim 2).
 We anticipate that our work will demonstrate that fetal thyrotoxicosis is a novel factor
contributing to the generation of congenital abnormalities currently considered idiopathic, shedding
important light into their etiology. This project will increase the appreciation of the potential risks of
fetal thyrotoxicosis early in development and encourage close assessment of thyroid conditions and
adequate clinical interventions in pregnant women and prospective mothers to better prevent
congenital malformations. We also anticipate obtaining novel insight into the sensitive time frames
and the responsible underlying molecular mechanisms by which thyroid hormone excess causes
these abnormalities. This will open new avenues of research and inform future studies.

## Key facts

- **NIH application ID:** 9880426
- **Project number:** 5R21DE028732-02
- **Recipient organization:** MAINEHEALTH
- **Principal Investigator:** Arturo Hernandez
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $215,000
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-02-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880426

## Citation

> US National Institutes of Health, RePORTER application 9880426, Congenital abnormalities resulting from fetal thyrotoxicosis (5R21DE028732-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9880426. Licensed CC0.

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