Environmental exposure to glyphosate and depressive symptoms: inflammatory mediation by TNF-α in a community-based study

Background: Environmental exposure to herbicides has received increasing attention as a possible contributor to mental health risk. Glyphosate, the most widely used herbicide worldwide, has been linked to immune activation and neuroinflammatory processes, yet its relationship with depressive symptoms in humans remains poorly understood. This study investigated the relationship between glyphosate exposure, inflammatory biomarkers, and depression, with a focus on systemic inflammatory pathways, including TNF-α, IL-1β, and NF-κB.

Methods: A community-based sample of adults (N≈64) was assessed using a structured environmental exposure questionnaire, biomarker analysis, and the Beck Depression Inventory (BDI). Biological samples were collected during the autumn season. Glyphosate exposure was categorized as none, sporadic, or occupational. Exposure was assessed via self-report and supported by biomarker measurements of glyphosate concentration in urine. Inflammatory markers (TNF-α, IL-1β, NF-κB) were also quantified in urine. Group differences were analyzed using non-parametric tests. Associations between inflammatory markers and depressive symptoms were examined using Spearman correlations. Multivariable linear and logistic regression models were adjusted for age, sex, and BMI, with exposure operationalized as a categorical variable. TNF-α was considered the primary biomarker of interest. Exploratory mediation analysis was conducted using a regression-based approach with 5,000 bootstrap resamples to estimate the average causal mediation effect (ACME). Analyses were restricted to participants with complete data.

Results: Higher glyphosate exposure was associated with increased TNF-α levels (p = 0.012) and greater depressive symptom severity (p=0.009). Occupational exposure was linked to a significantly higher risk of clinically relevant depression (OR = 2.85, 95% CI: 1.30–6.21, p = 0.009). TNF-α was positively correlated with BDI scores (r=0.41, p=0.002) and remained an independent predictor in adjusted models (β=0.36, p = 0.004; OR = 2.10, p = 0.006). Exploratory mediation analysis indicated a significant indirect effect consistent with partial mediation of the association between glyphosate exposure and depressive symptoms via TNF-α (ACME = 0.18, p = 0.01), accounting for approximately 37% of the total effect. No significant associations were observed for IL-1β or NF-κB.

Conclusions: These findings are consistent with a potential inflammatory pathway linking environmental herbicide exposure to depressive symptoms. While causality cannot be inferred due to the cross-sectional design, the results support an environmental psychiatry framework in which common chemical exposures may contribute to mental health risk through immune mechanisms. Residual confounding, particularly related to occupational and environmental factors, cannot be excluded. The collection of samples during a single season (autumn) may limit generalizability due to potential seasonal variation in both exposure and inflammatory markers. Further longitudinal studies are needed to confirm these associations and explore additional pathways.

Funding: The project is financed with funds from the state budget allocated by the Minister of Education and Science of the Republic of Poland within the framework of the programme “Perły Nauki” project number PN/01/0312/2022, with a total project value of 239,860.50 PLN.

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