Resveratrol Administration Reverses the Endometriosis-Mediated Outcomes via Tgfβ Signaling in Rats

Introduction Endometriosis (END) is a persistent, estrogen-dependent inflammatory disorder distinguished by the growth of endometrial-like tissue exterior to the uterine cavity, which comprises active endometrial glands and stroma, leading to chronic pelvic discomfort, dysmenorrhea, and infertility ; . END affects around 10% of women of reproductive age . It has been thoroughly examined in experimental animal models, specifically in rats and mice. Rats are often employed in research due to their larger size compared to mice, which simplifies surgical procedures . Moreover, nonhuman primates, such as baboons, are employed because of their analogous reproductive physiology; although ethical and financial constraints limit their utilization ; . Lesions can be induced by injecting minced endometrial tissue into the peritoneal cavity, closely resembling how lesions form and progress in humans ; . Consequently, animal models provide substantial understanding of the etiology and treatment of endometriosis. Molecular pathophysiology of endometriosis could be initiated through various molecules, for example: Transforming growth factor (TGF-β) is a versatile cytokine from the transforming growth factor superfamily, with three different mammalian isoforms: TGF-β1, TGF-β2, and TGF-β3. All normal cells contain TGF-β and its receptors, which can be synthesized by both normal and malignant cells . Elevated levels of TGF-β, particularly TGF-β1, have regularly been observed in the peritoneal fluid and endometrial tissue of individuals with endometriosis, promoting the development of the disease. It modulates immunological responses by inhibiting natural killer (NK) cell activity, hence compromising the immune system’s ability to eliminate ectopic endometrial cells, facilitating angiogenesis, survival, and implantation of these cells outside the uterine cavity ; ; . Cancer antigen-125 (CA-125) is a high molecular weight glycoprotein classified within the mucin family. It is mostly expressed on the surface of epithelial cells across several tissues, including the female reproductive, respiratory, and gastrointestinal systems. It is produced by normal cells in adult tissues originating from coelomic and Müllerian epithelia . It is a recognized tumor-associated antigen that serves as a biomarker in clinical contexts, particularly for the diagnosis and monitoring of ovarian cancer or other benign illnesses ; . Elevated CA-125 levels are observed in individuals with endometriosis, reflecting the inflammatory state and extent of pelvic lesion involvement ; ; . Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor present in various tissues that regulates gene expression in response to a broad spectrum of exogenous or endogenous ligands. It plays a crucial role in regulating immune responses, cellular differentiation, and maintaining physiological homeostasis ; ; . The nature of the ligand is critical, as it determines whether AhR activation promotes detoxification and homeostasis or induces toxicological effects ; ; Alghetaa, 2025). Toxic ligands, such as organochlorine insecticides commonly used in vector control, can provoke dysregulated AhR signaling associated with endocrine disruption, immune dysfunction, neurotoxicity, oxidative stress, and even carcinogenesis ; ; ; ; , b; . In contrast, certain natural ligands such as resveratrol, quercetin, tryptophan-derived metabolites, curcumin, and indole-3-carbinol induce protective responses and are vital for xenobiotic detoxification ; , b; ; ; ; . In the context of endometriosis, AhR interfaces with several signaling pathways, including hormonal and inflammatory cascades, thereby influencing disease pathophysiology ; ; . Modulating AhR activity through agonist or antagonist molecules may influence key mechanisms underlying disease progression, including inflammation, immune dysregulation, abnormal cell proliferation, and oxidative damage ; ; ; ; . To date, there is no definitive cure for endometriosis; current therapeutic strategies focus primarily on alleviating symptoms and/or its related infertility ; . Resveratrol (3, 5, 4’-trihydroxystilbene) (RES) is a naturally occurring polyphenolic compound belonging to the stilbene family. It is present in diverse dietary sources, including grapes, red wine, peanuts, berries, and particularly in medicinal herbs. RES has garnered considerable interest due to its wide range of biological functions and potential therapeutic applications ; ; ; ; . In the context of END, resveratrol offers a multifaceted therapeutic approach in dose-dependent fashion by attenuating inflammation, oxidative stress, cellular proliferation, and angiogenesis, while simultaneously enhancing apoptosis and modulating estrogenic activity ; , 2023a, b; ; ; ; . Accordingly, this study aimed to explore the effects of resveratrol and AhR antagonists on inflammatory markers and reproductive outcomes in a rat model of endometriosis.

Experimental animals This study has been conducted in the laboratory and animal house of the College of Veterinary Medicine University of Baghdad. Eighty-four adult female rats along with 10 adult male rats (Rattus norvegicus) both sexes were 8-10 weeks old and weighed about 180-220g at the start point of the experiments. All animals were housed in specific pathogen-free conditions, including a temperature-controlled environment (22±2ºC) and a 12-hour light/dark cycle. The animals have been provided with free access to standard food and water. The experimental design adhered to the ethical guidelines established by the Institutional Animal Care and Use Committee at the College of Veterinary Medicine, University of Baghdad, and received animal ethical approval (AUP# P.G.407), which complies with International Standards for the Care and Use of Laboratory Animals. The animals were randomly divided into the following groups: Naïve group (n=12 rats), donors for endometrial tissue transplantation (n=24 rats), recipients (n=48 rats) endometriotic rats and additional fertility-confirmed male rats (n=10) which were employed for fertility tests. Before any experiment performance, all rats were maintained for a two-week acclimatization period. Induction of experimental endometriosis Endometriosis (END) was induced using the methodology outlined by ; ; , with minor modifications (Figure 1). After a period of acclimation, donor rats received two subcutaneous injections of 0.6 mg/kg estradiol benzoate (E2) with a three-day interval to promote the growth and proliferation of endometrial tissue . On the following day of last E2 treatment, the donor rats were anesthetized by intraperitoneal injection of a ketamine-xylazine mixture , then euthanized by cervical dislocation after the toe-pinch reflex confirmation test was applied. Euthanized donor rats undergo a midline laparotomy to expose and excise the uterine horns, which are subsequently placed in a sterile petri dish containing warm phosphate buffered saline (PBS). The horns were longitudinally incised with fine scissors, and the endometrial layer was gently peeled using fine forceps. The collected layer was subsequently immersed in sterile PBS and chopped into small fragments (about 1 mm2) with a fine scalpel, after which about 50mg of the endometrial tissue fragments were suspended in sterile PBS before being delivered into the peritoneal cavity of recipient rats as demonstrated in Figure 1 . One donor rat was utilized for every two recipient rats to induce endometriosis in all endometriotic groups. All rats having endometrial transplants were treated with different compounds (AhR agonist and antagonist) in accordance with the experimental design, which will be discussed later, commencing the day following transplantation. However, Naïve rats received only an intraperitoneal injection of 500µL PBS. Animals grouping - Naïve group: non-endometriotic rats (n=12) served as a negative control group. - Endometriotic groups: endometriosis-induced rats (n=48) were divided into four subgroups, as follows: - END group: These endometriotic rats received no treatments and served as positive control. - END+RES group: Endometriotic rats received a daily oral dose of RES at 100mg/kg for four weeks . - END+AhR‾ group: Endometriotic rats received intraperitoneal injections of CH223191 at a dosage of 10mg/kg in a volume of 0.1ml/100g every three days for four weeks. - END+DMSO group: Endometriotic rats received dimethyl sulfoxide (DMSO) as the vehicle for the AhR antagonist intraperitoneally at a volume of 0.1 ml/100g b.w., the equivalent volume and concentration that was used for preparation of AhR treatment with three-day intervals for four weeks to normalize any biological effects it may cause ; ; . Table 1: Transforming growth factor-beta (Tgfβ), and glyceraldehyde-3-phosphate dehydrogenase (Gapdh) primers. | Gene | Forward '5-3' | Reverse '5-3' | NCBI accession No. | | Tgfβ | AGG GCT ACC ATG CCA ACT TC | CCA CGT AGT AGA CGA TGG GC | NM_017008.4 | | Gapdh | AGA GAC AGC CGC ATC TTC TT | ATG AAG GGG TCG TTG ATG GC | NM_021578.2 | Preparation of resveratrol (RES) and AhR antagonist, CH223191 (AhR‾) The current study utilized RES powder with a purity of ≥ 98% and AhR antagonist, CH223191 powder with a purity of ≥ 95%, both purchased from Hebei Guanlang Biotechnology, China. The powders were prepared by dissolving them in DMSO and then diluting the solution with distilled water to achieve the appropriate working concentration ; ; ; . Litter size (pups/dam) index For fertility assessment, three females from each experimental group were mated with two fertile males for 7 days. Then the number of offspring per female was recorded ; . Euthanasia and sample collection At the end of the experiments, nine rats from each group were euthanized by an overdose of a xylazine-ketamine combination before collection of uterine horn for histopathological examination, blood for biochemical assessments, and peritoneal exudates for further downstream analysis. The spleen was collected as well for gene expression studies. Gene expression investigation Spleen tissue was harvested, and approximately 10mg tissue was cut and mechanically smashed and then placed in a tube containing 3ml of RNAlater solution, and then frozen at -20°C until processed to extract the total RNA and evaluate the gene expression of Tgfβ . Utilizing quantitative real-time PCR (qRT-PCR) with specific primers (Table 1) and Gapdh as the housekeeping gene. The levels of normalized gene expression were calculated using the ΔΔCt method. Biochemical tests Blood samples were collected via cardiac puncture and kept in gel tubes for serum separation for assessing circulatory levels of transforming growth factor-beta (TGF-β) and cancer antigen-125 (CA-125). Peritoneal exudate examination Peritoneal exudate (PE) was collected for evaluating the TGF-β and CA-125 biomarkers. Briefly, the abdominal skin of euthanized animals was removed to expose the peritoneal sac, then approximately ten ml of PBS was intraperitoneally injected, and the animal was thoroughly rolled for several minutes to suspend all the peritoneal exudates. A small surgical incision was made to allow the peritoneal suspension to be leaked out in a petri-dish prior to its transfer to a conical tube for the centrifugation process. Supernatants were isolated in new Eppendorf tubes to be frozen until the analysis of the aforementioned biomarkers . Enzyme linked immunosorbent analysis (ELISA) TGF-β (BT-lab kit, China) and CA-125 (BT-lab kit, China) were assessed in the serum and PE of experimental animals at the endpoint of all experiments according to each kit’s manufacturer protocol . Histopathological findings examination The left uterine horn was dissected and preserved in 10% neutral-buffered formalin for histopathological assessments . Statistical analysis Data were analyzed using GraphPad Prism software (Version 10, 2024; San Diego, CA, USA; https://www.graphpad.com). One-way analysis of variance (ANOVA), Tukey’s multiple comparisons test was employed to compare group means. Furthermore, to assess the equality of variances across the multiple groups in One-way ANOVA, Brown-Forsythe test was used as well. Whilst, to assess the equality of variances among different samples, Bartlett’s test has been employed too. QQ-plots were used to assess the normality of samples distribution. P-value less than 0.05 were considered statistically significant. Statistical significance in the figures is indicated as follows: *P<0.05, **P<0.01, ***P<0.001 and #P<0.0001. For further information about the statistical methodology, Supplementary Tables S1-S6 are available.

Litter size (pups/dam) The results of litter size (pups/dam) showed a significant decrease (P<0.05) in the END and END+DMSO groups in comparison with the Naïve, END+RES, and END+AhR‾ groups. No significant differences were observed among the Naïve, END+RES and END+AhR‾ groups, nor among the END, END+AhR‾, and END+DMSO groups, as illustrated in Figure 2. Expression of transforming growth factor-beta (Tgfβ) in splenocytes and translated protein in circulatory and peritoneal fluids The results of Tgfβ gene expression in splenocytes statistically showed a significant (P<0.05) increase in the END group in comparison to all other groups (Figure 3A). Figure 3B, C illustrate that the circulatory and peritoneal exudate concentration (ng/L) of TGF-β protein across the experimental groups was significantly (P<0.05) elevated in the END and END+DMSO groups in comparison with all other groups. Endometriotic rats treated with RES showed a reduction of circulatory and PE TGF-β levels to nearby Naïve group levels (Figure 3B, C). However, blocking of AhR in the END+AhR‾ group led to significant (P<0.05) upregulation of PE protein in comparison with the Naïve and END+RES groups (Figure 3C) but insignificant changes in circulatory TGF-β in the same compared groups (Figure 3B). Levels of cancer antigen-125 (CA-125) in serum and PE The statistical analysis of CA-125 concentrations (U/ml) in the circulation and peritoneal exudate of the experimental groups is illustrated in (Figure 4A, B). CA-125 showed significant (P<0.05) increases in the END, END+AhR‾, and END+DMSO groups in comparison with the Naïve and END+RES groups. However, neither significant distinctions were observed between the Naïve and END+RES groups nor among the END, END+AhR‾, and END+DMSO groups. Histopathological investigation of the uterine horn Histopathological examination of uterine horn cross-sections stained with hematoxylin and eosin (H and E) revealed notable pathological alterations in the END, END+AhR‾, and END+DMSO groups (Figures 6, 8, and 9, respectively), in contrast to the Naïve and END+RES groups (Figures 5 and 7, respectively). Observed hyperplasia of endometrial and stromal cells, vacuolar degeneration in several stromal regions, infiltration of inflammatory cells around endometrial glands, and neutrophil aggregation within endometrial glands. These findings are indicative of an inflammatory response and endometrial tissue remodeling, hallmark features of endometriosis in the employed experimental model.

Immune-inflammatory dysregulation and aberrant angiogenesis are implicated in the pathogenesis of endometriosis (END), contributing to both reproductive dysfunction and histopathological abnormalities across human and animal models ; ; ; . In our experimental END model, we observed significant impairments in reproductive performance, specifically a reduction in litter size, along with elevated levels of TGF-β and CA-125 in both serum and/or peritoneal exudate (PE), and distinct pathological changes in uterine horn histology. These findings support and extend previous studies reporting a negative correlation between elevated CA-125 and TGF-β levels and fertility in endometriosis patients ; . The observed reproductive dysfunctions in the END, END+AhR‾, and END+DMSO groups is likely a multifactorial outcome of chronic inflammation, oxidative stress, and hormonal imbalance, which are hallmarks of END that adversely affect ovulatory function, endometrial receptivity, and embryo implantation ; ; ; ; Leone Roberti Maggiore et al., 2024). TGF-β is one of the mediators that is involved, and it is particularly important for promoting immunosuppressive and fibrotic processes in the endometriotic environment. Increased TGF-β levels have repeatedly been associated with survival, invasion, and angiogenesis of ectopic lesions ; ; . In our investigation, the increase correlated with unfavorable histological characteristics, indicating a mechanistic association between TGF-β overexpression and tissue remodeling in the uterine horn. Furthermore, TGF-β, in synergy with IL-6, facilitates the differentiation of naïve CD4+ T cells into Th17 cells, hence enhancing IL-17 production, which is a significant factor in inflammatory amplification and lesion persistence ; ; . Our findings corroborate previous studies indicating increased IL-17 levels in endometriosis patients, which upregulate the expression of anti-apoptotic genes (e.g., Bcl-2, MCL1), suppress NK cell cytotoxicity, and activate ERK1/2 signaling, hence facilitating ectopic cell survival ; . TGF-β also activates the SMAD pathway and inhibits the tumor suppressor PTEN, thereby increasing EMT markers and adhesion molecules that facilitate lesion invasiveness and fibrogenesis ; ; . Conversely, inhibition of TGF-β and NF-κB signaling has been shown to reduce fibrosis and lesion burden in deep endometriosis, making these pathways possible targets for treatment . Although cancer antigen 125 (CA-125) exhibits limited sensitivity and specificity and is elevated in multiple disorders, it remains a recognized biomarker. When utilized alongside other diagnostic methods, it assists in differentiating individual with endometriosis from those without the condition ; ; . Our observation of elevated CA-125 in END-related groups, particularly those untreated with resveratrol, supports its continued relevance in preclinical evaluation of disease progression ; . Histological examination revealed marked abnormalities in the END, END+AhR‾, and END+DMSO groups, including vacuolar degeneration, irregular glandular architecture, and pronounced infiltration of inflammatory cells (especially eosinophils and monocytes). These findings reflect the oxidative stress and cytokine-driven inflammation associated with END ; . As well as the histological distortions that may be associated with elevated TGF-β levels, further implicating this cytokine in immune responses and fibrotic remodeling in the tissue of the uterine horn ; . Interestingly, this study showed that the used vehicle, DMSO has no distinct biological effects in endometriotic rats, this streamed with previous studies . The present study employed CH223191, a selective AhR antagonist (AhR⁻), and resveratrol (RES), a natural polyphenolic compound known to function as AhR agonist, to evaluate the effects of AhR modulation on key pathophysiological parameters associated with endometriosis. The utilization of AhR agonist or antagonist molecules influences several hallmarks of distinct diseases and modifies their progression ; . By disrupting and controlling several critical pathophysiological processes, including immunological responses, inflammation, xenobiotic metabolism, angiogenesis, cell survival, and proliferation ; ; ; . CH223191 binds to the AhR ligand-binding domain, competing with other ligands for AhR binding and also suppressing AhR signaling pathways ; , 2025). By contrast, some research suggests that RES has a high affinity to bind with AhR and compete with other ligands to regulate AhR signaling as well as modulate the effects of AhR activation and offer a protective mechanism against potential detrimental effects ; ; . RES exerted marked protective effects, including reductions in TGF-β and CA-125 levels, histological restoration of uterine horn, and improved reproductive outcomes. These findings are consistent with prior research demonstrating that the RES can inhibit TGF-β signaling to suppress the proliferation and migration of cancer cells . RES can decrease levels of IL-17 and interferon-gamma (IFN-γ) as well as suppress the angiogenesis-related genes such as VEGF and MMP-9, so obstructing the formation of new blood vessels and limiting the growth and proliferation of endometrial cells ; ; ; . Moreover, the efficacy of RES as an anti-inflammatory, anti-oxidative, anti-proliferative, anti-angiogenic, anti-invasive, anti-adhesive, and pro-apoptotic agent can inhibit disease progression and prevent dissemination of endometrial lesions , 2022; . Finally, our findings align with recent evidence indicating that AhR-targeted therapeutics, contingent upon ligand specificity and context, may either worsen or improve disease, highlighting the intricacy of this signaling pathway.

The findings of this study suggest that TGF-β signaling dysregulation implicated in the progression of endometriosis, as evidenced by increased Tgfβ gene expression and elevated inflammatory markers in END-induced rats. Additionally, the noted decrease in litter size among END and END+DMSO rats may indicate a considerable influence of systemic inflammation on reproductive outcomes. Resveratrol administration exhibited effectively reduced Tgfβ gene expression in splenocytes and lowered TGF-β and CA-125 levels in both serum and peritoneal fluid, underscoring its potential attenuated inflammatory, fibrotic, and angiogenic hallmarks of endometriosis. These results support the concept that focused modulation of AhR activity may be an effective method for controlling endometriosis, especially through agents that exhibit anti-inflammatory, anti-proliferative, and pro-apoptotic characteristics. Further investigations are necessary to clarify the molecular relationships between AhR and critical cytokine signaling pathways, as well as to examine the therapeutic applicability of AhR-targeted therapy. Furthermore, the integration of AhR modulators with existing or novel medications may produce synergistic effects that improve disease resolution and reproductive recovery in endometriosis. Acknowledgment Not applicable. Novelty Statement This research article provides deep insight into the mechanistic roles of resveratrol in modulation of endometriosis pathophysiology. Author’s Contribution HA design, conceptualization, review the draft and last version of this manuscript. AA wrote the draft, revised and wrote the last version of this manuscript. Both HA and AA have reviewed and approved the submitted version of the manuscript. Data availability The data is available from the corresponding author in reasonable request. Abbreviations AhR, Aryl Hydrocarbon Receptor; AhR‾, Aryl Hydrocarbon Receptor knocked down; Bcl-2, B-cell lymphoma 2; CA-125, cancer antigen-125; DMSO, dimethyl sulfoxide; EMT, epithelial-mesenchymal transition; END, Endometriosis; ERK 1/2, Extracellular Signal-Regulated Kinases 1/2; Gapdh, glyceraldehyde-3-phosphate dehydrogenase; IFN-γ, interferon-gamma; MCL1, myeloid cell leukemia-1; MCT, Monocarboxylate Transporters; MMP, matrix metalloproteinase; NF-kB, Nuclear Factor Kappa; NK, Natural Killer Cell; PE, Peritoneal exudate; RES, Resveratrol; VEGF, Vascular Endothelial Growth Factor. Generative AI and AI-assisted technology statement Authors disclose that they have not used any generative artificial intelligence or AI-assisted technology in forming this manuscript nor in generating its data. Conflict of interest The authors have declared no conflict of interest. Figures

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