1. Editor's Highlight: Pregnancy Alters Aflatoxin B1 Metabolism and Increases DNA Damage in Mouse Liver.
- Author
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Sriwattanapong K, Slocum SL, Chawanthayatham S, Fedeles BI, Egner PA, Groopman JD, Satayavivad J, Croy RG, and Essigmann JM
- Subjects
- Activation, Metabolic, Aflatoxin B1 metabolism, Aflatoxin B1 toxicity, Animals, Carcinogens metabolism, Cytochrome P-450 CYP1A2 metabolism, Cytochrome P-450 CYP3A metabolism, DNA Adducts metabolism, Female, Gestational Age, Glutathione Transferase metabolism, Guanine metabolism, Guanine toxicity, Hepatocytes metabolism, Isoenzymes metabolism, Liver metabolism, Maternal Exposure, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Pregnancy, Aflatoxin B1 analogs & derivatives, Carcinogens toxicity, DNA Damage, Guanine analogs & derivatives, Hepatocytes drug effects, Liver drug effects
- Abstract
Pregnancy is a complex physiological state, in which the metabolism of endogenous as well as exogenous agents is ostensibly altered. One exogenous agent of concern is the hepatocarcinogen aflatoxin B1 (AFB1), a foodborne fungal toxin, that requires phase I metabolic oxidation for conversion to its toxic and carcinogenic form, the AFB1-8,9-exo-epoxide. The epoxide interacts with cellular targets causing toxicity and cell death; these targets include the covalent modification of DNA leading to mutations that can initiate malignant transformation. The main detoxification pathway of the AFB1-epoxide involves phase II metabolic enzymes including the glutathione-S-transferase (GST) family. Pregnancy can modulate both phase I and II metabolism and alter the biological potency of AFB1. The present work investigated the impact of pregnancy on AFB1 exposure in mice. A single IP dose of 6âmg/kg AFB1 was administered to pregnant C57BL/6 J mice at gestation day 14 and matched non-pregnant controls. Pregnant mice accumulated 2-fold higher AFB1-N7-guanine DNA adducts in the liver when compared with nonpregnant controls 6âh post-exposure. Enhanced DNA adduct formation in pregnant animals paralleled elevated hepatic protein expression of mouse CYP1A2 and mouse homologs of human CYP3A4, phase I enzymes capable of bioactivating AFB1. Although phase II enzymes GSTA1/2 showed decreased protein expression, GSTA3, the primary enzymatic protection against the AFB1-epoxide, was unaffected at the protein level. Taken together, our results reveal that pregnancy may constitute a critical window of susceptibility for maternal health, and provide insight into the biochemical factors that could explain the underlying risks., (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology.)
- Published
- 2017
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