Primary endometrial 3D co-cultures: A comparison between human and rat endometrium

• Published in: The Journal of steroid biochemistry and molecular biology Vol. 194; p. 105458
• Main Authors: van den Brand, A.D., Rubinstein, E., de Jong, P.C., van den Berg, M., van Duursen, M.B.M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-11-2019; Elsevier BV
• Subjects: AhR gene; Animal models; Animals; Aromatase - metabolism; Aryl hydrocarbon receptor; Cell culture; Cell Line, Tumor; Cells, Cultured; Coculture Techniques; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P450; Cytochrome P450 1A1; Dioxins; Endometrium; Endometrium - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Estrogen Receptor alpha - genetics; Female; Gene expression; Hormone receptors; Hormones; Humans; Ligands; Metabolites; Polychlorinated Dibenzodioxins - pharmacology; Progesterone; Quinolones - pharmacology; Rats, Sprague-Dawley; Receptors, Aryl Hydrocarbon - genetics; Risk assessment; Stromal Cells - drug effects; Stromal Cells - metabolism; TCDD; Cytochrome P450 1A1; Aryl hydrocarbon receptor; Hormone receptors; Endometrium
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2019.105458

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•Primary human and rat endometrial cells retain their hormone responsiveness in vitro.•Only in rat endometrial cells, AHR gene expression was downregulated by hormones.•The potency of AHR ligands differs between human and rat endometrial cells.•Rat endometrial effects might not be representative for human endometrial effects.
Human and rat reproductive systems differ significantly with respect to hormonal cyclicity and endometrial cell behavior. However, species-differences in endometrial cell responses upon hormonal stimulation and exposure to potentially toxic compounds are poorly characterized. In this study, human and rat endometrial hormonal responses were assessed in vitro using a 3D co-culture model of primary human and rat endometrial cells. The models were exposed to the aryl hydrocarbon receptor (AHR) ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), laquinimod, and its AHR active metabolite DELAQ.
In both the human and rat endometrial models, estrogen receptor and progesterone receptor gene expression was modulated by the hormonal treatments, comparable to the in vivo situation. AHR gene expression in the human endometrial model did not change when exposed to hormones. In contrast, AHR expression decreased 2-fold in the rat model when exposed to predominantly progesterone, which resulted in a 2.8-fold attenuation of gene expression induction of cytochrome P450 1A1 (CYP1A1) by TCDD. TCDD and DELAQ, but not laquinimod, concentration-dependently induced CYP1A1 gene expression in both human and rat endometrial models. Interestingly, the relative degree of DELAQ to induce CYP1A1 was higher than that of TCDD in the human model, while it was lower in the rat model.
These data clearly show species-differences in response to hormones and AHR ligands between human and rat endometrial cells in vitro, which might greatly affect the applicability of the rat as translational model for human endometrial effects. This warrants further development of human relevant, endometrium-specific test methods for risk assessment purposes.