Reduced activities of key enzymes of gluconeogenesis as possible cause of acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats

doi:10.1016/0300-483X(91)90214-L

Toxicology

Volume 66, Issue 2, 25 February 1991, Pages 133-144

https://doi.org/10.1016/0300-483X(91)90214-L Get rights and content

Abstract

Male Sprague-Dawley rats (350–375 g) were injected i.p. with TCDD (25 [sublethal dose] and 125 μg/kg [lethal dose], respectively, in corn oil/acetone) or vehicle only; vehicle-treated animals were pair-fed to their TCDD-treated counterparts. 1,2,4,8,16, and 32 days (28 days for lethal dose) thereafter, animals were sacrificed and activities of two key enzymes of gluconeogenesis determined in livers of rats. In livers of pair-fed rats both enzyme activities were little affected. In the livers of TCDD-treated animals the activity of phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) decreased rapidly, exhibiting significant losses by the 2nd day after treatment. Time course and extent of loss of PEPCK activity (about 50%) were similar after either dose. The activity of glucose-6-phosphatase (G-6-Pase, EC 3.1.3.9) decreased more slowly as a result of TCDD treatment; statistically significant losses were observed by 4 or 8 days after the lethal and sublethal dose, respectively. These results confirm the hypothesis that reduced in vivo rates of gluconeogenesis in TCDD-treated rats are due to decreased activities of gluconeogenic enzymes. In an additional set of experiments, rats were treated with 125μg/kg TCDD, 25μ/kg TCDD, or with vehicle alone. The 25μg/kg or vehicle-treated rats were then pair-fed to rats dosed with 125μg/kg of TCDD. Mean time to death and body weight loss at the time of death were essentially identical in all groups, lending additional support to the hypothesis that reduced feed intake is the major cause of TCDD-induced death in male Sprague-Dawley rats. Both appetite suppression and reduced total PEPCK activity in whole livers occured in the same dose-ranges of TCDD, suggesting the possibility of a cause-effect relationship.

References (26)

C.L. Potter et al.
Hypothyroxinemia and hypothermia in rats in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin administration
Toxicol. Appl. Pharmacol.
(1983)
R. Walden et al.
Comparative toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in four (sub)strains of adult male rats
Toxicol. Appl. Pharmacol.
(1985)
B.J. Christian et al.
Intermediary metabolism of the mature rat following 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment
Toxicol. Appl. Pharmacol.
(1986)
J.R. Gorski et al.
Dose-response and time course of hypotheroxinemia and hypoinsulinemia and characterization of insulin hypersensitivity in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats
Toxicology
(1987)
J.R. Gorski et al.
Elevated plasma corticosterone levels and histopathology of the adrenals and thymuses in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats
Toxicology
(1988)
J.H. Exton
Gluconeogenesis
Metab. Clin. Exp.
(1972)
P.C. Butler et al.
Regulation of carbohydrate metabolism and response to hypoglycemia
Endocrinol. Metab. Clin. N. Am.
(1989)
G. Muzi et al.
Mode of metabolism is altered in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats
Toxicol. Lett.
(1989)
M.T.S. Hsia et al.
Delayed wasting syndrome and alterations of liver gluconeogenic enzymes in rats exposed to the TCDD congener 3,3′,4,4′-tetrachloroazoxybenzene
Toxicol. Lett.
(1985)
B.J. Christian et al.
Relationship of the wasting syndrome to lethality in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin
Toxicol. Appl. Pharmacol.
(1986)

M.M. Bradford

A rapid and sensitive method for the quantitation of microgram quantities of protein using the principle of protein-dye binding

Anal. Biochem.

(1976)

I. Petrescu et al.

Determination of phosphoenolpyruvate carboxykinase activity with deoxyguanosine 5′-diphosphate as nucleotide substrate

Anal. Biochem.

(1979)

E.S. Baginski et al.

Glucose-6-phosphatase

Cited by (71)

Obesity II: Establishing causal links between chemical exposures and obesity
2022, Biochemical Pharmacology
Citation Excerpt :
Initial studies associated exposure to high doses (25–200 µg/kg) of TCDD with hypoglycemia, hypoinsulinemia due to β-cell apoptosis and hypophagia, leading to the wasting syndrome reviewed in [505]. Lower doses (10 µg/kg) altered serum lipid concentrations by reducing the liver and adipose fatty acid synthesis rates and the activity of liver gluconeogenic enzymes [506,507]. However, opposite results were observed using PCB 77, another dl-PCB.
Obesity is a multifactorial disease with both genetic and environmental components. The prevailing view is that obesity results from an imbalance between energy intake and expenditure caused by overeating and insufficient exercise. We describe another environmental element that can alter the balance between energy intake and energy expenditure: obesogens. Obesogens are a subset of environmental chemicals that act as endocrine disruptors affecting metabolic endpoints. The obesogen hypothesis posits that exposure to endocrine disruptors and other chemicals can alter the development and function of the adipose tissue, liver, pancreas, gastrointestinal tract, and brain, thus changing the set point for control of metabolism. Obesogens can determine how much food is needed to maintain homeostasis and thereby increase the susceptibility to obesity. The most sensitive time for obesogen action is in utero and early childhood, in part via epigenetic programming that can be transmitted to future generations. This review explores the evidence supporting the obesogen hypothesis and highlights knowledge gaps that have prevented widespread acceptance as a contributor to the obesity pandemic. Critically, the obesogen hypothesis changes the narrative from curing obesity to preventing obesity.
Tributyltin exposure disturbs hepatic glucose metabolism in male mice
2019, Toxicology
Citation Excerpt :
Exposure to chemicals can disturb gluconeogenic enzymes activity. It has been reported that rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (25 and 125 ug/kg) suppressed gluconeogenesis via inhibition of PCK and G6P (Weber et al., 1991), while rats subchronic exposed to malathion showed increased blood glucose concentration accompanied by the stimulation of glycogen phosphorylase (GP) and PCK activities (Abdollahi et al., 2004). Administration of diazinon (15, 30 and 60 mg/kg) increased plasma glucose concentrations and increased the activities of hepatic GP and PEPCK in rats (Teimouri et al., 2006).
Some previous studies showed that organotin compounds induced diabetes in animal models. The underlying mechanisms should be further revealed. In this study, male KM mice were exposed to tributyltin (TBT) at 0.5, 5 and 50 μg/kg once every three days for 45 days. The TBT-treated mice exhibited an elevation of fasting blood glucose level and glucose intolerance. The fasting serum insulin levels were increased and reached a significant difference in the 50 μg/kg group; the glucagon levels were significantly decreased in all the treatments. Pancreatic β-cell mass was significantly decreased in all the treatments; α-cell mass showed a significant decrease in the 5 and 50 ug/kg groups. The transcription of pancreatic insulin gene (Ins2) showed an up-regulation and reached a significant difference in the 5 and 50 μg/kg groups, which would be responsible for the increased serum insulin levels. The transcription of glucagon gene (Gcg) in the pancreas was significantly down-regulated in the 5 and 50 ug/kg groups. The protein expression of hepatic glucagon receptor was down-regulated, while the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase was up-regulated accompanied by increased hepatic glycogen content. These results indicated that hepatic gluconeogenesis was enhanced during insulin resistance stage caused by TBT exposure, which would exert a potential risk inducing the development of diabetes mellitus.
Xenobiotic Receptors in the Crosstalk Between Drug Metabolism and Energy Metabolism
2017, Drug Metabolism in Diseases
The aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and the constitutive androstane receptor (CAR) are three liver-enriched xenobiotic receptors. These xenobiotic receptors transcriptionally regulate the expression of drug-metabolizing enzymes and transporters, which are essential components of xenobiotic response in protecting the hosts from the accumulation of harmful chemicals. More recent research has uncovered interesting endobiotic functions of these xenobiotic receptors, including their regulation of the energy metabolism and energy homeostasis. Meanwhile, disruptions of energy homeostasis, such as type 2 diabetes and obesity, have an impact on drug metabolism. This chapter will focus on the recent progress on the integral role of AhR, PXR, and CAR in the crosstalk between drug metabolism and energy homeostasis.
Effects of a single exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on macro- and microstructures of feeding and drinking in two differently TCDD-sensitive rat strains
2011, Pharmacology Biochemistry and Behavior
Citation Excerpt :
Their body weight (BW) set-point seems to be adjusted to a lower level following exposure, since TCDD-treated rats are capable of defending their lowered BW level against various feeding challenges (Pohjanvirta and Tuomisto, 1990a, 1990b; Seefeld et al., 1984a, 1984b; Tuomisto et al., 1999a). Although the loss of BW results from hypophagia and depletion of energy stores (Christian et al., 1986; Weber et al., 1991), neither force-feeding (Gasiewicz et al., 1980; Tuomisto et al., 1999a) nor obesity or high-energy diet (Tuomisto et al., 1999a) could postpone the time of death following lethal doses of TCDD. Furthermore, wasting is not a consequence of nausea or an alteration in energy metabolism or locomotor activity (Pohjanvirta et al., 1994; Potter et al., 1986; Seefeld et al., 1984a; Seefeld and Peterson, 1984).
In rats, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes anorexia that may lead to fatal wasting but has hitherto been poorly characterized. Therefore, we studied in-depth feeding and drinking behaviors of TCDD-sensitive L–E rats for 5 (100 μg/kg; lethal dose) or 10 (10 μg/kg; sublethal) days and of TCDD-resistant H/W rats for 14 (100 or 1000 μg/kg; both sublethal) days postexposure to TCDD. The 1000-fold higher resistance of H/W rats to acute lethality of TCDD results from a mutation in their AH receptor (AHR). We split days into four (morning, daytime, evening, and night) or two (light/dark) circadian periods and took the repeated nature of the data into account. In L–E rats at 100 μg/kg, the feed intake dropped precipitously, due to reduced meal sizes. In H/W rats, the hypophagia remained moderate and stemmed from a reduced meal frequency. While the suppression in L–E rats peaked during the morning (at 100 μg/kg), the main effects in H/W rats were seen during the constant light or dark phases. Furthermore, chronologic data analysis revealed alterations in consecutive feeding and drinking patterns. Thus, striking differences were found between these strains in the timing and structure of consummatory behaviors, suggesting involvement of the AHR in these behaviors.
Characterization of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-provoked strong and rapid aversion to unfamiliar foodstuffs in rats
2011, Toxicology
A conspicuous but scantly studied feature of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity is avoidance of unfamiliar foodstuffs, which seems to be one of the very few exquisitely sensitive behavioural effects in adult laboratory animals. Here we characterized this peculiar response further after low doses of TCDD. The time-course of the novelty avoidance, the role of nutriment form and dependence of the aversion on the time lag between TCDD exposure and the presentation of a novel food item was determined using rats with different sensitivities to lethality of TCDD. Rats were offered chocolate, liquid nutriment or familiar feed with an unfamiliar texture and the consumptions were measured for varying periods. Aversion to a novel food item (chocolate) emerged within 5.5 h after TCDD exposure. A lag of a week or more between TCDD exposure and the presentation of chocolate abolished the avoidance whereas simultaneous presentation of chocolate with TCDD treatment rendered the rats oblivious to the chocolate's presence for over 40 days. Rats avoided also liquid nutriments when these were coupled with TCDD administration but this faded much sooner than chocolate aversion. Even a change in feed texture at the exposure was able to elicit the response. However, habituation was found to interfere with the aversion. These findings indicate that temporal proximity to TCDD exposure is a requisite for the avoidance response which emerges rapidly and may linger on for extended periods, but is not strictly confined to any specific food type. The molecular mechanisms of this tantalizing behavioural alteration remain to be determined.
Identification of the aryl hydrocarbon receptor target gene TiPARP as a mediator of suppression of hepatic gluconeogenesis by 2,3,7,8- tetrachlorodibenzo-p-dioxin and of nicotinamide as a corrective agent for this effect
2010, Journal of Biological Chemistry
Citation Excerpt :
Whereas fasting or nutrient deprivation normally increases gluconeogenesis and stimulates food intake (11, 12), TCDD produces a fasting or starvation-like state in which gluconeogenesis and food intake are both decreased (7, 13). In mammalian liver TCDD is known to decrease the expression and activity of PEPCK and G6Pase, enzymes controlling gluconeogenic flux (7, 14–16), but the mechanism for these effects remains obscure (1, 3). As PGC1α is a critical transcriptional coactivator for PEPCK and G6Pase, we hypothesized that a negative interaction between AHR activation and PGC1α function, although not previously recognized, might help to explain TCDD suppression of gluconeogenesis.
The environmental toxin TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin, dioxin) produces diverse toxic effects including a lethal wasting syndrome whose hallmark is suppressed hepatic gluconeogenesis. All TCDD toxicities require activation of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor. Whereas the mechanism for AHR induction of target genes is well understood, it is not known how AHR activation produces any TCDD toxicity. This report identifies for the first time an AHR target gene, TiPARP (TCDD-inducible poly(ADP-ribose) polymerase, PARP7) that can mediate a TCDD toxicity, i.e. suppression of hepatic gluconeogenesis. TCDD suppressed hepatic glucose production, expression of key gluconeogenic genes, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase), and NAD⁺ levels, and increased PARP activity and TiPARP expression. TCDD also increased acetylation and ubiquitin-dependent proteosomal degradation of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α), a coactivator of PEPCK and G6Pase transcription. TiPARP overexpression reproduced TCDD effects on glucose output and NAD⁺ levels whereas TiPARP silencing diminished them. TiPARP overexpression also increased PGC1α acetylation and decreased PGC1α levels. In contrast, silencing of cytochromes P450 (CYP) 1A, main AHR-induced genes, did not alter TCDD suppression of gluconeogenesis. The vitamin B3 constituent, nicotinamide (NAM), prevented TCDD suppression of glucose output, NAD⁺, and gluconeogenic genes and stabilized PGC1α. The corrective effects of NAM could be attributed to increased NAD⁺ levels and suppression of AHR target gene induction. The results reveal that TiPARP can mediate a TCDD effect, that the AHR is linked to PGC1α function and stability and that NAM has novel AHR antagonist activity.

View all citing articles on Scopus

^∗: Present address: North America Science Associates, Northwood, OH 43619, U.S.A.

^∗∗: Present address: Istituto di Medicina di Lavoro, Universitá di Perugia, I-06100 Perugia, Italy.

View full text

Reduced activities of key enzymes of gluconeogenesis as possible cause of acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats

Abstract

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicology

Toxicology

Metab. Clin. Exp.

Endocrinol. Metab. Clin. N. Am.

Toxicol. Lett.

Toxicol. Lett.

Toxicol. Appl. Pharmacol.

Anal. Biochem.

Anal. Biochem.