A circular toxicity approach to isoprostanes: From markers of oxidative stress, to epidemiological warning systems and agents of aquatic toxicity.

Isoprostanes (IsoPs) are a class of oxidation products naturally formed in vivo that are indicative of endogenous oxidative stress. In individuals with chronic and oxidative stress related diseases, IsoPs are increased to pathological levels. Since they are excreted through urine into sewage systems, IsoPs can be detected in wastewater treatment plants' (WWTPs) effluents and thus can be used to evaluate the health status of a given population. The underlying principle is that higher isoprostanes WWTPs' levels correspond to populations undergoing higher levels of oxidative stress, and thus disease. However, IsoPs are not eliminated by WWTPs and will end up being released into the aquatic environment, where they will be available for uptake by aquatic species. Being bioactive molecules, it has been suggested that IsoPs in the environment may elicit oxidative stress in aquatic organisms. In this context, we have critically reviewed the available data on IsoPs as products and effectors of toxicity, and propose the new concept of "circular toxicity". In general, IsoPs excreted by humans as a consequence of oxidative stress are released into the aquatic environment where they may interact with aquatic organisms and induce the production of more IsoPs. These stress markers, in turn, will also be excreted, increasing the already high levels of stressors in the aquatic environment and thus create an escalating cycle of oxidative stress.

A case of contagious toxicity? Isoprostanes as potential emerging contaminants of concern.

Isoprostanes are useful biomarkers of human and animal health, being representative of oxidative stress processes, and having biological impacts associated with toxicity and disease. Isoprostanes are also chemically stable, a property facilitating population-level health assessments through wastewater sampling. However, as biologically-active entities, the presence of isoprostanes in domestic effluents could have toxic impacts on biota in receiving environments. As such it is proposed that isoprostanes are emerging organic contaminants of particular concern. Fish and aquatic invertebrates may be affected by the presence of isoprostanes in wastewaters through mechanisms such as reproductive impairment, cardiovascular disturbance and/or oxidative stress. This would represent a unique scenario of "contagious" toxicity, whereby human health has a direct toxicological consequence on aquatic animal health.

Cyclopentenone isoprostanes are novel bioactive products of lipid oxidation which enhance neurodegeneration.

Oxidative stress and subsequent lipid peroxidation are involved in the pathogenesis of numerous neurodegenerative conditions, including stroke. Cyclopentenone isoprostanes (IsoPs) are novel electrophilic lipid peroxidation products formed under conditions of oxidative stress via the isoprostane pathway. These cyclopentenone IsoPs are isomeric to highly bioactive cyclopentenone prostaglandins, yet it has not been determined if these products are biologically active or are formed in the brain. Here we demonstrate that the major cyclopentenone IsoP isomer 15-A2t-IsoP potently induces apoptosis in neuronal cultures at submicromolar concentrations. We present a model in which 15-A2t-IsoP induced neuronal apoptosis involves initial depletion of glutathione and enhanced production of reactive oxygen species, followed by 12-lipoxygenase activation and phosphorylation of extracellular signal-regulated kinase 1/2 and the redox sensitive adaptor protein p66shc, which results in caspase-3 cleavage. 15-A2t-IsoP application also dramatically potentiates oxidative glutamate toxicity at concentrations as low as 100 nm, demonstrating the functional importance of these molecules in neurodegeneration. Finally, we employ novel mass spectrometric methods to show that cyclopentenone IsoPs are formed abundantly in brain tissue under conditions of oxidative stress. Together these findings suggest that cyclopentenone IsoPs may contribute to neuronal death caused by oxidative insults, and that their activity should perhaps be addressed when designing neuroprotective therapies.

Cytotoxicity of the E(2)-isoprostane 15-E(2t)-IsoP on oligodendrocyte progenitors.

Oxidant stress plays a significant role in the pathogenesis of periventricular leukomalacia (PVL). Isoprostanes (IsoPs) are bioactive products of lipid peroxidation abundantly generated during hypoxic-ischemic injuries. Because loss of oligodendrocytes (OLs) occurs early in PVL, we hypothesized that IsoPs could induce progenitor OL death. 15-E(2t)-IsoP but not 15-F(2t)-IsoP elicited a concentration-dependent death of progenitor OLs by oncosis and not by apoptosis, but exerted minimal effects on mature OLs. 15-E(2t)-IsoP-induced cytotoxicity could not be explained by its conversion into cyclopentenones, because PGA(2) was hardly cytotoxic. On the other hand, thromboxane A(2) (TxA(2)) synthase inhibitor CGS12970 and cyclooxygenase inhibitor ibuprofen attenuated 15-E(2t)-IsoP-induced cytotoxicity. Susceptibility of progenitor OLs was independent of TxA(2) receptor (TP) expression, which was far less in progenitor than in mature OLs. However, TxA(2) synthase was detected in precursor but not in mature OLs, and TxA(2) mimetic U46619 induced hydroperoxides generation and progenitor OL death. The glutathione synthesis enhancer N-acetylcysteine prevented 15-E(2t)-IsoP-induced progenitor cell death. Depletion of glutathione in mature OLs with buthionine sulfoximine rendered them susceptible to cytotoxicity of 15-E(2t)-IsoP. These novel data implicate 15-E(2t)-IsoP as a product of oxidative stress that may contribute in the genesis of PVL.