Gregor Luthe

Receptor interactions by polybrominated diphenyl ethers versus polychlorinated biphenyls: a theoretical Structure-activity assessment.

The extensive body of literature regarding the interaction of polychlorinated biphenyls (PCBs) with transcription factors (receptors) has great value to understand similarities and distinctions and in formulating hypotheses regarding the activity of polybrominated diphenyl ethers (PBDEs) toward those same receptors. Our goal is to present the most comprehensive overview of PBDE effects on AhR, CAR, PXR, ER, AR, PR, DHT, TH, T3, T4 and IGF, as well as hypothetical biological activities of PPAR, RyR, GR and GABA. Aside the influence of the conformation of the ligand, we discuss its constitution influencing the binding affinity: size and polarizability, hydrophilicity, Gibbs free energy of solvation, inductive and mesomeric effects. We evaluate the techniques to determine the biologically relevant conformation of these halogenated hydrocarbons, including computation methods, X-ray and microwave spectroscopy. A novel fluoro-tagged ligand approach holds promise as tools for illuminating the steric and electronic effects in ligand-receptor interaction. Based on our assessment, we predict that PBDEs do not exhibit AhR activity themselves, but impurities are responsible for these effects.

Trimethylsilyldiazomethane: a safe non-explosive, cost effective and less-toxic reagent for phenol derivatization in GC applications.

Diazomethane is a highly explosive and toxic gas routinely employed for the quantitative and clean derivatization of phenols. We investigated the commercially available trimethylsilyldiazomethane in the presence of diisopropylethylamine as a safe, non-explosive and less-toxic alternative using six phenolic polychlorinated biphenyls as model analytes and fluoro-tagged analogues as internal standards. We compared yields and derivatization times of each method employing a liver microsomal extract as a real matrix. Steric hindrance and electronic properties of the analytes were also investigated. The alternative method afforded equal to higher derivatization yields with increased reaction times, up to 100 min, while explosion and toxic exposure risks were minimized and cost efficiency was increased above 25%. These findings demonstrate that non-explosive trimethylsilyl diazomethane produces comparable derivatization results to the dangerous diazomethane under the conditions studied.

Toxicity assessment of air-delivered particle-bound polybrominated diphenyl ethers

Human exposure to polybrominated diphenyl ethers (PBDEs) can occur via ingestion of indoor dust, inhalation of PBDE-contaminated air and dust-bound PBDEs. However, few studies have examined the pulmonary toxicity of particle-bound PBDEs, mainly due to the lack of an appropriate particle-cell exposure system. In this study we developed an in vitro exposure system capable of generating particle-bound PBDEs mimicking dusts containing PBDE congeners (BDEs 35, 47 and 99) and delivering them directly onto lung cells grown at an air-liquid interface (ALI). The silica particles and particles-coated with PBDEs ranged in diameter from 4.3 to 4.5 μm and were delivered to cells with no apparent aggregation. This experimental set up demonstrated high reproducibility and sensitivity for dosing control and distribution of particles. ALI exposure of cells to PBDE-bound particles significantly decreased cell viability and induced reactive oxygen species generation in A549 and NCI-H358 cells. In male Sprague-Dawley rats exposed via intratracheal insufflation (0.6 mg/rat), particle-bound PBDE exposures induced inflammatory responses with increased recruitment of neutrophils to the lungs compared to sham-exposed rats. The present study clearly indicates the potential of our exposure system for studying the toxicity of particle-bound compounds.

Xenobiotic geometry and media pH determine cytotoxicity through solubility.

Polychlorinated biphenyls (PCBs), a class of 209 individual congeners, have become persistent and ubiquitous environmental contaminants. The health impacts of PCBs, such as cancer, cardiovascular disease, developmental toxicity, and neurotoxicity, have been widely reported, but for many of these, the mechanisms of toxicity are still poorly understood. Many mechanistic studies involve cultured cells where the biological activity is dependent upon the solubility of the xenobiotic. In the present study, we investigated the factors that determine solubility as measured by diffraction spectroscopy and have modeled, with semiempirical and ab initio molecular orbital methods, the dihedral angle and calculated the dipole moment of a series of monofluorinated analogues (F-PCBs 3) of 4-chlorobiphenyl (PCB 3) as model compounds in vacuum and in water. We found a strong positive correlation between the dihedral angle, the rotation energy, the cavitation energy, the solubility, and the cytotoxicity in three human cell lines. The dipole moment was of minor influence. We also determined the influence of pH changes in a medium containing 10% fetal bovine serum (FBS), changes that could be expected when cells in culture are removed from a CO 2 incubator even for a short time. We found that the solubility is strongly affected by the pH and that this effect is not reversed by subsequent pH readjustment. In a study examining cytotoxicity, we showed that the actual pH and the pH history of a medium containing FBS were of major influence. We suggest that pH-driven changes in the tertiary and quaternary structure of albumin are responsible. These observations have implications for studies of the biological activity of semisoluble compounds, like PCBs and related compounds.

PCDDs, PCDFs, and PCBs co-occurrence in TiO2 nanoparticles.

In the present study, we report on the co-occurrence of persistent organic pollutants (POPs) adsorbed on nanoparticular titanium dioxide (TiO2). We report on the finding of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) on the surface of commercially available TiO2 nanoparticles, being formed during the fabrication process of the TiO2. Thereby, the samples comprise PCBs with higher congener numbers or, in the absence of PCBs, a high concentration of PCDDs and PCDFs. This new class of POPs on an active catalytic surface and the great range of applications of nanoparticular TiO2, such as in color pigments, cosmetics, and inks, give rise to great concern due to their potential toxicity.

Nanoparticular surface-bound PCBs, PCDDs, and PCDFs-a novel class of potentially higher toxic POPs

In a previous study, Env Sci Poll Res:1-7, 2015 showed that polychlorinated biphenyls (PCBs), polychlorinated dibenzo dioxins (PCDDs), and polychlorinated dibenzo furanes (PCDFs) are found in commercially available (nano) particular titanium dioxide as a result of the fabrication. Here, we give a brief perspective and reason the toxicity of these new classes of persistent organic pollutants (POPs) by reviewing also their nanoparticular properties, such as surface-to-volume ratio, photocatalytic activity, polarity shifts, and stealth effect. These insights point towards a new class of POPs and toxicologic effects, which are related to the size but not a result of nanotechnology itself. We pave the way to the understanding of until now unresolved very complex phenomena, such as the indoor exposure, formation, and transformation of POP and sick-building syndrome. This is a fundamental message for nanotoxicology and kinetics and should be taken into account when determining the toxicity of nanomaterials and POPs separately and as a combination.

Mechanistic insights into the specificity of human cytosolic sulfotransferase 2A1 (hSULT2A1) for hydroxylated polychlorinated biphenyls through the use of fluoro-tagged probes

Determining the relationships between the structures of substrates and inhibitors and their interactions with drug-metabolizing enzymes is of prime importance in predicting the toxic potential of new and legacy xenobiotics. Traditionally, quantitative structure activity relationship (QSAR) studies are performed with many distinct compounds. Based on the chemical properties of the tested compounds, complex relationships can be established so that models can be developed to predict toxicity of novel compounds. In this study, the use of fluorinated analogues as supplemental QSAR compounds was investigated. Substituting fluorine induces changes in electronic and steric properties of the substrate without substantially changing the chemical backbone of the substrate. In vitro assays were performed using purified human cytosolic sulfotransferase hSULT2A1 as a model enzyme. A mono-hydroxylated polychlorinated biphenyl (4-OH PCB 14) and its four possible mono-fluoro analogues were used as test compounds. Remarkable similarities were found between this approach and previously published QSAR studies for hSULT2A1. Both studies implicate the importance of dipole moment and dihedral angle as being important to PCB structure in respect to being substrates for hSULT2A1. We conclude that mono-fluorinated analogues of a target substrate can be a useful tool to study the structure activity relationships for enzyme specificity.