title: Modulation of glutathione and glutamate-L-cysteine ligase by methylmercury during mouse development.
abstract: The antioxidant tripeptide glutathione has been proposed to be important in defense against oxidative stress and heavy metal toxicity. We evaluated alterations in glutathione regulation and synthesis associated with low-level chronic methylmercury (MeHg) exposure in the developing mouse fetus. Female C57Bl/6 mice were given 0, 3, or 10 ppm MeHg in the drinking water for 2 weeks prior to breeding and throughout pregnancy. Fetuses were collected on gestational days (gd) 12 and 16. Total glutathione, reduced glutathione (GSH), oxidized glutathione (GSSR), and glutamate-L-cysteine ligase (Glcl) activity were assessed in yolk sacs and fetuses at gd 16. Western and Northern blots for Glcl-catalytic (Glclc) and Glcl-regulatory (Glclr) subunits were performed on gd 12 and gd 16 fetuses. There were no changes in total glutathione in gd 16 mouse fetuses with exposure, but there were dose-related decreases in GSH and increases in GSSR. In contrast, visceral yolk sacs exhibited an increase in total glutathione in the low-dose groups, but no changes in the high-dose group. There were no changes in Glcl activity in fetuses, but there was a 2-fold increase in Glcl activity in yolk sacs from both low-dose and high-dose groups. There was a 2-fold induction in GLCLC: mRNA and protein in the gd 16 yolk sacs at both 3 and 10 ppm MeHg. No treatment-related changes in Glclr protein in either gd 12 or gd 16 yolk sacs or fetuses were found. Thus, the yolk sac is capable of up-regulating Glclc and GSH synthetic capacity in response to MeHg exposure. This increase appears to be sufficient to resist MeHg-induced GSH depletion in the yolk sac; however fetal glutathione redox status is compromised with exposure to 10 ppm MeHg.
authors.affiliation: Department of Environmental Health, University of Washington, Seattle, Washington 98195, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Thompson
authors.forename: C C
authors.initials: CC
authors.lastname: White
authors.forename: C M
authors.initials: CM
authors.lastname: Krejsa
authors.forename: D L
authors.initials: DL
authors.lastname: Eaton
authors.forename: T J
authors.initials: TJ
authors.lastname: Kavanagh
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005333:Fetus / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D008628:Mercury / Q000378:metabolism; D008767:Methylmercury Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D015017:Yolk Sac / Q000378:metabolism
chemical_list: D008767:Methylmercury Compounds; D005721:Glutamate-Cysteine Ligase; D008628:Mercury; D005978:Glutathione