Odnos hepatotoksičnosti i doze dekabromovanog difeniletra u ciljnom tkivu kod subakutno izloženih Wistar pacova
Sažetak
Uvod/Cilj. Prema podacima iz brojnih studija na životinjama, dekabromovani difeniletar (BDE-209) najznačajnije toksične efekte ispoljava na jetri, homeostazi hormona štitaste žlezde, reproduktivnom i nervnom sistemu. BDE-209 ispoljava toksične efekte delom preko receptora za aromatične ugljovodonike (Ah) i posledične indukcije mikrozomalnih enzima jetre. Cilj rada bio je procena hepatotoksičnog efekta u odnosu na dozu BDE-209 u ciljnom tkivu kod subakutno oralno eksponovanih Wistar pacova. Metode. Efekti su ispitivani na mužjacima Wistar pacova, mase 200–240 g, koji su putem oralne sonde primali doze od 1 000, 2 000 ili 4 000 mg BDE-209/kg telesne mase (tm) dan, tokom 28 dana. Životinje su tretirane u skladu sa odlukom Etičkog komiteta Vojnomedicinske akademije u Beogradu br. 9667-1/2011. Procena hepatotoksičnih efekata bazirana je na merenju relativne mase jetre, unosa vode i hrane, biohemijskih parametara funkcije jetre [aspartat aminotransferaza (AST), alanin aminotransferaza (ALT), alkalna fosfataza (ALP), gama glutamil transferaza (γ-GT)], parametara oksidativnog stresa u homogenatima jetre [malondialdehid (MDA), superoksid dizmutaza (SOD), -SH)] i morfoloških i histoloških promena na jetri. Za procenu odnosa interna doza – odgovor izračunavana je donja granica pouzdanosti granične Benchmark doze (BMDL) od 5% (BMDL5) ili 10% (BMDL10) primenom PROAST softvera. Rezultati. Koncentracije BDE-209 iznosile su 0,269, 0,569 i 0,859 mg/kg jetre nakon aplikacije 1 000, 2 000, odnosno 4 000 mg BDE-209/kg tm/dan. Interna doza u našoj studiji korelisala je sa eksternom dozom prema jednačini: interna doza (mg BDE-209/kg jetre) = 0,0002 ´ eksterna doza (mg/kg tm/dan) + 0,0622 (r = 0,972; p < 0,05). Hepatotoksičnost je potvrđena na osnovu nalaza o povećanju aktivnosti enzima AST i γ-GT, kao i stepena patohistološkog oštećenja jetre. Najniža BMDL5 u eksperimentu od 0,07228 mg BDE-209/kg jetre, koja koreliše sa eksternom dozom od 39 mg/kg tm/dan izračunata je za aktivnost AST i ukazuje na to da je aktivnost AST ujedno i najosetljiviji biomarker hepatotoksičnosti BDE-209 kod subakutno eksponovanih pacova. Zaključak. Rezultati prezentovane studije daju doprinos pitanju toksikološkog profila BDE-209 sa fokusom na odnos između interne doze i hepatotoksičnih efekata. Kritična interna doza za efekat na AST od 0,07 mg/kg jetre, koja koreliše sa eksternom dozom od 39 mg/kg tm/dan, jeste ujedno i najniža kritična doza do sada definisana za hepatotoksične efekte BDE-209. Kritičan efekat koji se bazira na dozi u ciljnom tkivu u većini slučajeva može se smatrati preciznije definisanim od kritičnog efekta definisanog na bazi oralno primenjene doze, naročito za nedegradabilne supstance sa niskim stepenom apsorpcije, kao što je BDE-209.
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