Discussion

Female Wistar rats with delayed senescence of tyrosine hydroxylase (TH) neurons in the TIDA area of the hypothalamus, demonstrated using RNA scope ISH (mRNA) and IHC (protein expression), have been shown to have an increased incidence of uterine adenocarcinomas. Laser dissection targeted microarray analysis of the hypothalamus, pituitary and uterus revealed down-regulation of pituitary prolactin and hypothalamic GABA B receptors, with up regulation of uterine oestrogen receptor alpha (ESR1) - confirmed by immunostaining for ESR1 showed in the uterus. These results suggest that maintenance of prolactin control and prolongation of oestrus cycling are key targets in uterine carcinogenicity
In acute and subchronic dietary toxicity studies with gaba receptor antagonists in Wistar rats, adrenal cortical hypertrophy and decreased triglycerides have been shown to be excellent markers of compound potency. The observed hypertrophy is related to medullary catecholamine release. Using RNA scope (ISH), 4 (α3 and 5; and β1 and3) of the 9 gaba A receptor isoforms showed consistent positive staining in the rat adrenal medulla, suggesting that the selection of compounds which do not target these particular isoforms, might reduce the potential risk of phaeocytochromas in long term bioassays