In Utero Exposure to Benzo[a]pyrene Increases Adiposity and Causes Hepatic Steatosis in Female Mice, and Glutathione Deficiency Is Protective

Toxicol Lett. 2013 Nov 25;223(2):260-7. doi: 10.1016/j.toxlet.2013.09.017. Epub 2013 Oct 6.

Abstract

Polycyclic aromatic hydrocarbons (PAHs), including benzo[a]pyrene (BaP), are ubiquitous environmental pollutants found in tobacco smoke, air pollution, and grilled foods. Reactive metabolites and reactive oxygen species generated during PAH metabolism are detoxified by reactions involving glutathione (GSH). Early life exposures to tobacco smoke and air pollution have been linked to increased risk of obesity and metabolic syndrome. We investigated the independent and interactive effects of prenatal exposure to BaP and GSH deficiency due to deletion of the modifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in GSH synthesis, on adiposity and hepatic steatosis in adult female F1 offspring. We mated Gclm(+/-) dams with Gclm(+/-) males and treated the pregnant dams with 0, 2, or 10mg/kg/day BaP in sesame oil by oral gavage daily from gestational day 7 through 16. We analyzed metabolic endpoints in female Gclm(-/-) and Gclm(+/+) littermate F1 offspring. Prenatal BaP exposure significantly increased visceral adipose tissue weight, weight gain between 3 weeks and 7.5 months of age, hepatic lipid content measured by oil red O staining, and hepatic fatty acid beta-oxidation gene expression in Gclm(+/+), but not in Gclm(-/-), female offspring. Hepatic expression of lipid biosynthesis and antioxidant genes were decreased and increased, respectively, in Gclm(-/-) mice. Our results suggest that reported effects of pre- and peri-natal air pollution and tobacco smoke exposure on obesity may be mediated in part by PAHs. GSH deficiency is protective against the metabolic effects of prenatal BaP exposure.

Keywords: Fatty liver; Glutamate cysteine ligase; Glutathione; Obesity; Polycyclic aromatic hydrocarbons; Prenatal programming.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipose Tissue / drug effects
  • Adiposity / drug effects*
  • Animals
  • Antioxidants / pharmacology
  • Benzo(a)pyrene / toxicity*
  • Body Weight / drug effects
  • Environmental Pollutants / toxicity
  • Fatty Liver / chemically induced*
  • Fatty Liver / etiology
  • Fatty Liver / pathology
  • Female
  • Gene Expression Regulation
  • Glutamate-Cysteine Ligase / deficiency
  • Glutamate-Cysteine Ligase / genetics
  • Glutamate-Cysteine Ligase / metabolism
  • Glutathione / deficiency*
  • Kidney / drug effects
  • Liver / drug effects
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • Obesity / etiology
  • Oxidative Stress
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced
  • Prenatal Exposure Delayed Effects / pathology*

Substances

  • Antioxidants
  • Environmental Pollutants
  • Benzo(a)pyrene
  • GCLM protein, mouse
  • Glutamate-Cysteine Ligase
  • Glutathione