Maternal hyperthyroidism increases the prevalence of foregut atresias in fetal rats exposed to adriamycin.

PURPOSE: Gastrointestinal malformations such as esophageal atresia with tracheoesophageal fistula (EA/TEF) and duodenal atresia (DA) have been reported in infants born to hyperthyroid mothers or with congenital hypothyroidism. The present study aimed to test whether maternal thyroid status during embryonic foregut division has any influence on the prevalence of EA/TEF and DA in an accepted rat model of these malformations. METHODS: Pregnant rats received either vehicle or 1.75 mg/kg i.p. adriamycin on gestational days 7, 8 and 9. Transient maternal hyper or hypothyroidism was induced by oral administration of levothyroxine (LT4, 50 µg/kg/day) or propylthiouracil (PTU, 2 mg/kg/day), respectively, on days 7 to 12 of gestation. Plasma cholesterol, total T3, free T4 and TSH were measured at gestational days 7, 12, and 21. At the end of gestation, the mothers were sacrificed and embryo-fetal mortality was recorded. Fetuses were dissected to determine the prevalence of esophageal and intestinal atresias. RESULTS: At gestational day 12, mothers treated with LT4 or PTU had hyper or hypothyroid status, respectively; plasma cholesterol levels were similar. In the adriamycin-exposed fetuses from hyperthyroid mothers, the embryonal resorption rate and the prevalence of both EA/TEF and DA were significantly higher than in the other groups; maternal hypothyroidism during the same period did not have significant effect on the prevalence of atresias. CONCLUSIONS: Maternal hyperthyroidism during the embryonic window corresponding to foregut cleavage increased the prevalence of both EA/TEF and duodenal atresia in fetal rats exposed to adriamycin. This suggests that maternal thyroid hormone status might be involved in the pathogenesis of foregut atresias and invites further research on this likely clinically relevant issue in humans.

Molecular insights into congenital disorders of the digestive system.

Recent work is providing new insights into molecular mechanisms of digestive system development and their alteration in clinically significant disorders. An understanding of these mechanisms has largely been gained through the use of animal models, because many of the basic processes required in embryogenesis are functionally conserved among species. Such conserved factors include cell-cell signaling pathways and the regulation of gene expression. Disruption of these pathways have been implicated in several congenital disorders of the digestive system, including Hirschsprung disease, malrotation, altered sphincter development, Meckel diverticulum, biliary atresia, Alagille syndrome, pancreatic heterotopias, and pancreatic agenesis. In this review, we highlight recent studies in digestive system development, which elucidate mechanisms underlying congenital disorders of the human digestive system.