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Vrednotenje mošusnih dišav kot okoljskih endokrinih motilcev in silico
ID Caf, Anja (Avtor), ID Jakopin, Žiga (Mentor) Več o mentorju... Povezava se odpre v novem oknu

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Izvleček
Sintezne mošusne dišave (SMD) so sestavine, dodane izdelkom z namenom izboljšanja njihovega vonja. Pogosto jih najdemo v detergentih, mehčalcih in kozmetičnih izdelkih. Vnosu SMD v okolje se ob vsakodnevni uporabi dišav ne moremo izogniti. Ljudje smo SMD izpostavljeni predvsem preko nanosa kozmetičnih izdelkov in v določeni meri tudi preko prehranjevanja z morskimi organizmi, kar vodi do bioakumulacije dišav v maščobnem tkivu. V okolju so SMD podvržene različnim potem in mehanizmom razgradnje, med katerimi prevladujejo reakcije oksidacije in redukcije. Nastali razgradni produkti so lahko bolj toksični od starševske spojine, zato smo jih vključili v raziskavo. SMD imajo visoke vrednosti log P, zato so odporne na razgradnjo v okolju in nagnjene k procesu bioakumulacije. V magistrski nalogi smo enaindvajsetim reprezentativnim SMD in njihovim razgradnim produktom določili ekotoksikološki profil, okoljski vpliv in endokrino toksičnost. Uporabili smo računalniške programe VegaNIC, Endocrine Disruptome in ECOSAR, ter na podlagi napovedanih rezultatov ocenili, katera izmed SMD je potencialno najbolj in katera je najmanj varna. Endokrini potencial SMD smo določili na podlagi afinitete vezave spojin na 14 človeških jedrnih receptorjev, in sicer smo ugotovili, da imajo preiskovane SMD najvišjo afiniteto vezave na receptorje AR, AR an,, ERα, ERβ in ERβ an. Poleg afinitete vezave posameznih dišav na receptorje smo prav tako upoštevali napovedano vrednost log P, biokoncentracijski faktor (BCF), akutno toksičnost in pojavnost teh spojin v okolju. S povečanjem vrednosti parametra log P se poveča verjetnost za nalaganje dišav v maščobnem tkivu, hkrati pa se poveča tudi verjetnost za bioakumulacijo teh spojin v okolju. Bioakumulativni potencial dišav lahko napovemo tudi na podlagi visoke vrednosti faktorja BCF. Toksičnost preiskovanih dišav smo ocenili na podlagi podatkov o akutni toksičnosti, ki smo jih pridobili iz izračunanih vrednosti LC50. Nižja vrednost LC50 nakazuje na večjo akutno toksičnost dišave in večje tveganje za vodne organizme. Na osnovi napovedanih rezultatov smo ocenili, da je najvarnejša mošusna dišava MC-4, saj izkazuje nizek potencial za bioakumulacijo, polega tega pa ima najnižjo verjetnost vezave na večino jedrnih receptorjev. Kar nakazuje na nizek potencial za endokrino aktivnost. Sicer smo ugotovili, da je spojina MC-4 toksična za določeno vrsto rib, kar pomeni, da imajo lahko tudi relativno varne SMD določene neželene učinke. Med najbolj toksične SMD smo uvrstili galaksolid (HHCB) in njegov razgradni produkt, HHCB lakton, ter ambretolid. Ob upoštevanju ekotoksikoloških lastnosti in pojavnosti SMD v okolju predstavljata HHCB in HHCB lakton največje tveganje za okolje in organizem. Kljub trenutni nizki pojavnosti v okolju pa moramo biti iz vidika endokrinega potenciala pozorni tudi na ambretolid. Rezultati, ki smo jih pridobili s pomočjo in silico metod, nakazujejo na to, da bo treba v prihodnosti izvesti več študij na temo SMD in njihovih razgradnih produktov, hkrati pa predstavljajo odlično orodje za usmeritev nadaljnjih in vivo ter in vitro študij.

Jezik:Slovenski jezik
Ključne besede:sintezne mošusne dišave, razgradni produkti, bioakumulacija, okoljski vpliv, endokrini potencial, ekotoksikološki profil, in silico napoved
Vrsta gradiva:Magistrsko delo/naloga
Organizacija:FFA - Fakulteta za farmacijo
Leto izida:2022
PID:20.500.12556/RUL-141386 Povezava se odpre v novem oknu
Datum objave v RUL:29.09.2022
Število ogledov:724
Število prenosov:44
Metapodatki:XML DC-XML DC-RDF
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Sekundarni jezik

Jezik:Angleški jezik
Naslov:In silico evaluation of musk fragrances as environmental endocrine disruptors
Izvleček:
Synthetic musk fragrances (SMD) are compounds added to products to enhance their scent. They are often found in detergents, fabric softeners, and cosmetic products. Due to the daily use of fragrances, the introduction of SMD into the environment cannot be avoided. People are exposed to SMD mostly through the application of cosmetic products and to a certain extent also through consuming marine organisms, which leads to bioaccumulation of fragrances in fatty tissues. In the environment, SMD are subjected to various pathways and mechanisms of degradation, with oxidation and reduction being the dominant reactions. The resulting degradation products can be even more toxic than the parent compound, which is why they were included in our research. SMD have high log P values, which makes them resistant to environmental degradation and prone to bioaccumulation. In the Master's thesis, we determined the ecotoxicological profile, environmental impact, and endocrine toxicity of twenty-one representative SMD and their degradation products. We used the computer programs VegaNIC, Endocrine Disruptome, and ECOSAR, and based on the predicted results, we evaluated which of the SMD is potentially the safest and which is the least safe. The endocrine potential of SMD was determined based on the binding affinity of the compounds to 14 human nuclear receptors. We found that the tested SMD have the highest binding affinity to AR, AR an, ERα, ERβ, and ERβ an receptors. In addition to the binding affinity of individual fragrances to receptors, we also considered the predicted log P value, the BCF factor, acute toxicity, and the occurrence of these compounds in the environment. By increasing the value of the log P parameter, the probability of fragrance accumulation in the adipose tissue increases, as well as the probability of bioaccumulation of such compounds in the environment. The bioaccumulative potential of fragrances can also be predicted based on a high value of the BCF factor. The toxicity of the researched fragrances was assessed based on the acute toxicity data obtained from the calculated LC50 values. A low LC50 value indicates a greater acute toxicity of the fragrance and a greater risk to aquatic organisms. Based on the predicted results, we estimated that the safest musk fragrance is MC-4, as it shows a low potential for bioaccumulation, and has the lowest probability of binding to most nuclear receptors. The latter suggests a low endocrine effect of this fragrance. We otherwise found that the compound MC-4 is toxic to a certain type of fish, which highlights the fact that even relatively safe SMD can possess certain side effects. The compound HHCB, its degradation product HHCB lactone, and ambrettolide were ranked among the most toxic SMD. In view of the ecotoxicological properties and occurrence of SMD in the environment, HHCB and HHCB lactone represent the greatest risk to the environment and the organism. Despite the current low occurrence in the environment, we must also take into account ambrettolide from the point of view of endocrine potential. The results we obtained by in silico methods indicate that in the future it will be necessary to carry out more studies on SMD and their degradation products. At the same time, they represent an excellent tool for directing further in vivo and in vitro studies.

Ključne besede:synthetic musk fragrances, breakdown products, bioaccumulation, environmental impact, endocrine potential, ecotoxicological profile, in silico prediction

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