Heart as a target organ in 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity: decreased beta-adrenergic responsiveness and evidence of increased intracellular calcium.

Abstract

The heart has not been regarde4 as a major target organ of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity notwithstanding that lethal cardiac dysfunction can occur in the absence of histopathological changes. To assess possible TCDD cardiotoxicity, we studied the effect of TCDD five days after treatment (10 jug/kg of body weight; single dose given i.p. in corn oil) on the contractility of guinea pig right ventricular papillary muscle. Controls were treated with corn oil. TCDD treatment significantly decreased fi-adrenergic responsiveness. In papillary muscles from TCDD-treated guinea pigs, the positive inotropic effect of isoproterenol (0.03-0.3 1AM) was decreased by a mean of 65% (P < 0.001), and the enhancement in the velocity of relaxation was 60% less than in the controls (P < 0.05). On the other hand, TCDD treatment did not alter the positive inotropic effect of lower concentrations of isoproterenol (0.1-10 nM). After TCDD, responsiveness to low-frequency stimulation (0.1 and 0.25 Hz) was enhanced, responsiveness to increases in extracellular Ca2+ concentration was attenuated, and isoproterenol-elicited aftercontractions in K+-depolarized preparations were increased in magnitude. Collectively, the latter findings suggest that in addition to decreasing I3-adrenergic responsiveness, TCDD increases the intracellular Ca2+ concentration in papMary muscle. Finally, slow Ca2+ channels were not blocked after TCDD treatment, inasmuch as isoproterenol restored contractility equally effectively in K+ -depolarized TCDDtreated and control papillary muscles. Our findings indicate that TCDD causes a specific pattern of cardiac dysfunction in a mammalian species, selectively augmenting or decreasing different cardiac responses. The cardiac changes are consistent with reported membrane effects of TCDD; further, they suggest that the heart may be a major target organ for TCDD toxicity. 2,3,7, is the prototype of a group of chemically related, highly toxic environmental chemicals. Binding by TCDD and other toxic polyhalogenated biphenyls to specific cytosolic and nuclear receptors leads to induction of a group of enzymes, the best-characterized of which are specific isozymes of cytochrome P-450. These chemicals also elicit a symptom complex characterized by weight loss, thymic involution, tumor promotion, edema, increased mortality, and in some species,

The Seveso studies on early and long-term effects of dioxin exposure: a review.

“…This hypothesis is supported by the early postaccident occurrence of the deaths, the advanced age of some of the affected people, and the prevailing chronic type of cardiovascular disorders (40). TCDD alters lipid metabolism, cardiac function, and morphology in experimental studies with animals (45)(46)(47)(48)(49)(50)(51)(52), although data for humans are still inconclusive (53 (44). In addition, the immunotoxic action of dioxin may have impaired defense mechanisms that usually protect against respiratory infection episodes, which play major roles in the natural history of COPD (54).…”

Evaluation of Cardiovascular Outcomes among U.S. Workers Exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

“…These effects dioxin congeners. Concern about the toxic-include ventricular dilatation (1), cardiac ity of this and other dioxinlike congeners edema (1,2), valvulitis (2), myocardial Abbreviations used: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; APAF, abnormal peripheral arterial flow; BMI, body mass index; Cl, confidence interval; ECG, electrocardiogram; HDL, high-density lipoprotein; ICD-9, International Classification of Disease, 9th revision; mm Hg, millimeters of mercury; OR, odds ratio; RR, risk ratio; SE, standard error; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin TCP, 2,4,5-trichlorophenol. degeneration (3), preatherosclerotic lesions in the aorta (4), and altered cardiac contractility (5)(6)(7)(8).…”

Aryl Hydrocarbon Receptor Activation Produces Heart-Specific Transcriptional and Toxic Responses in Developing Zebrafish

“…An initial reduction in heart weight in developing mice seems to cause progressive cardiac hypertrophy (Lin et al, 2001;Thackaberry et al, 2005b). TCDD exposure during development also causes alterations in heart structure and function in birds (Cheung et al, 1981;Rifkind et al, 1985;Brunstrom and Lund, 1988;Canga et al, 1988Canga et al, , 1993Walker et al, 1997;Walker and Catron, 2000;Sommer et al, 2005), including a reduction in cardiac myocyte number, a decrease in myocyte proliferation, and an increase in apoptosis (Ivnitski et al, 2001).…”