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Published on: September 17, 2021
Oxidative stress mediated by the TLR4/NOX2 signalling axis is involved in polystyrene microplastic-induced uterine
1College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
Abstract:
Microplastics (MPs), as a new environmental pollutant, have received widespread attention worldwide. Uterine fibrosis is one of the main factors of female reproductive disorders. However, it is unclear whether the female reproductive disorders caused by MPs are related to uterine fibrosis. Therefore, in this study, we constructed female mouse models exposed to polystyrene microplastics (PS-MPs). We found that PS-MP exposure resulted in endometrial thinning and severe collagen fibre deposition in female mice. Further mechanistic studies found that PS-MP exposure increased the expression of high mobility group Box 1 (HMGB1) and acetyl-HMGB1, further activating the Toll-like receptor 4/NADPH oxidase 2 (TLR4/NOX2) signalling axis and eventually causing oxidative stress. Afterwards, oxidative stress elicited the activation of Notch and the transforming growth factor β (TGF-β) signalling pathway, leading to increased levels of fibrotic proteins and collagen. Correspondingly, PS-MP treatment upregulated the expression of TLR4 and NOX2 and the level of reactive oxygen species (ROS) and increased the levels of fibrotic protein and collagen in mouse endometrial epithelial cells cultured in vitro. Conversely, inhibition of the TLR4/NOX2 signalling pathway effectively reduced the level of ROS in cells, weakened the upregulation of Notch and TGF-β signalling by PS-MPs, and efficiently reduced the expression of fibrotic and collagen genes. In summary, we demonstrated a new mechanism by which MPs induce uterine fibrosis in mice, that is, by inducing oxidative stress to activate the Notch and TGF-β signalling pathways by triggering the TLR4/NOX2 signalling axis. Targeting TLR4/NOX2 signalling may consequently prove to be an innovative therapeutic option that is effective in alleviating the reproductive toxicity of PS-MPs. Our study sheds new light on the reproductive toxicity of MPs and provides suggestions and references for comparative medicine and clinical medicine.
Insights
Polystyrene microplastics (PS-MPs) exposure causes uterine fibrosis in female mice by inducing oxidative stress via the Toll-like receptor 4/NADPH oxidase 2 (TLR4/NOX2) pathway. Targeting this pathway may mitigate reproductive toxicity from microplastic exposure.
Area of Science:
- Environmental Science
- Toxicology
- Reproductive Biology
Background:
- Microplastics (MPs) are emerging environmental pollutants with widespread global concern.
- Uterine fibrosis is a significant contributor to female reproductive disorders.
- The link between microplastic exposure and uterine fibrosis remains largely unexplored.
Purpose of the Study:
- To investigate the potential role of microplastics in inducing uterine fibrosis.
- To elucidate the underlying molecular mechanisms linking microplastic exposure to uterine fibrosis.
- To explore potential therapeutic targets for mitigating microplastic-induced reproductive toxicity.
Main Methods:
- Construction of female mouse models exposed to polystyrene microplastics (PS-MPs).
- Analysis of endometrial tissue for fibrosis markers and collagen deposition.
- Investigation of molecular pathways including HMGB1, TLR4/NOX2, Notch, and TGF-β signaling.
- In vitro studies using mouse endometrial epithelial cells exposed to PS-MPs.
Main Results:
- PS-MP exposure led to endometrial thinning and significant collagen deposition in mice.
- PS-MPs activated the TLR4/NOX2 signaling axis, increasing oxidative stress (ROS).
- Oxidative stress subsequently activated Notch and TGF-β pathways, promoting fibrosis.
- Inhibition of TLR4/NOX2 signaling ameliorated PS-MP-induced fibrosis and oxidative stress in vitro.
Conclusions:
- Microplastic exposure induces uterine fibrosis through oxidative stress mediated by the TLR4/NOX2 signaling axis.
- Activation of Notch and TGF-β pathways is a key downstream event in microplastic-induced fibrosis.
- Targeting the TLR4/NOX2 pathway presents a potential therapeutic strategy against microplastic reproductive toxicity.
