Is GDF15 or PGC-1α involved in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced wasting syndrome? Evidence from a TCDD-sensitive and a TCDD-resistant rat strain

Abstract

A drastic body weight loss, the wasting syndrome, is a hallmark of the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but its mechanism is still elusive. The present study sought to find out whether the growth differentiation factor 15 (GDF15) or peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) plays a role in the wasting syndrome. To this end, we analyzed serum and liver samples stored from our previous studies in rats. In the first study, TCDD-sensitive Long-Evans (Turku/AB; L-E) and TCDD-resistant Han/Wistar (Kuopio; H/W) rats were exposed to 100 or 50 µg/kg TCDD (both ultimately lethal to all L-E but non-lethal to H/W rats), while food-restricted control (FRC) L-E rats were fed according to the food consumption of the TCDD-treated L-E rats. Serum GDF15 concentration was similarly elevated in both strains from day 1 on over the entire 10-day observation period, while it remained unaffected in FRC rats. Liver Gfd15 mRNA abundance increased in TCDD-exposed L-E rats alone. In the second study, other AHR agonists (β-naphthoflavone and IMA-08401) were tested in TCDD-sensitive Sprague Dawley rats. They failed to augment Gdf15 expression. Additionally, TCDD did not affect Gdf15 gene expression in H4IIE rat hepatoma cells. Hepatic PGC-1α protein levels plummeted in TCDD-treated L-E rats by 10 days, but this was not reflected in Pgc1a gene expression, in which FRC rats exhibited a prominent rise. We conclude that GDF15 does not appear to be causally related to the wasting syndrome, whereas the drastic decrease in hepatic PGC-1α protein may have importance in its mechanism.