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

Kanokwan Sriwattanapong, Stephen L. Slocum, Supawadee Chawanthayatham, Bogdan I. Fedeles, Patricia A. Egner, John D. Groopman, Jutamaad Satayavivad, Robert G. Croy, John M. Essigmann

Research output: Contribution to journalArticlepeer-review

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 6 mg/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 6h 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.

Original languageEnglish (US)
Pages (from-to)173-179
Number of pages7
JournalToxicological Sciences
Volume160
Issue number1
DOIs
StatePublished - Nov 1 2017

Keywords

  • Aflatoxin B1
  • DNA adducts
  • Early life exposure
  • Maternal exposure
  • Maternal fetal health axis

ASJC Scopus subject areas

  • Toxicology

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