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

Abstract

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.