Assessing anti-estrogenic effects of AHR ligands in primary human and rat endometrial epithelial cells.

Published on Jul 12, 2020in Reproductive Toxicology3.143
· DOI :10.1016/J.REPROTOX.2020.07.003
A.D. van den Brand2
Estimated H-index: 2
(UU: Utrecht University),
E. Rubinstein2
Estimated H-index: 2
+ 2 AuthorsMbm van Duursen1
Estimated H-index: 1
(VU: VU University Amsterdam)
Abstract Unopposed estrogenic action in the uterus can lead to the development of endometrial cancer in both humans and rats. Aryl hydrocarbon receptor (AHR) activation gives rise to anti-estrogenic actions and may consequently reduce the development of endometrial cancer. In this study, the anti-estrogenic potential of the AHR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and DELAQ, a metabolite of the pharmaceutical laquinimod, was assessed in in primary human and rat endometrial epithelial cells (EECs) with and without co-exposure to endogenous hormones. In human EECs, estradiol and progesterone did not affect AHR gene expression, but in rat EECs, progesterone decreased Ahr expression (1.4-fold). In accordance, AHR-mediated induction of Cyp1a1/1b1 expression by DELAQ and TCDD decreased in hormone-treated rat EECs. DELAQ was 22-fold more potent than TCDD in human EECs in inducing CYP1A1/1B1 gene expression, while DELAQ was approximately 16-33-fold less potent than TCDD in rat EECs. In human EECs, 10 nM DELAQ decreased estradiol-induced expression of growth-regulated estrogen receptor binding 1 (GREB1) by 1.8-fold. In rat EECs, both DELAQ and TCDD did not affect the expression of estradiol-induced genes. This study shows that AHR ligand DELAQ, but not TCDD, causes anti-estrogenic effects in primary human EECs. Furthermore, although AHR-mediated CYP1A1/1B1/Cyp1a1/1b1 induction by DELAQ and TCDD was stronger in rat EECs than human EECs, this did not result in apparent anti-estrogenic effects in the rat cells. This study shows that primary human and rat endometrial cells respond differently towards hormones and AHR ligands. This should be considered in human risk assessment based on rodent studies.
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