Submitted to: Toxicological Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/29/2007
Publication Date: 2/2/2008
Citation: Aragon, A.C., Kopf, P.G., Campen, M.J., Huwe, J.K., Walker, M.K. 2008. In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure: Effects on fetal and adult cardiac gene expression and adult cardiac and renal morphology. Toxicological Sciences 101(2):321-330. Interpretive Summary: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant known to cause numerous health effects in animals. In this study, mice were used as a model to investigate the degree to which TCDD affects the heart and kidneys of a developing fetus. Pregnant mice were given a single dose of TCDD late in their pregnancy. Several markers for cardiac function and development were monitored in the mouse fetuses. Compared to control fetuses, the TCDD-exposed fetuses showed altered functions of the heart. These cardiac dysfunctions continued to be observed as the mice reached adulthood. In addition, an increase in the size of certain heart compartments and lesions in the kidney were observed in the mice exposed to TCDD prenatally. The results of this study suggest that exposure to TCDD during development (as fetuses or infants) may increase the risk of cardiovascular problem in adulthood.
Technical Abstract: The mouse heart is a target of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during fetal development, and microarray analysis demonstrates significant changes in expression of cardiac genes involved in extracellular matrix (ECM) remodeling. We tested the hypothesis that developmental TCDD exposure would disrupt cardiac ECM expression and be associated with changes in cardiac morphology in adulthood. In one study, time-pregnant C57BL/6 mice were dosed with corn oil or 1.5, 3.0, or 6.0 mg TCDD/kg on gestation day (GD) 14.5 and sacrificed on GD 17.5, when changes in fetal cardiac mRNA expression were analyzed using quantitative PCR. TCDD induced mRNA expression of genes associated with ECM remodeling (matrix metalloproteinase 9 and 13, preproendothelin- 1 [preproET-1]), cardiac hypertrophy (atrial natriuretic peptide, beta-myosin heavy chain, osteopontin), and aryl hydrocarbon receptor (AHR) activation (cytochrome P4501A1, AHR repressor). Further, all TCDD-induced changes required the AHR since gene expression was not altered in AHR knockout fetuses. In a second study, time-pregnant mice were treated with corn oil or 6.0 mg TCDD/kg on GD 14.5, and male offspring were assessed for changes in cardiac gene expression and cardiac and renal morphology at 3 months. All TCDD-induced changes in cardiac gene expression observed fetally, except for preproET-1, remained induced in the hearts of adult male offspring. Adult male offspring of TCDD-exposed dams also displayed cardiac hypertrophy, decreased plasma volume, and mild hydronephrosis. These results demonstrate that in utero and lactational TCDD exposures alter cardiac gene expression and cardiac and renal morphology in adulthood, which may increase the susceptibility to cardiovascular dysfunction.