Toksični efekti niskih doza olova na modelu subakutne izloženosti pacova

Abstract

Novija istraživanja ukazuju da svaka izloženost olovu, pa čak i veoma niskim dozama može biti štetna. Podaci o toksičnim mehanizmima i efektima olova iz dosadašnjih animalnih i humanih studija se uglavnom zasnivaju na izloženosti visokim dozama, te stoga postoji potreba da se ispitaju mehanizmi toksičnog dejstva i da se utvrde toksični efekti u uslovima produžene izloženosti niskim dozama olova. Imajući navedeno u vidu, cilj ove disertacije bio je da se na modelu subakutne izloženosti pacova ispita uticaj niskih doza olova na različite organe i sisteme organa. Studija je sprovedena na animalnom modelu Wistar pacova koji su podeljeni u 7 grupa po 6 jedinki od kojih je jedna grupa bila kontrolna a 6 ostalih grupa je tretirano tokom 28 dana rastućim dozama olova 0,1; 0,5; 1; 3; 7; 15 mg Pb/kg t.m./dan. Nakon 24 h od poslednje doze, pacovi su žrtvovani na human način a krv i organi su uzeti na dalju analizu. U krvi su određivani hematološki parametri, biohemijski parametri, hormoni, parametri oksidativnog statusa, bioelementi i olovo, dok su organi podvrgnti patohistološkoj analizi i u njima su određivani parametri oksidativnos stausa, bioelementi, olovo i aktivnost enzima acetilholinesteraze. Primena olova u šest niskih rastućih doza omogućila je modelovanje odnosa doza-odgovor i dobijanje Benchmark doza za ispitivane toksične efekte. Rezultati su pokazali da olovo pri niskim dozama, može ispoljiti toksične efekte skoro na svim ispitivanim organima. Dobijeni rezultati daju uvid u distribuciju olova između krvi i tkiva kao i internim dozama olova koje dovode do štetnih efekata. Izmenjeni profil hematoloških i biohemijskih parametara, zajedno sa izmenjenim nivoima bioelemenata, nastalim oksidativnim stresom, izmenjenom aktivnošću acetilholinesteraze i patohistološkom analizom ispitivanih tkiva, ukazuju na toksične efekte nakon subakutne oralne ekspozicije olovu. Najveći naučni doprinos ove doktorske disertacije je ispitivanje zavisnosti doza–odgovor za svaki pojedinačni parametar kao i određivanje Benchmark doze, koja će dalje doprineti sigurnijoj proceni rizika po zdravlje ljudi pri izloženosti niskim dozama olova. Najniža Benchmark doza dobijena u studiji je za efekat smanjenja nivoa testosterona u serumu pacova što predstavlja kritični toksični efekat studije. Sledeći efekti jesu inhibicija SOD u bubrezima, povećanje nivoa Cu u femuru, sniženje Cu u krvi i povećanje MDA u srcu, a zatim, povećanje TOS u mozgu, povećanje Zn u pankreasu i sniženje Cu u jetri.

Recent research indicates that exposure to very low lead doses can be harmful. Data on the toxic mechanisms and effects of lead from previous animal and human studies are mainly based on exposure to high doses, and therefore there is a need to investigate the toxic mechanism and to determine toxic effects under conditions of prolonged exposure to low lead doses. Having this in mind, the aim of this dissertation was to examine the effects of low lead doses on various organs and organ systems in a subacute exposure rat model. The study was conducted on an animal model of Wistar rat. The rats were divided into 7 groups, with 6 rats in each, where one of the them was a control group. The rats from 6 other groups were treated for 28 days with increasing doses of 0.1; 0.5; 1; 3; 7; 15 mg Pb /kg b.w./day. After 24 hours from the last dose, rats were sacrificed and blood and organs were taken away for further analysis. Haematological parameters, biochemical parameters, hormones, oxidative status parameters, bioelements, and lead were determined in the blood, while the organs were subjected to pathohistological analysis and determination of oxidative status parameters, bioelements, lead and acetylcholinesterase enzyme activity. The use of lead in six low-increasing doses enable the modelling of the dose-response relationship and the obtaining of the Benchmark dose for the tested toxic effects. The results showed that lead at low doses can have toxic effects on almost all examined organs. The obtained results provide insight into the distribution of the lead between blood and tissues as well as the internal doses of lead that lead to harmful effects. Altered profiles of hematological and biochemical parameters, together with altered levels of bioelements, oxidative stress, altered acetylcholinesterase activity, and pathohistological analysis of examined tissues, indicate adverse effects after subacute lead exposure. The greatest scientific contribution of this doctoral dissertation is the examination of dose-response relationships for each individual parameter as well as the determination of the Benchmark dose, which will further contribute to a safer assessment of human health risk of low lead dose exposure. The lowest Benchmark dose obtained in the study was for the effect of reducing testosterone levels in rat serum, which is a critical toxic effect of the study. The next determined effects are inhibition of SOD in the kidneys, increased levels of Cu in the femur, decreased Cu in the blood and increased MDA levels in the heart, then, an increase in TOS in the brain, an increase in Zn in the pancreas and a decrease in Cu in the liver.