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. 2024 Mar 19;10(6):e28121.
doi: 10.1016/j.heliyon.2024.e28121. eCollection 2024 Mar 30.

Sex differences in inflammation correlated with estrogen and estrogen receptor-β levels in azoxymethane/dextran sodium sulfate-induced colitis-associated colorectal cancer mice

Seoyoung Jang  1 , Hyejin Han  1   2 , Yeonsoo Oh  1   2 , Yuri Kim  1   2
Affiliations

Sex differences in inflammation correlated with estrogen and estrogen receptor-β levels in azoxymethane/dextran sodium sulfate-induced colitis-associated colorectal cancer mice

Seoyoung Jang et al. Heliyon. .

Abstract

Colorectal cancer (CRC) is a type of cancer that develops in the colon or rectum and is the second leading cause of cancer-related death worldwide. Several epidemiology studies have identified a significant sexual dimorphism in CRC, with women exhibiting a lower incidence rate and delayed onset compared to men. This study aims to investigate the sexual dimorphism in the inflammatory response in colitis-associated CRC and its relationship with estrogen and estrogen receptors. An azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model was used to induce colitis-associated CRC. Five-week-old male and female mice were randomly assigned into either the control group or the AOM/DSS CRC group, with 10 mice in each group. Colitis-associated CRC was induced by injecting AOM (10 mg/kg) and administering two-cycles of DSS treatment in the drinking water. The results revealed a significant decrease in colon length exclusively in the female group, indicating more severe colonic inflammation (P < 0.01). A significant interaction was identified between sex and AOM/DSS treatment in the female AOM/DSS group, with higher visceral fat weight compared to their male counterparts (P < 0.05). The female AOM/DSS group also exhibited elevated production of M1 macrophage-related pro-inflammatory cytokines, suggesting increased tumor-associated macrophage activity. Surprisingly, the male AOM/DSS group showed a marked increase in serum estradiol levels, while the female AOM/DSS group exhibited a decrease compared to the normal control group. Additionally, a notable upregulation of both estrogen receptor α and estrogen receptor β expression was observed in the colon tissues of the AOM/DSS groups compared to the normal control groups, with estrogen receptor β expression being particularly pronounced in females. Taken together, our findings suggest that a decline in endogenous estrogen and increased estrogen receptors potentially contribute to the pro-inflammatory response in early CRC by augmenting cytokine expressions associated with M1 macrophage polarization in females.

Keywords: Colitis; Colorectal cancer; Estrogen; Estrogen receptor; Macrophage; Sexual dimorphism.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Sex differences in DAI score, fat composition, and the colon length in colitis-associated CRC cancer mice model. (A) Changes of DAI scores, (B) Subcutaneous fat weight, (C) Visceral fat weight (sum of mesenteric, perirenal, and gonadal adipose tissues), and (D) Length of colon, and (E) Concentration of serum TNF-α were analyzed. Each set of data was presented as the means ± SEM. *Bonferroni correction for multiple comparisons following two-way ANOVA. *P < 0.05 and **P < 0.01. CRC, colorectal cancer; DAI, disease activity index.
Fig. 2
Fig. 2
Expression of M1 and M2 macrophage polarization markers in whole colon tissue of colitis-associated CRC cancer mice model. (A) mRNA expressions of (a) Ifn-γ and markers, (b) Tnf-α, (c) Il-6, and (d) Il-12 and (B) The mRNA expressions of (a) Il-4, (b) Arg1, and (c) Cd206 were analyzed by RT-qPCR. Tbp expression served as loading control. Each set of data was presented as the means ± SEM. *Bonferroni correction for multiple comparisons following two-way ANOVA. *P < 0.05, **P < 0.01 and ***P < 0.001. CRC, colorectal cancer.
Fig. 3
Fig. 3
Serum levels of 17β estradiol and expression of ER-α and ER-β in colon tissue of colitis-associated CRC mice. (A) Serum 17β estradiol levels were assessed by ELISA. (B) The mRNA expression of (a) Esr1 and (b) Esr2 was confirmed by RT-qPCR. Tbp expression was served as loading control. (C) Representative blots were shown and (a) ER-α and (b) ER-β expression levels were quantified. GAPDH was used as loading control. Full images of uncropped for (C) are provided in Supplementary Fig. 3C(a) and Supplementary Fig. 3C(b). Each value was presented as the means ± SEM. * Bonferroni correction for multiple comparisons following two-way ANOVA. *P < 0.05, **P < 0.01, ***P < 0.001. CRC, colorectal cancer.
Fig. 4
Fig. 4
Correlation between colon length and ER expression in colitis-associated CRC mice. Correlation of colon length and (A) Esr1 mRNA expression, (B) ER-α protein expression, (C) Esr2 mRNA expression, and (D) ER-β protein expression. (a) whole, (b) male, and (c) female mice. Pearson's correlation coefficient was used for the statistical analyses. The solid line represents the linear function for each mouse and correlation of whole, male, or female mice are shown respectively. P < 0.05 was considered statistically significant. The 95% confidence intervals for each correlation analysis were derived as follows. (A) (a) [-0.5975 to −0.04479], (b) [-0.7413 to −0.002578], (c) [-0.6557 to 0.1639]. (B) (a) [-0.6526 to −0.1345], (b) [-0.7522 to −0.02738], (c) [-0.7254 to 0.03186]. (C) (a) [-0.6015 to −0.05107], (b) [-0.6737 to 0.1324], (c) [-0.7030 to 0.07741]. (D) (a) [-0.6376 to −0.1093], (b) [-0.6522 to 0.1700], (c) [-0.7623 to −0.05082]. CRC, colorectal cancer.
None
Uncropped scans of the Western blots presented in Fig. 3C(a). The first blot of each row is the representative blot shown in the figure. The red boxes mark the borders of the detected band of each antibody. The molecular weight markers are shown on the blots. No 1, 2: Normal control male, No 3, 4: Normal control female, No. 5, 6: AOM/DSS male, 7, 8: AOM/DSS female.
None
Uncropped scans of the Western blots presented in Fig. 3C(b). The first blot of each row is the representative blot shown in the figure. The red arrows and boxes mark the borders of the detected band of each antibody. The molecular weight markers are shown on the blots. No 1, 2: Normal control male, No 3, 4: Normal control female, No. 5, 6: AOM/DSS male, 7, 8: AOM/DSS female.
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