Effects of chronic particulate matter exposure on endometriosis-associated signaling pathways and disease progression.

Abstract

Exposure to PM2.5 (particulate matter <2.5 μm) has been implicated in increasing the risk of endometriosis and worsening its symptoms. However, the molecular mechanisms and direct associations remain unclear. This study explored whether PM2.5 contributes to the onset or progression of endometriosis using in vitro and in vivo models. Endometrial (EM) cells from women without endometriosis were cultured to the second passages (P2) with or without exposure to PM2.5 at a concentration of 200 µg/ml (N = 5 for each group). Z-stack confocal imaging confirmed PM accumulation in the nucleus and cytoplasm of exposed EM cells. Initial PM exposure at the primary passage (P0) led to decreased proliferation, migration, anti-apoptosis, and oxidative stress, accompanied by downregulation of associated pathways. However, repeated PM exposure during subculturing to P2 led to increased proliferation, enhanced anti-apoptotic activity, and elevated oxidative stress. Given the similarity of these gene expression alterations to those observed in endometriosis, an endometriosis-induced mouse model was established to assess the potential of repeated PM exposure to exacerbate the condition in vivo. To investigate the in vivo effects, an endometriosis-induced mouse model was developed using female C57BL/6 mice exposed to low (10 mg/kg/day) or high (20 mg/kg/day) doses of PM2.5 for 4 weeks (n = 6 for each group). PM exposure significantly enlarged endometriotic lesions compared to controls (no PM exposure). Upregulated gene expression in endometriotic lesions included anti-apoptotic (Bcl2/Bax), proliferative (p-ERK), inflammatory (p-NF-κB, p-c-jun, IL-6, IL-1β), and migration (MMP-2, MMP-9) markers. PM exposure altered estrogen receptor (ER) expression, resulting in a decreased ERα/ERβ ratio in both dose groups. The control group exhibited a ratio of 1.03 ± 0.09, while the low-dose and high-dose mice had ratios of 0.57 ± 0.08 (P = 0.02) and 0.46 ± 0.26 (P = 0.03), respectively. In conclusion, PM2.5 exposure alters gene expression related to cell growth, survival, oxidative stress, and migration in EM cells and exacerbates endometriotic lesions in vivo, likely through ER modulation. These findings suggest PM2.5 may contribute to other estrogen-dependent conditions, such as leiomyoma or adenomyosis, by influencing ER pathways.