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The everyday use of household and personal care products (HPCPs) generates an enormous amount of chemicals, of which several groups warrant additional attention, including: (i) parabens, which are widely used as preservatives; (ii) bisphenols, which are used in the manufacture of plastics; (iii) UV filters, which are essential components of many cosmetic products; and (iv) alkylphenol ethoxylates, which are used extensively as non-ionic surfactants. These chemicals are released continuously into the environment, thus contaminating soil, water, plants and animals. Wastewater treatment and water disinfection procedures can convert these chemicals into halogenated transformation products, which end up in the environment and pose a potential threat to humans and wildlife. Indeed, while certain parent HPCP ingredients have been confirmed as endocrine disruptors, less is known about the endocrine activities of their halogenated derivatives. The aim of this review is first to examine the sources and occurrence of halogenated transformation products in the environment, and second to compare their endocrine-disrupting properties to those of their parent compounds (i.e., parabens, bisphenols, UV filters, alkylphenol ethoxylates). Albeit previous reports have focused individually on selected classes of such substances, none have considered the problem of their halogenated transformation products. This review therefore summarizes the available research on these halogenated compounds, highlights the potential exposure pathways, and underlines the existing knowledge gaps within their toxicological profiles.

Endocrine-disrupting chemicals (EDCs) are exogenous substances that interfere with the normal function of the human endocrine system. These chemicals can affect specific nuclear receptors, such as androgen receptors (ARs) or estrogen receptors (ER) α and β, which play a crucial role in regulating complex physiological processes in humans. It is now more crucial than ever to identify EDCs and reduce exposure to them. For screening and prioritizing chemicals for further experimentation, the use of artificial neural networks (ANN), which allow the modeling of complicated, nonlinear relationships, is most appropriate. We developed six models that predict the binding of a compound to ARs, ERα, or ERβ as agonists or antagonists, using counter-propagation artificial neural networks (CPANN). Models were trained on a dataset of structurally diverse compounds, and activity data were obtained from the CompTox Chemicals Dashboard. Leave-one-out (LOO) tests were performed to validate the models. The results showed that the models had excellent performance with prediction accuracy ranging from 94% to 100%. Therefore, the models can predict the binding affinity of an unknown compound to the selected nuclear receptor based solely on its chemical structure. As such, they represent important alternatives for the safety prioritization of chemicals. Bibliografija: str. 13-15.

Uvod: Endokrine motnje so pomembni zapleti po presaditvi srca. Najizrazitejše spremembe v endokrinem sistemu potekajo v prvem letu po presaditvi, ko je tudi izrazito pospešena kostna prenova in izguba mineralne kostne gostote (MKG). Na njo najbolj vpliva zdravljenje z metilprednizolonom, glede na predklinične raziskave in raziskave na živalskih modelih tudi različni imunosupresivi. Z meritvijo MKG in pokazateljev kostne prenove ne prepoznamo vseh bolnikov, ki so ogroženi za zlom, sistem FRAX pa ni primeren za to specifično populacijo. Mikroarhitektura je pomemben dejavnik za trdnost kosti. Ocenimo jo z metodo TBS (ang. Trabecular bone score). TBS je indeks, ki iz slik dvoenergijske rentgenske absorpciometrije posredno oceni trabekularno mikroarhitekturo. V populacijah s pomenopavzalno ali z glukokortikoidno osteoporozo, s sladkorno boleznijo (SB) tipa 1 in tipa 2 ter po presaditvi ledvice je TBS neodvisno od MKG izboljšal prepoznavo bolnikov z večjim tveganjem za zlom. Do sedaj še ni bila opredeljena pojavnost vseh možnih endokrinih zapletov po presaditvi srca, vpliv imunosupresivov na biokemične pokazatelje kostne prenove, mineralno kostno gostoto in na učinkovitost zdravljenja z ZK ter vloga TBS pri bolnikih po presaditvi srca. Metode: Zastavili smo raziskavo iz treh delov. V prvem, retrospektivnem delu smo opredelili pogostnost posameznih endokrinih obolenj in njihovo hkratno pojavnost na 123 preiskovancih v prvem letu po presaditvi srca. V drugem delu smo opravili presečno raziskavo pri 123 preiskovancih manj kot 9 mesecev po presaditvi srca, z longitudinalnim sledenjem do prvega kontrolnega pregleda 6–12 mesecev po prvem pregledu. Proučevali smo razlike v vplivu imunosupresivnih protokolov ciklosporin A/mikofenolne kisline (CsA/MK) in takrolimus/mikofenolne kisline (T/MK), na MKG in pokazatelja kostne prenove, in sicer na fragment kolagena tipa 1 iz telopeptidne regije (CTX), na referenčni pokazatelj kostne razgradnje in N-terminalni del propeptida kolagena tipa 1 (PINP), na referenčni pokazatelj kostne izgradnje ter učinek zdravljenja z zoledronsko kislino (ZK). V tretjem delu smo opravili presečno raziskavo, kjer smo pri 87 preiskovancih opravili meritev MKG, TBS in pri delu preiskovancev rentgensko slikanje hrbtenice. Rezultati: Osteopenijo je imelo 59 (48,0 %), osteoporozo 26 (21,1 %), vsaj 1 osteoporozni zlom je imelo 21 (17.1 %) bolnikov. Pomanjkanje 25-OH vitamina D (25OHD) je bilo prisotno pri 64 (54,7 %) bolnikih, sekundarni hiperparatiroidizem pri 19 (17,3 %), novo nastala sladkorna bolezen po presaditvi (NODAT) ali SB tipa 2 pri 39 (31,7 %) in disfunkcija ščitnice pri 15 (13,9 %). Večina bolnikov je imela od 2 do 3 endokrini motnji, le 4,1 % pa ni imela nobene endokrine motnje. Skupina s T/MK je imela ob kontrolnem pregledu višji PINP (p < 0,001) in nižji CTX (p < 0,001) glede na prvi pregled. Skupina s CsA/MK ni imela razlik med prvim in kontrolnim pregledom (PINP p = 0,114 in CTX p = 0,433). Skupina T/MK in zdravljena z ZK je imela znižane pokazatelje kostne prenove (CTX p < 0,001 in PINP p < 0,001), glede na preiskovance, ki ZK niso prejeli. V skupini CsA/MK ni bilo statistično pomembnih razlik med skupino, zdravljeno z ZK, in skupino, ki ni prejela ZK (CTX p = 0,573 in PINP p = 0,635). Znižan TBS je imelo 48 (55,2 %) in znižano MKG 46 (52,9 %) bolnikov. Največ zlomov vretenc je bilo v skupini z osteopenijo (9 zlomov) in znižanim TBS (9 zlomov). Ocenjevani parametri niso učinkovito napovedovali prisotnosti zlomov glede na površino pod krivuljo ROC (p > 0,05 za vse parametre). Med TBS in ITM preiskovancev je bila negativna korelacija (Spearmanov koeficient –0,508 p < 0,001). Najnižje vrednosti TBS so bile v skupini bolnikov med 3 in 5 let po presaditvi srca (1.249 (IQR 1.172–1.292)). V skupini več kot 5 let po presaditvi srca je TBS (1.341 (IQR 1.228–1.382)) primerljiv z obdobjem neposredno po presaditvi srca (1.346 (IQR 1.257–1.413)). Zaključek: Z retrospektivnim delom raziskave smo ugotovili, da so bile najpogostejše endokrine motnje v zgodnjem obdobju po presaditvi srca hipovitaminoza 25OHD, znižan MKG in hipogonadizem pri moških bolnikih. Pri večini so bile hkrati prisotne 2 ali 3 endokrine motnje. V drugem delu smo ugotovili, da so preiskovanci, ki so prejemali T/MK, imeli ob kontroli porast pokazatelja kostne izgradnje in upad pokazatelja kostne razgradnje in ob zdravljenju z ZK pomembno znižana oba pokazatelja kostne prenove. V skupini, ki je prejemala CsA/MK, ni bilo razlik. V tretjem delu smo dokazali, da TBS v primerjavi z MKG ni izboljšal napovedi za osteoporozni zlom. Deleža bolnikov z znižanim TBS in MKG sta bila primerljiva. TBS je bil za razliko od MKG odvisen od časa po presaditvi srca. Background: Endocrine disturbances are important complications post heart transplant (HT). Most dynamic changes in endocrine system occur in the first year, also increased bone turnover and rapid mineral bone density (BMD) reduction. Treatment with methylprednisolone has the largest effect on BMD. According to preclinical and animal studies also other immunosuppressives have deleterious effects on bone. With measurement of bone turnover markers (BTM) and BMD, we do not recognize all patients at risk of fracture. FRAX calculator is not suitable for this specific population. Microarchitecture is important factor in bone strength. We can assess it with trabecular bone score (TBS). TBS is an index which is acquired from dual energy X-ray absorptiometry and indirectly estimates trabecular microarchitecture. TBS independently from measurement of BMD identifies patients at risk of fractures in different populations, such as postmenopausal and glucocorticoid induced osteoporosis, in diabetes mellitus (DM) type 1 or type 2 and after kidney transplant. Until now there was not investigated incidence of all possible endocrine disturbances post HT, effect of immunosuppressives on BTM’s, BMD, efficiency of treatment with zoledronic acid (ZA) and role of TBS in patients post HT. Methods: We set up a three-part survey. In first retrospective part we examined prevalence of different endocrine abnormalities and their coincidence in 123 patients in first year post HT. In second part we conducted cross-sectional study on 123 patients less than 9 months post HT, with longitudinal follow-up 6-12 months after first outpatient visit. We investigated differences in effect of immunosuppressive protocols cyclosporine A/mycophenolic acid (CsA/MA) and tacrolimus/mycophenolic acid (T/MA) on BMD and BTM C-terminal telopeptide (CTX) as a reference marker of bone resorption and procollagen type 1 N-terminal propeptide (PINP) as a reference marker of bone formation and the effect of treatment with ZA. In third part we conducted cross-sectional study on 87 patients. We assessed BMD, TBS and in part of cohort also X-ray of the spine. Results: Osteopenia was present in 59 (48,0%), osteoporosis in 26 (21,1%), at least 1 osteoporotic fracture in 21 (17.1%) patients. Deficiency or insufficiency of 25-OH-vitamin D (25OHD) was present in 64 (54,7%) patients, secondary hyperparathyroidism in 19 (17,3%), new onset diabetes after transplantation (NODAT) or DM type 2 39 (31,7%) and thyroid dysfunction in 15 (13,9%). Most patients had 2 do 3 endocrine disturbances, only 4,1% did not have any endocrine disturbances. Group T/MK, had higher PINP (p < 0,001) and lower CTX (p < 0,001) on control visit. No differences in BTM were present in group CsA/MK between first and control visit (PINP p = 0,114 and CTX p = 0,433). Group T/MK treated with ZA, had reduced BTM (CTX p < 0,001 and PINP p < 0,001) in regard to patients who did not receive ZA. In group CsA/MK there were no differences between group treated with ZA and which did not receive ZA (CTX p = 0,573 and PINP p = 0,635). Degraded or partially degraded TBS had 48 (55,2%) and reduced BMD 46 (52,9%). The greatest number of fractures occurred in group with osteopenia (9 fractures) and partially degraded TBS (9 fractures). According to area under the ROC curve none of the parameters predicted presence of fractures (all parameters p > 0.05). There was negative correlation between TBS and BMI (Spearman's Rho ⠒0,508 p < 0,001). The lowest TBS was in group between 3- and 5-years post HT (1.249 (IQR 1.172⠒1.292)). In group more than 5 years post HT TBS (1.341 (IQR 1.228⠒1.382)) was comparable to group immediately post HT (1.346 (IQR 1.257⠒1.413)). Conclusions: In retrospective part of study, we found that in early period post HT, most prevalent endocrine disorders were low 25OHD, low BMD and hypogonadism in men. Most patients had multiple endocrine disorders. In second part we found that patients receiving T/MA had an increase of PINP and decrease of CTX on follow-up. When treated with ZA both BTM decreased. There were no differences in group receiving CsA/MA. In third part we found that TBS in comparison with BMD does not improve prediction of osteoporotic fracture. Number of patients with degraded TBS and low BMD are comparable. TBS was dependent of time from HT and was not BMD.