Mycotoxin-Induced Oxidative Stress and Its Impact on Human Folliculogenesis: Examining the Link to Reproductive Health

Abstract

Climate change has contributed to increased mycotoxin contamination in food systems, posing a growing threat to human health, including reproductive health. Our study aimed to investigate how mycotoxins entering the follicular fluid affect oxidative stress processes. We analyzed 88 follicular fluid samples from infertile patients for common mycotoxins, including deoxynivalenol (DON), zearalenone (ZEN), its main metabolite alpha-zearalenol (aZOL), and aflatoxin M1 (AfM1), and examined their relationship with oxidative stress markers (MDA, SOD, GPx, CAT, and TAOC) and hormones (cortisol, estradiol, and anti-Müllerian hormone). Higher mycotoxin levels were associated with increased oxidative stress, particularly elevated MDA levels, and disrupted antioxidant enzyme activity. Notably, DON showed a positive correlation with SOD and estradiol levels, indicating a compensatory antioxidant response, while AfM1 served as a negative predictor. The metabolite aZOL was strongly linked to cortisol, with effects influenced by estradiol levels, implying endocrine-disrupting activity. Importantly, the interaction between DON and AMH appeared to impact dominant follicle development, suggesting a potential mechanism by which environmental toxins impair fertility without directly reducing oocyte or embryo counts. These results highlight the complex, dose-dependent effects of mycotoxins on oxidative and hormonal balances within the follicular environment, with implications for oocyte quality and reproductive success. Better understanding these mechanisms could help develop early diagnostic markers and targeted interventions to improve fertility outcomes in women exposed to changing environmental conditions.

Keywords: anti-Müllerian hormone (AMH); deoxynivalenol (DON); endocrine disruption; estradiol; follicular fluid; infertility; mycotoxins; oocyte quality; oxidative stress; zearalenone (ZEN).

Figure 1

Effects of follicular fluid mycotoxins on the total number of oocytes and usable embryos. The Pareto diagrams display the relative effect and its significance (red line) on folliculogenesis. The AMH level is a significant positive predictor of the total number of oocytes obtained after stimulation and retrieval (A) ffaZOL concentration also has a positive effect on oocyte number, but it did not reach the level of significance. None of the factors examined proved to be significant regarding the number of usable embryos (B).

Figure 2

Correlation Matrix of Antioxidants, Hormones, MDA, and Mycotoxins in the Follicular Fluid. The table shows positive and negative correlations between the concentrations of mycotoxins, hormones, MDA, and antioxidants measured in the follicular fluid. All measured concentrations were standardized to protein levels. The Spearman coefficient (r) values are displayed in the cells. Positive correlations are highlighted in blue, while negative correlations are highlighted in red. Empty cells indicate that Spearman’s r coefficient is less than 0.01. The intensity of the colors reflects the strength of the correlation.

Figure 3

illustrates multiple linear relationships among mycotoxins, MDA, SOD, and cortisol in follicular fluid. The figure displays regression relationships along with their residual plots. A positive linear relationship is observed between (A): Cortisol and aZOL, (B): MDA and DON, and (C): SOD and DON. The trend lines are highlighted in red. The bottom row presents the residual plots from the linear regression corresponding to the top images. Due to outliers and variations in standard deviations observed in the figures, transformation models were also applied to prevent statistical bias.

Figure 4

Regression analysis of factors influencing GPx concentration in follicular fluid. The level of GPx in follicular fluid shows a strong positive relationship with ffE2 (F (1, 30) = 22.25, p < 0.0001), ffMDA (F (1, 30) = 6.755, p < 0.05), and ffCAT (F (1, 30) = 20.18, p < 0.0001). The level of ffaZOL also has a weak positive effect (F (1, 30) = 9.594, p < 0.01). We found a negative regression relationship with cortisol (F (1, 30) = 4.897, p < 0.05). In this model, a multivariate regression including several predictors explained 62.96% of the variability in GPx. The results showed that the negative effects of DON and TAOC were at trend level (p = 0.0846, p = 0.0629), likely due to the relatively small sample size. The green color indicates a positive effect, while the blue color indicates a negative effect.