Synthesis of polychlorinated biphenyls and their metabolites with a modified Suzuki-coupling

A modified procedure for the synthesis of polychlorinated biphenyls (PCBs) utilizing the Suzuki-coupling, a palladium-catalyzed cross-coupling reaction, is described. The coupling of (chlorinated) benzene boronic acids with bromochlorobenzenes, using Pd(dppf)(2)Cl(2) (dppf = 1,1'-bis(diphenylphosphino)ferrocene) as the catalyst and aqueous sodium carbonate as the base, gave the desired PCB congeners in moderate to good yields. Eleven PCB congeners, including environmentally important PCB congeners and metabolites, were synthesized using this modified procedure. This new catalyst Pd(dppf)(2)Cl(2) offers the advantage of being less air-sensitive and has a longer shelf life compared to Pd(PPh(4))(4). Three new (di-)methoxylated PCB congeners were synthesized using the same procedure by either coupling a chlorinated benzene boronic acid with a bromo (di-)methoxybenzene or by coupling a (di-)methoxy benzene boronic acid with a chlorinated bromobenzene. The dimethoxylated PCB congeners were readily converted into the respective dihydroxylated PCB derivatives using boron tribromide in dichloromethane. This approach offers the advantage of high selectivity and moderate to good yields compared to conventional methods such as the Cadogan reaction and allows the use of less toxic starting materials.     

A Simple Field Method to Determine Mercury Volatilization from Soils (3 pp)

Background Estimations of gaseous mercury volatilization from soils are often complex, stationary and expensive. Our objective was to develop a mobile and more simple, easy to handle and more cost-effective field method allowing rapid estimates of potential Hg emissions from soils. Methods. The study site is located in Germany, about 100 kilometers south-westerly of Berlin and influenced by the river Elbe and its tributary Saale river. The site is representative for a lot of other floodplain locations at the river Elbe and highly polluted with Hg and other heavy metals. For our study we developed a system consisting of a glass chamber gas, two gold traps, a battery operated pump and a gas meter. Adsorbed total gaseous mercury (TGM) in the gold traps was determined by use of atomic absorption spectrometry (AAS). Results and Discussion. In contrast to the common used flux chambers we designed a chamber without inlet and named it gas suck up chamber (GSC). TGM fluxes determined with the GSC showed a very close linear correlation (r = 0.993) between the TGM content in the gold traps and the corresponding pumped gas volume. The TGM adsorbed, increased proportional with increasing gas volume indicating homogenous concentrations of gaseous mercury in the soil air sucked. In contrast to the commonly used dynamic flux chamber with the aim of precisely measuring actual fluxes of Hg from a defined soil area, we focused on developing of a measurement system which will allow rapid estimates of potential Hg emissions of a site. Earlier research at the study site indicated a high potential for releasing volatile Hg from the soil to the atmosphere. Indeed, due to the high Hg content of the soil significant amounts of TGM could be detected and no shortage was reached. Conclusion. Our initial measurements are still too few in number neither to generalize the achieved results nor discuss controlling factors and processes. However, we are pleased to communicate that the developed GSC is well suited to become an effective sampling set up to rapidly estimate the magnitude of Hg volatilization from soils. Outlook. Further measurements at other polluted locations are necessary to verify the GSC method. In addition the use of a mercury analyzer instead of gold traps is planned for faster risk assessments.     

Earth system analysis and management

A research strategy based upon models of intermediate complexity addressing crucial aspects of global environmental change is presented. The key idea behind that strategy is to compress system complexity either by formal techniques such that first-order aspects are preserved, or to employ semi-qualitative schemes to describe and simulate the dominant dynamical patterns identified by panoramic inspection.Specific realizations of the overall heuristic philosophy are introduced as elements of a comprehensive research program on global change. Topics encompass global climate modeling, a decision analysis framework for managing the global warming problem by balancing adaptation and mitigation efforts, a generic approach to integrated regional climate impact assessment and its implementation in specific regions, as well as a new technique to link regional and global patterns of environmental change by using advanced modeling tools.     

On the elasticity of range limits during periods of expansion

Dispersal is known to play a crucial role in the formation of species' ranges. Recent studies demonstrate that dispersiveness increases rapidly during the range expansion of species due to a fitness increase for dispersers at the expanding front. R. D. Holt concluded, however, that emigration should decline after the period of invasion and hence predicted some range contraction following the initial expansion phase. In this study, we evaluate this hypothesis using a spatially explicit individual-based model of populations distributed along environmental gradients. In our experiments we allow the species to spread along a gradient of declining conditions. Results show that range contraction did emerge in a gradient of dispersal mortality, caused by the rapid increase in emigration probability during invasion and selection disfavoring dispersal, once a stable range is formed. However, gradients in growth rate, local extinction rate, and patch capacity did not lead to a noticeable contraction of the range. We conclude, that the phenomenon of range contraction may emerge, but only under conditions that select for a reduction in dispersal at the range edge in comparison to the core region once the expansion period is over.     

Information processing in models for density-dependent emigration: A comparison

Density-dependent emigration has been recognized as a fitness enhancing strategy. Yet, especially in the modelling literature there is no consensus about how density-dependent emigration should quantitatively be incorporated into metapopulation models. In this paper we compare the performance of five different dispersal strategies (defined by the functional link between density and emigration probability). Four of these strategies are based on published functional relationships between local population density and emigration probability, one assumes density-independent dispersal. We use individual-based simulations of time-discrete metapopulation dynamics and conduct evolution experiments for a broad range of values for dispersal mortality and environmental stochasticity. For each set of these conditions we analyze the evolution of emigration rates in ‘monoculture experiments’ (with only one type of dispersal strategy used by all individuals in the metapopulation) as well as in selection experiments that allow a pair-wise comparison of the performance of each functional type. We find that a single-parameter ‘asymptotic threshold’ strategy - derived from the marginal value theorem - with a decelerating increase of emigration rate with increasing population density, out-competes any other strategy, i.e. density-independent emigration, a ‘linear threshold’ strategy and a flexible three-parameter strategy. Only when environmental conditions select for extremely high emigration probabilities (close to one), strategies may perform approximately equally. A simple threshold strategy derived for the case of continuous population growth performs even worse than the density-independent strategy. As the functional type of the dispersal function implemented in metapopulation models may severely affect predictions concerning the survival of populations, range expansion, or community changes we clearly recommend to carefully select adequate functions to model density-dependent dispersal.     

Chiral polychlorinated biphenyls: absorption,metabolism and excretion—a review

Seventy eight out of the 209 possible polychlorinated biphenyl (PCB) congeners are chiral, 19 of which exist under ambient conditions as stable rotational isomers that are non-superimposable mirror images of each other. These congeners (C-PCBs) represent up to 6 % by weight of technical PCB mixtures and undergo considerable atropisomeric enrichment in wildlife, laboratory animals, and humans. The objective of this review is to summarize our current knowledge of the processes involved in the absorption, metabolism, and excretion of C-PCBs and their metabolites in laboratory animals and humans. C-PCBs are absorbed and excreted by passive diffusion, a process that, like other physicochemical processes, is inherently not atropselective. In mammals, metabolism by cytochrome P450 (P450) enzymes represents a major route of elimination for many C-PCBs. In vitro studies demonstrate that C-PCBs with a 2,3,6-trichlorosubstitution pattern in one phenyl ring are readily oxidized to hydroxylated PCB metabolites (HO-PCBs) by P450 enzymes, such as rat CYP2B1, human CYP2B6, and dog CYP2B11. The oxidation of C-PCBs is atropselective, thus resulting in a species- and congener-dependent atropisomeric enrichment of C-PCBs and their metabolites. This atropisomeric enrichment of C-PCBs and their metabolites likely plays a poorly understood role in the atropselective toxicity of C-PCBs and, therefore, warrants further investigation.     

Effects of thiol antioxidants on the atropselective oxidation of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) by rat liver microsomes

Chiral polychlorinated biphenyl (PCB) congeners, such as PCB 136, are atropselectively metabolized to various hydroxylated PCB metabolites (HO-PCBs). The present study investigates the effect of two thiol antioxidants, glutathione and N-acetyl-cysteine (NAC), on profiles and chiral signatures of PCB 136 and its HO-PCB metabolites in rat liver microsomal incubations. Liver microsomes prepared from rats pretreated with phenobarbital were incubated with PCB 136 (5 μM) in the presence of the respective antioxidant (0–10 mM), and levels and chiral signatures of PCB 136 and its HO-PCB metabolites were determined. Three metabolites, 5-136 (2,2′,3,3′,6,6′-hexachlorobiphenyl-5-ol), 4-136 (2,2′,3,3′,6,6′-hexachlorobiphenyl-4-ol), and 4,5-136 (2,2′,3,3′,6,6′-hexachlorobiphenyl-4,5-diol), were detected in all incubations, with 5-136 being the major metabolite. Compared to microsomal incubations without antioxidant, levels of 4,5-136 increased with increasing antioxidant concentration, whereas levels of PCB 136 and both mono-HO-PCBs were not affected by the presence of either antioxidant. PCB 136, 4-136, and 5-136 displayed significant atropisomeric enrichment; however, the direction and extent of the atropisomeric enrichment was not altered in the presence of an antioxidant. Because 4,5-136 can either be conjugated to a sulfate or glucuronide metabolite that is readily excreted or further oxidized a potentially toxic PCB 136 quinone, the effect of both thiol antioxidants on 4,5-136 formation suggests that disruptions of glutathione homeostasis may alter the balance between both metabolic pathways and, thus, PCB 136 toxicity in vivo.     

Development of a synthetic PCB mixture resembling the average polychlorinated biphenyl profile in Chicago air

Studies of environmental and toxic effects of polychlorinated biphenyls (PCBs) are ideally performed with PCB mixtures reflecting the composition of environmental PCB profiles to mimic actual effects and to account for complex interactions among individual PCB congeners. Unfortunately, only a few laboratory studies employing synthetic PCB mixtures have been reported, in part because of the challenges associated with the preparation of complex PCB mixtures containing many individual PCB congeners. The objective of this study was to develop a PCB mixture that resembles the average PCB profile recorded from 1996 to 2002 at a satellite station of the Integrated Atmospheric Deposition Network located at the Illinois Institute of Technology (IIT) in Chicago, Illinois, using commercial PCB mixtures. Initial simulations, using published Aroclor profiles, showed that a mixture containing 65% Aroclor 1242 and 35% Aroclor 1254 was a good approximation of the target profile. A synthetic Chicago air mixture (CAM) was prepared by mixing the respective Aroclors in this ratio, followed by GC/MS/MS analysis. Comparison of the PCB profile of the synthetic mixture with the target profile suggests that the synthetic PCB mixture is a good approximation of the average IIT Chicago air profiles (similarity coefficient cos θ = 0.82; average relative percent difference = 84%). The synthetic CAM was also a reasonable approximation of the average of 184 PCB profiles analyzed in 2007 at 37 sites throughout Chicago as part of the University of Iowa Superfund Basic Research Program (isbrp), with a cos θ of 0.70 and an average relative percent difference of 118%. While the CAM and the two Chicago air profiles contained primarily di- to pentachlorobiphenyls, higher chlorinated congeners, including congeners with seven or eight chlorine atoms, were underrepresented in the synthetic CAM. The calculated TCDD toxic equivalency quotients of the synthetic CAM (2.7 ng/mg PCB) and the IIT Chicago air profile (1.6 ng/mg PCB) were comparable, but lower by two orders of magnitude than the isbrp Chicago air profile (865 ng/mg PCB) due to surprisingly high PCB 126 levels in Chicago air. In contrast, the calculated neurotoxic equivalency quotients of the CAM (0.33 mg/mg PCB) and the two Chicago air profiles (0.44 and 0.30 mg/mg PCB, respectively) were similar. This study demonstrates the challenges and methods of creating and characterizing synthetic, environmental mixtures of PCBs.     

Atropisomers of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) exhibit stereoselective effects on activation of nuclear receptors in vitro

PCB 136 is an environmentally relevant chiral PCB congener, which has been found in vivo to be present in form of rotational isomers (atropisomers). Its atropselective biotransformation or neurotoxic effects linked with sensitization of ryanodine receptor suggest that it might interact also with other intracellular receptors in a stereospecific manner. However, possible atropselective effects of PCB 136 on nuclear receptor transactivation remain unknown. Therefore, in this study, atropselective effects of PCB 136 on nuclear receptors controlling endocrine signaling and/or expression of xenobiotic and steroid hormone catabolism were investigated. PCB136 atropisomers were found to exert differential effects on estrogen receptor (ER) activation; (+)-PCB 136 was estrogenic, while (?)-PCB 136 was antiestrogenic. In contrast, inhibition of androgen receptor (AR) activity was not stereospecific. Both PCB136 stereoisomers induced the constitutive androgen receptor (CAR)-dependent gene expression; however, no significant stereospecificity of PCB 136 atropisomers was observed. PCB136 was a partial inducer of the pregnane X receptor (PXR)-dependent gene expression. Here, (?)-PCB 136 was a significantly more potent inducer of PXR activity than (+)-PCB 136. Taken together, the present results indicate that at least two nuclear receptors participating in endocrine regulation or metabolism, ER and PXR, could be regulated in an atropselective manner by chiral PCB 136. The enantioselective enrichment of PCB atropisomers in animal and human tissues may thus have significant consequences for endocrine-disrupting effects of chiral ortho-substituted PCB congeners.