Induction of aryl hydrocarbon receptor in granulosa cells by endoplasmic reticulum stress contributes to pathology of polycystic ovary syndrome

Abstract

Recent studies have uncovered the critical role of aryl hydrocarbon receptor (AHR) in various diseases, including obesity and cancer progression, independent of its previously identified role as a receptor for endocrine-disrupting chemicals (EDCs). We previously demonstrated that endoplasmic reticulum (ER) stress, a newly recognized local factor in the follicular microenvironment, is activated in granulosa cells from patients with polycystic ovary syndrome (PCOS) and a mouse model of the disease. By affecting diverse functions of granulosa cells, ER stress contributes to PCOS pathology. We hypothesized that expression of AHR and activation of its downstream signaling were upregulated by ER stress in granulosa cells, irrespective of the presence of EDCs, thereby promoting PCOS pathogenesis. In this study, we found that AHR, AHR nuclear translocator (ARNT), and AHR target gene cytochrome P450 1B1 (CYP1B1) were upregulated in the granulosa cells of PCOS patients and model mice. We examined CYP1B1 as a representative AHR target gene. AHR and ARNT were upregulated by ER stress in human granulosa-lutein cells (GLCs), resulting in an increase in the expression and activity of CYP1B1. Administration of the AHR antagonist CH223191 to PCOS mice restored estrous cycling and decreased the number of atretic antral follicles, concomitant with downregulation of AHR and CYP1B1 in granulosa cells. Taken together, our findings indicate that AHR activated by ER stress in the follicular microenvironment contributes to PCOS pathology, and that AHR represents a novel therapeutic target for PCOS.

Pharmacological blockage of the AHR-CYP1A1 axis: a call for in vivo evidence

“…Using a murine model of PCOS induced by dehydroepiandrosterone (DHEA), they observed no cyclicity in the estrous cycle and alteration in ovarian morphology. CH-223191 (10 mg/kg) subcutaneous administration restored the loss of cyclicity and ovarian morphology with a decrease in atretic antral follicles, which occurred simultaneously with a downregulation in the AHR-CYP1B1 axis in the granulosa cells [83].…”

Temporal relationship between alterations in the gut microbiome and the development of polycystic ovary syndrome‐like phenotypes in prenatally androgenized female mice

“…Ovarian sections were analyzed by two investigators using an Olympus BX50 Fluorescence Microscope (Olympus, Tokyo, Japan). The number of atretic antral follicles and corpora lutea were counted in every sixth section across the entire ovary, as previously described 29 . Atretic follicles were recognized by the presence of an attenuated granulosa cell layer, shrinkage, and degenerate oocyte nuclei 30 .…”

“…The number of atretic antral follicles and corpora lutea were counted in every sixth section across the entire ovary, as previously described. 29 Atretic follicles were recognized by the presence of an attenuated granulosa cell layer, shrinkage, and degenerate oocyte nuclei. 30 For adipose tissue, two representative micrographs were taken per sample at a 40× magnification using a light microscope (Olympus BX50 Fluorescence Microscope; Olympus).…”

Investigation of the Mechanism of Zishen Yutai Pills on Polycystic Ovary Syndrome: A Network Pharmacology and Molecular Docking Approach

“…Luteolin and emodin can improve the environment of high insulin levels by promoting PI3K/AKT pathway [ 50 , 51 ] and thus upregulating CYP1B1 gene expression, which is a potential target gene of ZSYTP and PCOS, and CYP1B1 is involved in steroid and lipogenesis and metabolism [ 52 ] and also relates to improving the aromatase activity of ovarian granulosa cells in an environment of high insulin levels, which enhanced expression of FSH receptors and increased estrogen produciton. The sensitivity of granulosa cells to FSH was increased, thereby improving follicular dysgenesis [ 53 ], which in turn reduces the number of atretic follicles and restores the motility cycle.…”

“…e sensitivity of granulosa cells to FSH was increased, thereby improving follicular dysgenesis [53], which in turn reduces the number of atretic follicles and restores the motility cycle.…”