ToxSci Advance Access originally published online on September 11, 2003
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Toxicological Sciences 76, 407-417 (2003)
Copyright © 2003 by the Society of Toxicology
REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY |
Insulin Regulation in AhR-null Mice: Embryonic Cardiac Enlargement, Neonatal Macrosomia, and Altered Insulin Regulation and Response in Pregnant and Aging AhR-null Females
* Molecular and Environmental Toxicology Center, Department of Nutritional Sciences, University of Wisconsin, 1415 Linden Drive, Madison, Wisconsin 53706;
Department of Mathematics and Statistics, MSC03 2150, 1 University of New Mexico, Albuquerque, New Mexico 87131;
Department of Pediatrics, University of New Mexico, 2211 Lomas Blvd NE, Albuquerque, New Mexico 87131;
Medical Lab Sciences, MSC09 5250, 1 University of New Mexico, Albuquerque, New Mexico 87131; and
¶ College of Pharmacy, MSC09 5360, 1 University of New Mexico, Albuquerque, New Mexico 87131
The aryl hydrocarbon receptor (AhR) was originally characterized because of its high affinity binding of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin. However, studies using AhR-null mice have demonstrated the importance of this protein in normal physiology and development. Here we demonstrate that AhR-null embryos develop cardiac enlargement, and that this phenotype is dependent, at least in part, on the maternal genotype. Neonates born to AhR-null females had increased heart weights regardless of the neonatal genotype, an outcome also observed in gestational diabetes. The cardiac hypertrophy markers, beta-myosin heavy chain and atrial natriuretic factor, and the cardiac proliferative index were increased in AhR-null embryos, indicating that the cardiac enlargement is associated with myocyte hypertrophy and hyperplasia, which begin prior to birth. Importantly, two- to three-month-old pregnant and seven-month-old nonpregnant females, but not nonpregnant three-month-old AhR-null females had significantly decreased fasting plasma insulin levels and a reduced ability to respond to exogenous insulin compared to controls. Despite these alterations in insulin regulation and responsiveness, pregnant AhR females did not have abnormal glucose tolerance tests and did not develop hyperglycemia, classic characteristics of gestational diabetes. However, twenty-three percent of seven-month-old AhR-null females did have altered glucose tolerance tests, but did not show hyperglycemia or increased hemoglobin A1C concentration under normal feeding conditions. While the ultimate cause of the neonatal phenotype remains unclear, these studies establish that the AhR is required for normal insulin regulation in pregnant and older mice and for cardiac development in embryonic mice.
Key Words: insulin regulation; embryonic cardiac enlargement; neonatal macrosomia; AhR.
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