Bioaccumulation of PCB & DDE methyl sulfones in marine mammals and their interactions with receptor proteins

PCB and DDE-Methyl sulphone metabolites are the product of enzymatic and bile acid entero hepatic metabolism in the final phase (III) of PCB and DDE detoxification in mammals following hepatic microsomal cytochrome P450-dependent metabolism (phase I) and conjugation (phase II). There is good evidence that PCB and DDE methyl sulphone (MSF) metabolites interfere with steroid binding to a receptor protein in uterine epithelium (uteroglobin - UG2 and bronchial epithelium (clara cell secretory protein - CCSP). UG and CCSP are homologous 16,000 Da proteins with different tissue-specific functions. UG binds progesterone in the pre-implantation uterus to signal localised endometrial thickening and capillary formation, vital for successful attachment of the fertilised embryo. PCB-MSFs can displace progesterone in the mammalian uterus due to their higher affinity for UG, resulting in implantation failure or early fetal death. CCSP however, functions to sequester phospholipase A2 (PLA2) released in response to stress (pathogenic infection / injury) to suppress inflammatory responses triggered by PLA2 in bronchial epithelium. CCSP is also known as retinol-binding protein (RBP) transporting retinol (vit A) to target epithelia for a functional immune response*. Studies with Harbour Seals demonstrated displacement of retinol from RBP by hydroxy-PCB metabolites resulting in immunosuppression. PCB-MSFs have been shown to accumulate in clara cells and uterine epithelium in laboratory radioactive tracer studies and CCSP-knock out studies with mice. PCB and DDE -MSFs burdens have been found in marine mammals, suggesting they may be subject to reproductive and immuno-toxic effects of these metabolites. This study determines PCB and DDE-MSFs burdens in tissues (including lung & uterus) of Harbour Seal (Phoca vitulina) and Striped Dolphin (Stenella coeruleoalba) morbillivirus victims and characterises the marine mammalian UG/CCSP protein

Multimode waveguides of Photodefinable epoxy for optical backplane applications

We developed photodefined, multimode-fiber compatible waveguides based on epoxies. These waveguides will be embedded in backplane PCB’s for optical interconnect applications using 850 nm VCSELs as light sources. Apart from very low loss, the material selection took into account, PCB compatibility and low yellowing due to high temperature processing (for PCB lamination and soldering). The waveguides showed losses < 0.06 dB/cm at 832 nm and 633 nm. Their loss increase after aging (1 hr at 185 °C) was limited to 0.04 dB/cm at 850 nm. Waveguides realized on FR-4 (epoxyfiberglass)PCB material are demonstrated

A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.

A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m(2)/day or 150 mg/m(2)/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m(2)/day or 125 mg/m(2)/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity

Metabolism of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) atropisomers in tissue slices from phenobarbital or dexamethasone-induced rats is sex-dependent.

1. Chiral polychlorinated biphenyls (PCBs) such as PCB 136 enantioselectively sensitize the ryanodine receptor (RyR). In light of recent evidence that PCBs cause developmental neurotoxicity via RyR-dependent mechanisms, this suggests that enantioselective PCB metabolism may influence the developmental neurotoxicity of chiral PCBs. However, enantioselective disposition of PCBs has not been fully characterized. 2. The effect of sex and cytochrome P450 (P450) enzyme induction on the enantioselective metabolism of PCB 136 was studied using liver tissue slices prepared from naïve control (CTL), phenobarbital (PB; CYP2B inducer) or dexamethasone (DEX; CYP3A inducer) pretreated adult Sprague-Dawley rats. PCB 136 metabolism was also examined in hippocampal slices derived from untreated rat pups. 3. In liver tissue slices, hydroxylated PCB (OH-PCB) profiles depended on sex and inducer pretreatment, and OH-PCB levels followed the rank orders male &gt; female and PB &gt; DEX &gt; CTL. In contrast, the enantiomeric enrichment of PCB 136 and its metabolites was independent of sex and inducer pretreatment. Only small amounts of PCB 136 partitioned into hippocampal tissue slices and no OH-PCB metabolites were detected. 4. Our results suggest that enantioselective metabolism, sex and induction status of P450 enzymes in the liver may modulate the neurotoxic outcomes of developmental exposure to chiral PCBs

Evaluating the Role of the Steroid and Xenobiotic Receptor (SXR/PXR) in PCB-153 Metabolism and Protection against Associated Adverse Effects during Perinatal and Chronic Exposure in Mice.

BACKGROUND:Polychlorinated biphenyls (PCBs) are environmental toxicants; PCB exposure has been associated with adverse effects on wildlife and humans. However, the mechanisms underlying these adverse effects are not fully understood. The steroid and xenobiotic receptor [SXR; also known as the pregnane X receptor (PXR) and formally known as NR1I2] is a nuclear hormone receptor that regulates inducible metabolism of drugs and xenobiotics and is activated or inhibited by various PCB congeners. OBJECTIVES:The aim of this study was to investigate the effects of exposure to PCB-153, the most prevalent PCB congener in human tissues, on SXR knockout mice (SXRKO) and to elucidate the role of SXR in PCB-153 metabolism and promotion of its harmful effects. METHODS:Wild-type (WT) and SXRKO mice were chronically or perinatally exposed to a low dose (54μg/kg/d) of PCB-153. Blood, livers, and spleens were analyzed using transcriptome sequencing (RNA-seq) and molecular techniques to investigate the impacts of exposure on metabolism, oxidative stress, and hematological parameters. RESULTS:SXRKO mice perinatally exposed to PCB-153 displayed elevated oxidative stress, symptoms of hemolytic anemia, and premature death. Transcriptomal analysis revealed that expression of genes involved in metabolic processes was altered in SXRKO mice. Elevated levels of the PCB-153 metabolite, 3-OH-PCB-153, were found in exposed SXRKO mice compared to exposed WT mice. Blood hemoglobin (HGB) levels were lower throughout the lifespan, and the occurrence of intestinal tumors was larger in SXRKO mice chronically exposed to PCB-153 compared to vehicle and WT controls. DISCUSSION:Our results suggest that altered metabolism induced by SXR loss of function resulted in the accumulation of hydroxylated metabolites upon exposure to PCB-153, leading to oxidative stress, hemolytic anemia, and tumor development in a mouse model. These results support a major role for SXR/PXR in protection against xenobiotic-induced oxidative stress by maintaining proper metabolism in response to PCB-153 exposure. This role of SXR could be generally applicable to other environmental toxicants as well as pharmaceutical drugs. https://doi.org/10.1289/EHP6262

Application of Polychlorinated Biphenyl Signatures for Environmental Fingerprinting

Chapter 2 has been produced based on the original research of Megson et al., (2013b), which was published in Science of the Total Environment (DOI: http://dx.doi.org/10.1016/j.scitotenv.2013.04.082) (presented as Appendix A). Chapter 3 is based in part on the original research of Megson et al., (2013a), which was published in the Journal of Chromatography A (DOI: http://dx.doi.org/10.1016/j.chroma.2013.10.016) (presented as Appendix B). Chapter 5 has been produced based in part on the original research of Megson et al. (2014), which was published in Chemosphere (DOI: http://dx.doi.org/10.1016/j.chemosphere.2014.04.061) (presented as Appendix D).Polychlorinated Biphenyls (PCBs) are a group of 209 ‘man-made’ chlorinated organic compounds that were widely used in the 20th century for a variety of industrial uses. PCBs were first commercially produced in the 1929 and were manufactured until the 1980s when their use was phased out due to environmental and human health risks. However, due to their widespread use and persistence they are ubiquitous in the environment and remain a contaminant of concern. The structural properties that determine the persistence of PCBs in humans were therefore elucidated by statistical analysis of data from the National Health and Nutrition Examination Survey (NHANES). PCBs with chlorine bonding in the 2,5-and 2,3,6- positions (and 2- in di- and tri-chlorinated congeners) were rapidly biotransformed and so can be classed as episodic congeners whereas PCBs with chlorine bonding in the 2,3,4-, 2,4,5-, 3,4,5-, and 2,3,4,5- positions were more resistant to biotransformation and can therefore be classed as steady state congeners. A fundamental requirement of using PCB signatures for environmental fingerprinting is an effective analytical method capable of producing high resolution signatures from biological samples. An extraction and clean-up method was developed that was successfully applied to different biological matrices (blood and tissues). A two dimensional gas chromatography with time of flight mass spectrometry (GCxGC-ToFMS) method was designed and optimised to provide a congener specific method capable of identifying 200 out of the 209 PCBs, with detection limits in human serum in the range of 1 to 10 ng g-1 lipid. The extraction and detection methods were used to determine the source of PCB contamination and age date exposure in workers at a transformer dismantling plant. A total of 84 different PCB congeners were identified in the sera of 30 workers with concentrations of the 7 indicator PCBs ranging from 1.2 - 39 μg g-1 lipid. Analysis of PCB signatures was able to distinguish recent from prolonged exposure and also identified an additional source of inhalation exposure in a subgroup of workers. Analysis of 12 different tissue types obtained from the common guillemot (Uria aalge) suggested a high degree of perpetuation between the PCB signature in different tissue types. This shows that comparative assessments can be undertaken between animals using different tissue types and that small (1 g) samples of blood can be used as a non-lethal sampling technique. The regional provenance of 25 wrecked Leach’s storm petrels (Oceanodroma leucorhoa) was also determined using PCB signatures. Results from GCxGC-ToFMS analysis revealed distinctively different PCB signatures in birds from Canada and Europe. The findings reported in this thesis enhance our understanding of PCB signatures in the environment and show how they can be used effectively to age date and identify the source of exposure in humans and animals