Chronic Exposure Of Mice To Propylparaben Reduces Progesterone Receptor Signaling And Promotes Fibrosis In The Uterus

Pranav Volety¹, Athilakshmi Kannan¹, Jie Li¹, Milan K. Bagchi², Ayelet Ziv-Gal¹, and Indrani C. Bagchi¹

Departments of Comparative Biosciences¹, Molecular & Integrative Physiology², University of Illinois at Urbana-Champaign, Urbana, IL


Abstract Text:

Parabens are a class of widely used synthetic preservatives. Their ability to prevent microbial growth and extend product shelf life lends to their widespread usage, particularly in cosmetics and personal care products. Among them, propylparaben (PP) is one of the most common, often included in formulations to prevent the growth of harmful bacteria and fungi. Studies have shown that women tend to have higher levels of paraben exposure compared to men, likely due to greater use of these paraben containing products. Studies have suggested a potential link between parabens and reproductive problems due to their ability to mimic the steroid hormone estrogen and overall endocrine disrupting properties. However, the impact of chronic exposure to PP on the uterus remains unknown. Thus, we conducted studies in which adult female CD-1 mice were exposed for 6 months to either corn oil (vehicle control) or human relevant doses of PP (2, 20, and 200 µg/kg/day). Histological analyses by H&E staining of the uterine sections did not show any gross morphological alterations upon exposure to PP. However, further investigation employing RNA sequencing indicated the downregulation of several progesterone-regulated genes, such as SRY-Box Transcription Factor 17 (Sox17), Heart And Neural Crest Derivatives Expressed 2 (Hand2), Insulin-like Growth Factor Binding Protein 4 (Igfbp4), Bone Morphogenetic Protein 2 (Bmp2), CCAAT/Enhancer-Binding Protein Beta (Cebpb), Colony Stimulating Factor 1 (Csf1), and Decorin (Dcn) in the uteri of mice exposed to 2µg/kg/day of PP. Notably, some of these genes are implicated in extracellular matrix remodeling and tissue fibrosis. Consistent with this observation, the uteri from PP-exposed females exhibited an upregulation of fibrotic markers, including Collagen Type I Alpha 1 (Col1a1) and Collagen Type III Alpha 1 (Col3a1), and elevated Picrosirius Red staining of collagen fibers, commonly used to assess fibrosis and changes in the extracellular matrix. Since chronic inflammation, particularly involving macrophages, plays a central role in driving tissue fibrosis, we next determined the presence of macrophages in PP-exposed and unexposed uterine samples by immunostaining with F4/80 antibody, a well-established macrophage marker. Our studies revealed a significant increase in the population of macrophages in the uteri of mice exposed to PP, indicating heightened inflammation in response to this chemical. Collectively, our results demonstrate that chronic paraben exposure disrupts progesterone receptor signaling, induces a pro-inflammatory milieu, and promotes fibrotic remodeling of the uterine tissue. These findings may have significant implications for reproductive health, particularly for individuals with long-term exposure to parabens through the use of personal care products.