The effect of disulfiram on ethanol and/or cadmium subacute reproductive toxicity mechanisms in male rats

Dosadašnja istraživanja mehanizama toksičnosti alkohola i kadmijuma (Cd) pri pojedinačnoj i udruženoj izloženosti eksprimantalnih životinja potvrđuju da oba agensa dovode do reproduktivne toksičnosti. Brojne epidemiološke studije su takođe ukazale da su pušenje i alkoholizam uzročnici poremećaja u spermatogenezi i neplodnosti kod muškaraca. S obzirom na činjenicu da je duvanski dim značajan izvor izloženosti Cd, kao i da su alkoholičari uglavnom i pušači, potrebno je utvrditi kako disulfiram (DSF), lek koji se koristi u averzivnoj terapiji alkoholizma, utiče na reproduktivnu toksičnost izazvanu pomenutim toksikantima. Cilj ove studije je bio da se ispita efekat DSF na narušenu homeostazu bioelemenata, redoks i androgeni status u testisima pacova prethodno izloženih alkoholu i/ili Cd kao i tokom koekspozicije sa Cd. Slobodna sulfhidrilna grupa (–SH) u hemijskoj strukturi metabolita DSF, dietilditiokarbamata (DDTC), ukazuje na redukcioni i helirajući potencijal DSF koji umnogome može da promeni metabolizam kako ispitivanih toksičnih agenasa (alkohola i Cd), tako i esencijalnih bioelemenata, kao i endogenih jedinjenja koja poseduju –SH grupe zbog mogućih reakcija tiolnog ukrštanja. Studija na životinjama (mužjaci pacova Wistar soja, n = 288) je dizajnirana sa ciljem da se imitiraju navike alkoholičara-pušača pre i nakon uvođenja DSF. Životinje su bile izložene ispitivanim supstancama subakutno (alkoholu i DSF), odnosno subhronično (Cd). Alkohol, DSF i maslinovo ulje (MU) kao rastvarač za DSF, su davani putem oralne sonde (per os), a Cd intraperitonelano (i.p.), svakodnevno u jednoj dozi. Životinje su slučajnim odabirom podeljene na kontrolne grupe i 7 eksperimentalnih grupa, od kojih je svaka grupa podeljena u 4 ili 6 podgrupa (n = 6) u odnosu na dužinu izloženosti svakoj od ispitivanih supstanci pojedinačno ili njihovoj kombinovanoj primeni. Podela eksperimentalnih životinja na grupe u odnosu na trajanje ekspozicije (1, 3, 10, 21 i 42 dana) je sledeća: tri kontrolne grupe (K1-42 , MU1-21, i K1-21/MU22-42); tri grupe koje su individualno bile izložene ispitivanim agensima (A1-21, Cd1-42 i DSF1-21); i četiri grupe koje su bile paralelno izložene ispitivanim agesnima (A1-21/Cd1-21, A1-21/DSF22-42, Cd1-42/DSF22-42 i A1-21/Cd1-42/DSF22-42)...Previous animal studies on the mechanisms of toxicity after exposure or co-exposure to alcohol and cadmium (Cd) confirmed that both agents induce reproductive toxicity. Numerous epidemiological studies have also suggested that smoking and alcoholism cause disturbances in spermatogenesis and infertility in men. Due to the fact that tobacco smoke is an important source of Cd exposure, as well as alcoholics are usually smokers too, it is necessary to determine if disulfiram (DSF), a drug used in aversive therapy of alcoholism, affects the reproductive toxicity induced by the abovementioned toxicants. The aim of this study was to examine the effect of DSF on disturbed bioelements’ homeostasis, redox and androgen status in the testes of rats previously exposed to alcohol and / or Cd and during co-exposure with Cd. Free sulfhydryl group (-SH) in the chemical structure of the DSF’s metabolite, diethyldithiocarbamate (DDTC), indicates the reducing and chelating potential of DSF, which in many ways can change the metabolism of tested toxic agents (A and Cd), as well as essential bioelements, and endogenous compounds containing -SH groups due to possible reactions of thiol linking. The animal study (male Wistar rats, n = 288) was designed in order to imitate the conditions of alcoholics-smokers before and after the introduction of DSF. The animals were exposed to the tested substances subacute (alcohol and DSF) and subchronic (Cd). Alcohol, DSF, and olive oil (OL), as a solvent for DSF, were administered via oral gavage (per os), and Cd intraperitoneally, in a single daily dose. Animals were randomly divided into control groups and 7 experimental groups, each group was divided into 4 or 6 subgroups (n = 6) according to the duration of exposure to the tested substances alone or in combination. The division of the groups of the experimental animals with respect to the exposure time (1, 3, 10, 21 and 42 days) was as follows: three control groups (C1-42, OL1-21 and C1-21 / OL22-42); three groups which were independently exposed to the tested agents (A1-21, Cd1-42 and DSF1-21); and four groups that were subjected parallelly to the tested agents (A1-21 / Cd1-21, A1-21 / DSF22-42, Cd1-42 / DSF22-42 and A1-21 / Cd1-42 / DSF22-42)..