Association of some endocrine disrupting chemicals and chemical elements with premature ovarian failure
Introduction: The etiology of premature ovarian failure (POF) remains poorly understood, with approximately 75 % of cases classified as idiopathic. Among the potential risk factors, exposure to environmental pollutants has been proposed. This doctoral dissertation presents the first study comparing the concentrations of ten different endocrine-disrupting chemicals (EDCs) in urine and nine different chemical elements (CEs) in urine, serum, and whole blood between women with POF and healthy controls (HC), to assess exposure and identify potential associations of these substances with POF.
Methods: In this cross-sectional case–control study, 81 women (40 with POF and 41 healthy controls), aged between 20 and 46 years, were enrolled between January 2021 and September 2023 following approval by the National Medical Ethics Committee of the Republic of Slovenia and after obtaining signed informed consent. Blood and urine samples were analyzed for standard biochemical parameters using validated clinical diagnostic methods. The concentrations of CEs; including copper (Cu), zinc (Zn), selenium (Se), molybdenum (Mo), manganese (Mn), arsenic (As), cadmium (Cd), lead (Pb), and mercury (Hg) in urine, serum, and whole blood were measured using inductively coupled plasma mass spectrometry (ICP-MS). Urinary concentrations of EDCs; including bisphenol A (BPA), bisphenol S (BPS), bisphenol F (BPF), methylparaben (MeP), ethylparaben (EtP), benzylparaben (BzP), propylparaben (PrP), butylparaben (BuP), isobutylparaben (isoBuP), and triclosan (TCS) were measured using gas chromatography coupled with tandem mass spectrometry (GC-MS/MS). Participants completed structured questionnaires on demographic characteristics, health status, lifestyle, and dietary habits.
Data were analyzed using the Mann-Whitney U test, Student’s t-test, Fisher’s exact test, Kendall’s tau correlation, and logistic regression models adjusted for body mass index (BMI), age, and hematocrit, as well as univariate and multivariate linear regression models. Urinary CEs and EDC concentrations were normalized to creatinine and specific gravity. For compounds with fewer than 50 % of measurements below the limit of detection (LOD) or limit of quantification (LOQ), values were imputed using multiple imputation within the 0 – LOD/LOQ range. EDCs with more than 50% of values below the LOQ were classified into four categories; the first included all values below the LOQ, while the measured values were divided into tertiles.
Results: Analysis of biochemical parameters showed that, after Bonferroni correction, women with POF had significantly higher red cell distribution width (RDW) and lower mean platelet volume (MPV), urinary creatinine, and specific gravity compared to controls. No significant differences were observed in hepatic or renal function markers. Women with POF had higher BMIs and were more likely to live in rural agricultural areas. After correction, questionnaire data indicated significantly lower frequency of alcohol consumption and lipstick use, and a higher prevalence of waste burning near residences among the POF group.
Adjusted logistic regression models showed significantly lower urinary concentrations of Cu, Zn, Se, Mo, Cd, and Hg in the POF group compared to controls, while whole-blood Mn levels were higher. In serum, Cu levels were significantly higher in POF cases, whereas Pb, Cd, and Hg were significantly lower. No significant differences were observed for As. Among EDCs, BPA, BPF, MeP, BzP, PrP, BuP, iBuP, and TCS showed no significant differences between groups, while EtP and BPS levels differed significantly. In the POF group, the proportion of individuals with values in the highest EtP category (compared to the reference category < LOQ) was significantly greater, while the proportion in the highest BPS category was significantly lower, relative to controls.
Correlation analyses showed several weak to moderate associations between CEs, EDCs, and demographic or biochemical parameters. In total, univariate and multivariate linear regression analyses identified 17 statistically significant associations between questionnaire/biochemical predictors and CE/EDC concentrations. The highest number of significant predictors was found for urinary Se, including MPV, lipstick use, medication intake, pasta consumption frequency, and fruit tea intake within the previous 24 hours. The strongest effects were observed for urinary Cu, which was significantly associated with environmental pollution sources, particularly proximity to heavy traffic.
Conclusion: The findings of this study suggest potential associations between selected CEs, EDCs, and POF, including environmental exposures such as waste burning near residential areas. A key finding was the significantly lower urinary concentrations of most analyzed CEs (Zn, Se, Cu, Mo, Cd, and Hg) and BPS in women with POF compared to healthy controls. In contrast, serum levels of Cu were significantly higher, whereas concentrations of Cd, Hg, and Pb were lower in the POF group. Among all EDCs assessed, EtP was the only compound present at significantly higher levels in women with POF.
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