Effects of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) on liver phosphoenolpyruvate carboxykinase (PEPCK) activity, glucose homeostasis and plasma amino acid concentrations in the most TCDD-susceptible and the most TCDD-resistant rat strains

Abstract

Reduced gluconeogenesis due to decreased activity of key gluconeogenic enzymes in liver, together with feed refusal, has been suggested to play an important role in 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD)-induced lethality in rats. This study was carried out to further analyse the toxicological significance of reduced gluconeogenesis by comparing dose-responses and time-courses of effects of TCDD on the activity of phosphoenolpyruvate carboxykinase (PEPCK) in liver, liver glycogen concentration as well as plasma concentrations of glucose and amino acids in both genders of TCDD-sensitive Long-Evans (L-E) rats and TCDD-resistant Han/Wistar (H/W) rats. A dose-dependent decrease in PEPCK activity was observed in H/W rats, but in L-E rats the activity was not decreased. However, TCDD impaired the strong increase in liver PEPCK activity observed in pair-fed controls of the L-E strain. Liver glycogen concentrations were severely decreased in L-E rats and moderately in H/W rats. This effect seems to be secondary to reduced feed intake, since a similar decrease was seen in pair-fed controls. Decreases in plasma glucose concentrations were also more profound in L-E rats than in H/W rats, but pair-fed controls were generally less affected. Circulating concentrations of amino acids were markedly increased in TCDD-treated L-E rats, which is likely to reflect increased mobilization of amino acids and their decreased metabolism in liver. Reduction of liver PEPCK activity cannot account for the sensitivity difference of these two strains of rats in terms of mortality. Nevertheless, the response of both strains of TCDD-treated rats regarding gluconeogenesis is different from that seen in pair-fed controls and suggesting that impairment of this pathway contributes to the development of the wasting syndrome.

Aryl Hydrocarbon Receptor Regulates Distinct Dioxin-Dependent and Dioxin-Independent Gene Batteries

“…PEPCK is a key enzyme in gluconeogenesis, and studies in rodents have shown that acute toxicity of TCDD may be associated with reduced PEPCK activity, together with appetite suppression and inhibition of gluconeogenesis (Viluksela et al, 1999). We found that TCDD treatment decreased Pck1 mRNA levels in Ahr ϩ/ϩ mice but not in Ahr Ϫ/Ϫ mice (Fig.…”

“…These observations suggest that TCDD initiates a broad cellular effort to increase protein translation by increasing ribosome assembly and decreasing amino acid catabolism, possibly through Eif3-mediated changes in protein degradation rates. In fact, increased plasma amino acid levels have been observed in TCDD-treated rats (Viluksela et al, 1999).…”

Linking dioxins to diabetes: epidemiology and biologic plausibility.

“…Another link between Ah receptor and PPAR functions is that both receptors influence PEPCK activity or expression [PPARs (68)(69)(70) and Ah receptor (17,71)]. Additionally, both the Ah receptor and PPARα have been connected to hyperlipidemia [Ah receptor (72) and PPAR (73)], and type 2 diabetes is associated with abnormal lipid metabolism (74).…”

“…Adult-onset diabetes (13,14), whose incidence continues to rise in Western countries, is a metabolic disorder involving abnormal energy metabolism (15,16). Perhaps significantly, lethal poisoning by dioxins also involves disruption of energy metabolism, characterized by depletion of lipid stores of the affected animal (the "wasting syndrome") (17). In rats, Rozman (18) demonstrated nearly identical dose-response behavior by TCDD for suppression of food intake and inhibition of the enzyme phosphoenolpyruvate carboxykinase (PEPCK) involved in gluconeogenesis [although later work (19) with a wider range of rodents did not consistently affirm this correlation].…”

Low Doses of a PCB (Aroclor 1254) Affect the Body Weight by Decreasing the Activity of Glucose-6-Phosphatase in the Liver and Kidney Cells of Mice

“…As the majority of the studies pertaining to the metabolic effects of dioxin exposure use animal models mostly rodents, broad strain and species specificity demonstrates the sensitivity to wasting effect of dioxins [33,34,30,[35][36][37][38]. Many observations across such studies include impaired gluconeogenesis, decrease in body weight, and reductions in the glucose-6-phosphatase activity and gene expression of PEPCK [35,32,40,10,39].…”