20.500.12556/RUL-178794 ​Povezava nekaterih kemičnih motilcev endokrinega sistema s prezgodnjo odpovedjo delovanja jajčnikov Association of some endocrine disrupting chemicals with premature ovarian failure Končni naslov: POVEZAVA NEKATERIH ENDOKRINIH MOTILCEV IN KEMIČNIH ELEMENTOV S PREZGODNJO ODPOVEDJO DELOVANJA JAJČNIKOV Uvod: Etiologija prezgodnje odpovedi jajčnikov (POF) je slabo raziskana, saj vzrok ostaja v približno 75 % primerov neznan. Med možnimi dejavniki tveganja je tudi izpostavljenost okoljskim onesnaževalcem. Doktorska naloga predstavlja prvo raziskavo, ki primerja koncentracije 10 različnih endokrinih motilcev (EM) v urinu in 9 različnih kemičnih elementov (KE) v urinu, serumu in polni krvi pri ženskah s POF v primerjavi z zdravimi kontrolami (HC), da bi ugotovila njihovo izpostavljenost in morebitne povezave analiziranih snovi s POF. Metode: V presečno raziskavo primerov s kontrolami je bilo med januarjem 2021 in septembrom 2023, na podlagi dovoljenja Komisije za medicinsko etiko Republike Slovenije ter ob predhodno pridobljenih podpisanih informiranih soglasjih, vključenih 81 preiskovank (40 žensk s POF in 41 zdravih kontrol), starih med 20 in 46 let. Krvni in urinski vzorci so bili analizirani za osnovne biokemične parametre s standardnimi validiranimi metodami diagnostične klinične biokemije. Koncentracijo KE (bakra - Cu, cinka - Zn, selena - Se, molibdena - Mo, mangana - Mn, arzena - As, kadmija - Cd, svinca - Pb in živega srebra - Hg) v urinu, serumu in polni krvi smo analizirali z masno spektrometrijo z induktivno sklopljeno plazmo (ICP-MS), koncentracije EM (bisfenola A - BPA, bisfenola S - BPS, bisfenola F - BPF, metilparabena - MeP, etilparabena - EtP, benzilparabena - BzP, propilparabena - PrP, butilparabena - BuP, izobutilparabena - izoBuP in triklosana - TCS) v urinu pa z metodo plinske kromatografije s tandemsko masno spektrometrijo (GC-MS/MS). Udeleženke so izpolnile vprašalnike o demografskih in zdravstvenih podatkih, življenjskem slogu in prehrani. Podatki so bili analizirani z Mann-Whitney U-testom, Student t-testom, Fisher eksakt testom, Kendall tau korelacijo, logističnimi regresijskimi modeli (LRM), prilagojenimi glede na indeks telesne mase (ITM), starost in hematokrit ter univariatnimi in multivariatnimi modeli linearne regresije. Urinske koncentracije KE in EM so bile normalizirane na vrednosti kreatinina in specifično gostoto urina. Pri EM in KE z manj kot 50 % deležem meritev pod mejo kvantifikacije (LOQ) oziroma zaznave (LOD) so bile te imputirane s postopkom multiple imputacije v mejah vrednosti med 0 in LOQ/LOD. EM z več kot 50 % vrednosti pod LOQ so bili razvrščene v štiri kategorije; prva je vključevala vse meritve pod LOQ, izmerjene vrednosti pa so bile razdeljene v tercile. Rezultati: Analiza biokemičnih parametrov je pokazala, da so imele ženske s POF v primerjavi s kontrolami po Bonferroni korekciji značilno višjo širino porazdelitve rdečih krvničk (RDW) ter manjši kreatinin, specifično gostoto urina in povprečni volumen trombocitov (MPV). Ocena delovanja jeter in ledvic ni pokazala značilnih razlik med skupinama. POF skupina je imela višji ITM in večji delež bolnic s POF je prebival na podeželskih kmetijskih območjih. Od parametrov iz vprašalnika je po Bonferroni korekciji ostala statistično značilna nižja pogostost uživanja alkohola in uporabe rdečila za ustnice ter višja pojavnost sežiganja odpadkov v bližini bivališč pri POF skupini. Po prilagoditvi v LRM so bile pri bolnicah s POF v urinu značilno nižje koncentracije Cu, Zn, Se, Mo, Cd in Hg v primerjavi s kontrolami, medtem ko so bile koncentracije Mn v polni krvi višje. V serumu je bil Cu pri bolnicah s POF značilno povišan, medtem ko so bile koncentracije Pb, Cd in Hg nižje. Za As niso bile ugotovljene značilne razlike. Med skupinama po prilagoditvi v LRM ni bilo razlik v koncentracijah BPA, BPF, MeP, BzP, PrP, BuP, izoBuP in TCS. Vrednosti EtP in BPS so bile značilno različne med skupinama. Pri POF skupini je bil delež vrednosti v najvišji kategoriji koncentracij glede na referenčno kategorijo (< LOQ) značilno višji pri EtP in nižji pri BPS v primerjavi s kontrolno skupino. Korelacijska analiza je pokazala več šibkih do zmernih povezav med KE, EM ter demografskimi in biokemičnimi parametri. Rezultati analize univariatnih in nato multivariatnih modelov linearne regresije so skupno pokazali 17 značilnih povezav med neodvisnimi spremenljivkami vprašalnika in biokemije in odvisnimi spremenljivkami; koncentracijami KE in EM v bioloških vzorcih preiskovank. Največ značilnih napovednih spremenljivk je bilo ugotovljenih za koncentracijo Se v urinu, vključno z MPV, uporabo rdečila za ustnice, jemanjem zdravil, pogostostjo uživanja testenin ter pitjem sadnega čaja v zadnjih 24 urah. Najizrazitejši učinki pa so bili opaženi pri koncentraciji Cu v urinu, ki je bila značilno povezana z izpostavljenostjo okoljskim virom onesnaženja, predvsem bližino gostega prometa. Zaključek: Rezultati raziskave nakazujejo možne povezave med določenimi KE, EM in POF, vključno z izpostavljenostjo nekaterim okoljskim dejavnikom, kot je sežiganje odpadkov v bližini bivališč. Ključna ugotovitev je, da so bile koncentracije večine analiziranih KE (Zn, Se, Cu, Mo, Cd in Hg) ter BPS v urinu bolnic s POF značilno nižje, medtem ko so bile koncentracije Cu v serumu višje, Cd, Hg in Pb pa nižje v primerjavi s kontrolno skupino. Med vsemi preučevanimi EM je bil EtP edini, ki je bil pri bolnicah s POF prisoten v značilno višjih koncentracijah. 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. Kemični elementi endokrini motilci prezgodnja odpoved jajčnikov okolje reproduktivno zdravje Chemical elements endocrine disrupting chemicals premature ovarian failure environment reproductive health true false false Slovenski jezik Angleški jezik Doktorsko delo/naloga 2026-01-30 07:15:08 2026-01-30 07:15:20 2026-02-01 04:37:51 0000-00-00 00:00:00 2026 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 1970-01-01 38497 8513.pdf 8513.pdf 1 23A853B2B6B873285EF7F01AE4D41396 9ce2bc9e17b60325bfbede51cc89569d1ca7fc182a7520992a5303d6f394808d 080a386e-fda3-11f0-a1ba-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=226773 Medicinska fakulteta 0 0 0