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 > female and PB > DEX > 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

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

Phytocannabinoids as novel therapeutic agents in CNS disorders

The Cannabis sativa herb contains over 100 phytocannabinoid (pCB) compounds and has been used for thousands of years for both recreational and medicinal purposes. In the past two decades, characterisation of the body's endogenous cannabinoid (CB) (endocannabinoid, eCB) system (ECS) has highlighted activation of central CB1 receptors by the major pCB, Δ9-tetrahydrocannabinol (Δ9-THC) as the primary mediator of the psychoactive, hyperphagic and some of the potentially therapeutic properties of ingested cannabis. Whilst Δ9-THC is the most prevalent and widely studied pCB, it is also the predominant psychotropic component of cannabis, a property that likely limits its widespread therapeutic use as an isolated agent. In this regard, research focus has recently widened to include other pCBs including cannabidiol (CBD), cannabigerol (CBG), Δ9tetrahydrocannabivarin (Δ9-THCV) and cannabidivarin (CBDV), some of which show potential as therapeutic agents in preclinical models of CNS disease. Moreover, it is becoming evident that these non-Δ9-THC pCBs act at a wide range of pharmacological targets, not solely limited to CB receptors. Disorders that could be targeted include epilepsy, neurodegenerative diseases, affective disorders and the central modulation of feeding behaviour. Here, we review pCB effects in preclinical models of CNS disease and, where available, clinical trial data that support therapeutic effects. Such developments may soon yield the first non-Δ9-THC pCB-based medicines

Stigma scale of epilepsy - Validation process

Purpose: To validate a Stigma Scale of Epilepsy (SSE). Methods: The SSE was completed by 40 adult with epilepsy attending an Outpatient Epilepsy Clinic at the University Hospital of UNICAMP, and by 40 people from the community. People were interviewed on an individual basis; a psychologist read the questions to the subjects who wrote the answers in a sheet. The procedure was the same for all the subjects and completion took around ten minutes. Results: The SSE has 24 items. The internal consistency of the SSE showed alpha. Cronbach's coefficient 0.88 for the patients with epilepsy and 0.81 for the community. The overall mean scores of the Stigma Scale of Epilepsy formula were: 46 (SD=18.22) for patients and 49 (SD=13.25) for the community where a score of 0 would suggest no stigma, and 100 maximum stigma. Discussion: The SSE has satisfactory content validity and high internal consistency. It allows the quantification of the perception of stigma by patients and people from community; this can then be used for interventional studies, such as mass media campaign in minimizing the negative facets of stigma