Natalija Marinković

Dioxins and Human Toxicity

Dioxins and Human Toxicity The term dioxins usually refers to polychlorinated dibenzo-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). As 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) has the highest toxic potential, the toxic potentials of other PCDDs and PCDFs are defined in comparison with it. Human exposure to dioxins can be environmental (background), occupational, or accidental pollution. In the human body, dioxins are in part metabolised and eliminated, and the rest is stored in body fat. People vary in their capacity to eliminate TCDD, but it is also dose-dependent; the elimination rate is much faster at higher than lower levels. The liver microsomal P4501A1 enzyme oxygenates lipophilic chemicals such as dioxins. It is encoded by the CYP1A1 gene. Cytosolic aryl hydrocarbon receptor (AhR) mediates their carcinogenic action. It binds to dioxin, translocates to nucleus and together with hydrocarbon nuclear translocator (ARNT) and xenobiotic responsive element (XRE) increases the expression of CYP1A1. Dioxins are classified as known human carcinogens, but they also cause noncancerous effects like atherosclerosis, hypertension, and diabetes. Long-term exposures to dioxins cause disruption of the nervous, immune, reproductive, and endocrine system. Short-term exposure to high levels impairs the liver function and causes chloracne. The most sensitive population to dioxin exposure are the foetuses and infants. A large number of health effects have been documented in the scientific literature, and they all place dioxins among the most toxic chemicals known to man. Dioksini i njihova toksičnost za ljude Dioksini su skupina kemijskih spojeva koji obuhvaćaju poliklorirane dibenzo-dioksine (PCDD) i poliklorirane dibenzo-furane (PCDF). Najveći toksični potencijal (faktor ekvivalentne toksičnosti) ima 2,3,7,8-TCDD, dok su toksični potencijali drugih PCDD i PCDF određeni u odnosu na njega. Izloženost dioksinima može biti izravna: izloženost dioksinima emitiranim u okoliš kao posljedica nesreće, profesionalna izloženost te neizravna, tzv. pozadinska. Nakon ulaska u ljudski organizam dioksini se djelomično metaboliziraju i eliminiraju, a ostatak se pohranjuje u adipozno tkivo. Postoji određena varijabilnost između ljudi u kapacitetu eliminacije TCDD. Eliminacija TCDD ovisna je o dozi - kod veće izloženosti (izloženost višim koncentracijama) brzina eliminacije je viša nego kod manje izloženosti (izloženost nižim koncentracijama). Enzim P4501A1 najvažniji je u oksigenaciji lipofilnih supstrata poput dioksina. Kodiran je genom CYP1A1. AhR je stanični receptor koji djeluje kao transkripcijski faktor koji posreduje u njihovu karcinogenom učinku. AhR veže dioksin te se premješta u jezgru gdje zajedno s ARNT (engl. aryl hydrocarbon nuclear translocator) i XRE (engl. xenobiotic responsive element), smještenim u promotorskoj regiji gena za CYP1A1, uzrokuje povećani izražaj CYP1A1. Dioksini su karcinogeni spojevi, ali imaju i nekarcinogene učinke poput ateroskleroze, hipertenzije, dijabetesa, poremećaj živčanog, imunosnog, reproduktivnog i endokrinog sustava, posebice kod kronične izloženosti. Akutna izloženost uzrokuje oštećenja jetre i klorakne. Najosjetljivija skupina izloženosti dioksinu je dojenčad u prenatalnom i postnatalnom razdoblju. U znanstvenoj i stručnoj literaturi dokumentirani su brojni zdravstveni učinci kao posljedice izloženosti dioksinima te ih svi ističu kao jedne od najtoksičnijih kemijskih spojeva.

Polymorphisms of genes involved in polycyclic aromatic hydrocarbons' biotransformation and atherosclerosis.

Polycyclic aromatic hydrocarbons (PAHs) are among the most prevalent environmental pollutants and result from the incomplete combustion of hydrocarbons (coal and gasoline, fossil fuel combustion, byproducts of industrial processing, natural emission, cigarette smoking, etc.). The first phase of xenobiotic biotransformation in the PAH metabolism includes activities of cytochrome P450 from the CYP1 family and microsomal epoxide hydrolase. The products of this biotransformation are reactive oxygen species that are transformed in the second phase through the formation of conjugates with glutathione, glucuronate or sulphates. PAH exposure may lead to PAH-DNA adduct formation or induce an inflammatory atherosclerotic plaque phenotype. Several genetic polymorphisms of genes encoded for enzymes involved in PAH biotransformation have been proven to lead to the development of diseases. Enzyme CYP P450 1A1, which is encoded by the CYP1A1 gene, is vital in the monooxygenation of lipofilic substrates, while GSTM1 and GSTT1 are the most abundant isophorms that conjugate and neutralize oxygen products. Some single nucleotide polymorphisms of the CYP1A1 gene as well as the deletion polymorphisms of GSTT1 and GSTM1 may alter the final specific cellular inflammatory respond. Occupational exposure or conditions from the living environment can contribute to the production of PAH metabolites with adverse effects on human health. The aim of this study was to obtain data on biotransformation and atherosclerosis, as well as data on the gene polymorphisms involved in biotransformation, in order to better study gene expression and further elucidate the interaction between genes and the environment.