In some mammals, halogenated
aromatic hydrocarbon (HAH) exposure causes
wasting syndrome, defined as significant
weight loss associated with lethal outcomes. The most potent HAH in causing wasting is 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (
TCDD), which exerts its toxic effects through the
aryl hydrocarbon receptor (AHR). Since
TCDD toxicity is thought to predominantly arise from dysregulation of AHR-transcribed genes, it was hypothesized that
wasting syndrome is a result of to
TCDD-induced dysregulation of genes involved in regulation of food-intake. As the hypothalamus is the central nervous systems' regulatory center for food-intake and energy balance. Therefore,
mRNA abundances in hypothalamic tissue from two rat strains with widely differing sensitivities to
TCDD-induced
wasting syndrome:
TCDD-sensitive Long-Evans rats and
TCDD-resistant Han/Wistar rats, 23h after exposure to
TCDD (100μg/kg) or
corn oil vehicle.
TCDD exposure caused minimal transcriptional dysregulation in the hypothalamus, with only 6 genes significantly altered in Long-Evans rats and 15 genes in Han/Wistar rats. Two of the most dysregulated genes were
Cyp1a1 and Nqo1, which are induced by
TCDD across a wide range of tissues and are considered sensitive markers of
TCDD exposure. The minimal response of the hypothalamic transcriptome to a lethal dose of
TCDD at an early time-point suggests that the hypothalamus is not the predominant site of initial events leading to hypophagia and associated wasting.
TCDD may affect feeding behaviour via events upstream or downstream of the hypothalamus, and further work is required to evaluate this at the level of individual hypothalamic nuclei and subregions.