Distribution of mRNAs encoding the arylhydrocarbon receptor, arylhydrocarbon receptor nuclear translocator, and arylhydrocarbon receptor nuclear translocator-2 in the rat brain and brainstem

Abstract

Dioxin exposure alters a variety of neural functions, most likely through activation of the arylhydrocarbon receptor (AhR) pathway. Many of the adverse effects, including disruption of circadian changes in hormone release and depressed appetite, seem to be mediated by hypothalamic and/or brainstem neurons. However, it is unclear whether these effects are direct or indirect, because there have been no comprehensive studies mapping the expression of components of the AhR pathway in the brain. Therefore, we used a sensitive in situ hybridization histochemical (ISHH) method to map the neural expression of AhR mRNA, as well as those of the mRNAs encoding the AhR dimerization partners, arylhydrocarbon receptor nuclear translocator (ARNT) and ARNT2. We found that AhR, ARNT, and ARNT2 mRNAs were widely distributed throughout the brain and brainstem. There was no neuroanatomic evidence that AhR is preferentially colocalized with ARNT or ARNT2. However, ARNT2, unlike ARNT expression, was relatively high in most regions. The most noteworthy regions in which we found AhR, ARNT, and ARNT2 mRNA were several hypothalamic and brainstem regions involved in the regulation of appetite and circadian rhythms, functions that are disrupted by dioxin exposure. These regions included the arcuate nucleus (Arc), ventromedial hypothalamus (VMH), paraventricular nucleus (PVN), suprachiasmatic nucleus (SCN), nucleus of the solitary tract (NTS), and the dorsal and median raphe nuclei. This neuroanatomic information provides important clues as to the sites and mechanisms underlying the previously unexplained effects of dioxins in the central nervous system.

Cytochrome P450–mediated drug metabolism in the brain

“…For example, CAR and PXR are expressed highly in the liver, but at low levels in the brain, whereas PPARβ and δ, RXRβ and AhR may be expressed more highly in the brain than in the liver. 153,154 The expression of these nuclear receptors also varies among brain regions. For example, CAR was detectable only in the human caudate nucleus; 155 PXR was expressed at highest levels in the human thalamus, pons and medulla; 156 PPAR and RXR were expressed highly in the rat brainstem but at low levels in the substantia nigra; 157 and AhR was expressed highly in the rat olfactory cortex but at low levels in the amygdala.…”

Perinatal exposure of female rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin induces central precocious puberty in the offspring

“…Because the aryl hydrocarbon receptor (AhR) is ubiquitously distributed in various brain regions including the hypothalamus (Petersen et al 2000), and TCDD enters and distributes in the brain tissue from the blood circulation (Kakeyama et al 2003), it is reasonable to speculate that TCDD affects the GnRH surge-generating mechanism and elicits its toxicity by activating the AhR pathway. Other studies showed that TCDD distributed at the CNS exerts neurotoxicological effects: a high TCDD dose (10 mg/kg) administered to rats was shown to reduce LH secretion and the number of ova at ovulation (Petroff et al 2001).…”

Molecular interactions of the aryl hydrocarbon receptor and its biological and toxicological relevance for reproduction

“…Members of the AhR signaling pathway are expressed in the preoptic area of the brain (POA), a region known to control reproductive functions (Petersen et al 2000). The distribution pattern of AhR gene expression closely overlaps with that of glutamic acid decarboxylase (GAD) 67, the enzyme necessary for gamma-aminobutyric acid (GABA) synthesis.…”