In vitro and in vivo induction of cytochrome P450 by coplanar polychlorinated/brominated biphenyls (Co-PXBs) providing high TEQ in mother’s milk in Japan

• Published in: Toxicology (Amsterdam) Vol. 324; pp. 68 - 75
• Main Authors: Kakutani, Hideki, Aozasa, Osamu, Mizuno, Ayami, Akiyama, Ema, Nakao, Teruyuki, Ohta, Souichi
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 03.10.2014
• Subjects: 7-ethoxyresorufin-O-deethoxyrase activity; Adult; Animals; Aryl hydrocarbon receptor; Basic Helix-Loop-Helix Transcription Factors - drug effects; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biocompatibility; Breast Milk Expression; Coplanar polychlorinated/brominated biphenyls; Cytochrome P-450 CYP1A1 - biosynthesis; Cytochrome P-450 CYP1A1 - genetics; Cytochromes P450; Dose-Response Relationship, Drug; Emergency; Environmental Pollutants - metabolism; Environmental Pollutants - toxicity; Enzyme Induction; Exposure; Female; Hep G2 Cells; Hepatocytes - drug effects; Hepatocytes - enzymology; Humans; In vitro testing; Japan; Liver - drug effects; Liver - enzymology; Maternal Exposure; Mice; Mice, Inbred C57BL; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Milk; Milk, Human - metabolism; Polybrominated Biphenyls - metabolism; Polybrominated Biphenyls - toxicity; Polychlorinated Biphenyls - metabolism; Polychlorinated Biphenyls - toxicity; Receptors, Aryl Hydrocarbon - drug effects; Receptors, Aryl Hydrocarbon - metabolism; Risk Assessment; RNA, Messenger - biosynthesis; Toxic; Toxicity; Toxicology; Transcription, Genetic; Young Adult; Japan; Coplanar polychlorinated/brominated biphenyls; TCDD; Co-PBB; municipal solid waste; 7-ethoxyresorufin- O-deethoxyrase activity; aryl hydrocarbon receptor; polychlorinated dibenzo- p-dioxins and dibenzo- p-furans; LDH; polycyclic aromatic hydrocabons; coplanar polybrominated biphenyl; AROD; TDI; CYP; ethoxyresorufin- O-deethylase; relative potency; 2,3,7,8-tetrachlorobibenzo- p-dioxin; alkoxyresorufin- O-dealkylase; EROD; tolerable daily intake; Co-PCB; lactate dehydrogenase; AhR; toxic equivalency factor; cytochrome P450; PXDDs/DFs; PCDDs/DFs; MSW; coplanar polychlorinated/brominated biphenyl; PROD; polychlorinated/brominated dibenzo- p-dioxins and dibenzo- p-furans; brominated flame retardants; TEF; coplanar polychlorinated biphenyl; PAHs; BFRs; pentoxyresorufin- O-depenthylase; REP; GAPDH; Co-PXB; glyceraldehyde 3-phosphate dehydrogenase; 7-ethoxyresorufin-O-deethoxyrase activity; Aryl hydrocarbon receptor
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2014.07.008

Abstract Coplanar polychlorinated/brominated biphenyls (Co-PXBs) are environmental pollutants previously identified in market fish samples. In this study, we observed that mother’s milk in Japan is contaminated with Co-PXBs. Based on assumption that the toxicity of the same congener of PXDDs/DFs and Co-PXBs is nearly equal to that of the corresponding PCDDs/DFs and Co-PCBs, respectively, the toxic equivalent (TEQ) concentration was 10% of the total TEQ concentration (∑PCDDs/DFs, ∑PXDDs/DFs, ∑Co-PCBs and ∑Co-PXBs) in the milk. This observation suggested that humans, and especially infants, are exposed to high levels of Co-PXBs, which might cause adverse effects. However, the toxicity of Co-PXBs has to date not been reported. We assessed the toxic potency of Co-PXBs by studying their effect on the activity of cytochrome P450. Only the mRNA level and activity of CYP1A increased in a dose-dependent manner upon exposure to Co-PXBs. Substitution of bromine for chlorine into Co-PCBs provided higher CYP1A activity in in vitro and in vivo experiments. The expression level of aryl hydrocarbon receptor (AhR) mRNA was not altered, but luciferase activity, an indicator of AhR transcriptional activity, increased following treatment with Co-PXBs. The results suggest that CYP1A induction by Co-PXBs depended on AhR transcriptional activity and not on AhR expression. Although the TEFs of Co-PXBs are not set, if Co-PXBs are included in these calculations because of their higher toxicity compared to Co-PCBs, exposure to Co-PXBs cannot be neglected when assessing human health risks.