Abstract
One of the hallmarks of the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a drastically reduced feed intake by an unknown mechanism. To further elucidate this wasting syndrome, we followed the effects of a single large dose (100 μg/kg) of TCDD on the serum levels of several energy balance-influencing hormones, clinical chemistry variables, and hepatic aryl hydrocarbon receptor (AHR) expression in two rat strains that differ widely in their TCDD sensitivities, for up to 10 days. TCDD affected most of the analytes in sensitive Long-Evans rats, while there were few alterations in the resistant Han/Wistar strain. However, analyses of feed-restricted unexposed Long-Evans rats indicated several of the perturbations to be secondary to energy deficiency. Notable increases in ghrelin and glucagon occurred in TCDD-treated Long-Evans rats alone, which links these hormones to the wasting syndrome. The newly found energy balance regulators, insulin-like growth factor 1 and fibroblast growth factor 21 (FGF-21), appeared to function in concert in body weight loss-induced metabolic state, and FGF-21 was putatively linked to increased lipolysis induced by TCDD. Finally, we demonstrate a reverse set of changes in the AHR protein and mRNA response to TCDD and feed restriction, suggesting that AHR might function also as a physiological regulator, possibly involved in the maintenance of energy balance.
Highlights
Dioxins are a group of pervasive and biomagnifying environmental contaminants that cause concern for their high acute toxicity and teratogenicity in laboratory animals [1,2,3], and putative developmental effects in humans at body burdens of low ng/kg levels [4,5]
Our aim was to investigate the effects of a single dose of TCDD on serum levels of hormones and products/substrates of intermediary metabolism influencing peripheral and central nervous system (CNS) regulation of energy balance
In addition to the energy metabolism-related measurements, effects on the liver by TCDD and feed restriction were assessed through quantification of serum concentrations of the hepatic indicator enzymes alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT)
Summary
Dioxins are a group of pervasive and biomagnifying environmental contaminants that cause concern for their high acute toxicity and teratogenicity in laboratory animals [1,2,3], and putative developmental effects in humans at body burdens of low ng/kg levels [4,5]. Even high acute dioxin doses do not kill animals immediately, but death occurs in one to several weeks, and in many species (e.g., rats, mice, hamsters and guinea pigs), after substantially reduced feed intake and prominent weight loss [10,11,12,13], called the wasting syndrome. The mechanism of this derailment of body weight regulation has largely remained elusive in spite of over three decades of research effort
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