3 years ago

Pregnancy alters aflatoxin B1 metabolism and increases DNA damage in mouse liver.

Groopman, Sriwattanapong, Satayavivad, Egner, Fedeles, Essigmann, Chawanthayatham, Slocum, Croy
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 Phase II metabolism and alter the biological potency of AFB1. The present work investigated the impact of pregnancy on AFB1 exposure in mice. A single i.p. dose of 6 mg/kg AFB1 was administered to pregnant C57BL/6J mice at gestation day 14 and matched non-pregnant controls. Pregnant mice accumulated two-fold higher AFB1-N7-guanine DNA adducts in the liver when compared to non-pregnant controls 6 hours 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. While 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.

Publisher URL: http://doi.org/10.1093/toxsci/kfx171

DOI: 10.1093/toxsci/kfx171

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