Effect of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on Murine Heart Development: Alteration in Fetal and Postnatal Cardiac Growth, and Postnatal Cardiac Chronotropy

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related chemicals are potent cardiovascular teratogens in developing piscine and avian species. In the present study we investigated the effects of TCDD on murine cardiovascular development. Pregnant mice (C57Bl6N) were dosed with 1.5-24 microg TCDD/kg on gestation day (GD) 14.5. At GD 17.5, fetal mice exhibited a dose-related decrease in heart-to-body weight ratio that was significantly reduced at a maternal dose as low as 3.0 microg TCDD/kg. In addition, cardiocyte proliferation was reduced in GD 17.5 fetal hearts at the 6.0-microg TCDD/kg maternal dose. To determine if this reduction in cardiac weight was transient, or if it continued after birth, dams treated with control or 6.0 microg TCDD/kg were allowed to deliver, and heart weight of offspring was determined on postnatal days (P) 7 and 21. While no difference was seen on P 7, on P 21 pups from TCDD-treated litters showed an increase in heart-to-body weight ratio and in expression of the cardiac hypertrophy marker atrial natriuretic factor. Additionally, electrocardiograms of P 21 offspring showed that the combination of in utero and lactational TCDD exposure reduced postnatal heart rate but did not alter cardiac responsiveness to isoproterenol stimulation of heart rate. These results demonstrate that the fetal murine heart is a sensitive target of TCDD-induced teratogenicity, resembling many of TCDD-induced effects observed in fish and avian embryos, including reduced cardiocyte proliferation and altered fetal heart size. Furthermore, the combination of in utero and lactational TCDD exposure can induce cardiac hypertrophy and bradycardia postnatally, which could increase the risk of cardiovascular disease development.

Impact of cigarette smoke exposure on the expression of cardiac hypertrophic genes, cytochrome P450 enzymes, and oxidative stress markers in rats

“…The current knowledge of the mechanism of CYP1A1 induction by PAHs suggests a transcriptional regulation, in which the binding of PAH to cytosolic transcription factor, the aryl hydrocarbon receptor (AhR), is the first step in a series of events leading to carcinogenicity and mutagenicity (Whitlock, 1999) through binding to xenobiotic responsive elements (XRE) located in the promoter region of CYP1A1 resulting in the initiation of the mRNA transcription process (Whitlock, 1999;Pollenz, 2002). Mechanistically, the presence of XRE DNA sequences in the promoter region of several hypertrophic genes, particularly ANP, BNP, and β-MHC (Thackaberry et al, 2005;Turhan et al, 2005;Borlak and Thum 2002;Kvasnicka et al, 2001;Savouret et al, 2003), may suggest a mechanism of induction of hypertrophic genes by cigarette smoke exposure. This is supported by the observations that AhR activation by PAHs, the main constituent of cigarette and the most potent CYP1A1 inducer (Mimura and Fujii-Kuriyama, 2003), caused an induction of hypertrophic genes in rat cardiomyocye H9c2 cells which was associated with induction of several CYP1A1 gene .…”

Comparative developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the hamster, rat and guinea pig

“…Although mature animals display a wide interspecies variability to the acute toxic effects of TCDD, demonstrated by the 5000-fold difference in the acute LD 50 among species, evidence suggests that the developing embryo and fetus are uniquely sensitive to TCDD (McNulty, 1984;Olson et al, 1990;Peterson et al, 1993). There has been frequent use of the rat Gray et al, 1997;Huuskonen et al, 1994;Ikeda et al, 2005;Mably et al, 1992a,b,c) and mouse (Birnbaum et al, 1991;Ko et al, 2002;Neubert et al, 1973;Thackaberry et al, 2005;Weber and Birnbaum, 1985;Willey et al, 1998) as model systems to study the developmental toxicity of TCDD. However, only a few studies have utilized the hamster Olson and McGarrigle, 1992;Olson et al, 1990;Wolf et al, 1999) or guinea pig (Olson and McGarrigle, 1992).…”

TCDD-induced chick cardiotoxicity is abolished by a selective cyclooxygenase-2 (COX-2) inhibitor NS398

“…A common finding in all of these models is a reduction in myocyte proliferation, and consequently, a change in heart size with developmental exposure of TCDD (Jones et al, 2009;Antkiewicz et al 2005;Thackaberry et al 2005). In fish and avians, but not mammals, cardioteratogenicity of TCDD is associated with mortality (Kopf et al 2009).…”