Spatial glutathione and cysteine distribution and chemical modulation in the early organogenesis-stage rat conceptus in utero.
Glutathione (GSH), cysteine, and other low-molecular-weight thiols (LMWT) play a vital role in the detoxication of xenobiotics and endogenous chemicals. Differential alterations of LMWT status in various cell types of the developing embryo may underlie cell-specific sensitivity or resistance to xenobiotics and contribute to embryotoxicity. This study describes the spatial and temporal distribution of LMWTs in rat conceptuses and alterations produced by the non-teratogenic GSH modulator, acetaminophen (APAP). Pregnant female rats were given 125, 250, or 500 mg/kg APAP (po) on gestational day 9. Conceptal LMWT was localized histochemically using mercury orange in cryosections, and GSH and cysteine concentrations were measured by HPLC analysis. Mercury orange histofluorescence revealed a non-uniform distribution of LMWT in untreated conceptal tissues, with strongest staining observed in the ectoplacental cone (EPC), visceral yolk sac (VYS), and embryonic heart. Less intense staining was observed in the neuroepithelium. Following treatment with APAP, tissue-associated LMWT decreased dramatically except in the EPC, while exocoelomic fluid LMWT, and LMWT within embryonic lumens, increased. Exposure to 250 mg/kg APAP decreased embryonic GSH after 6 and 24 h by 46% and 38%, respectively. Acetaminophen (500 mg/kg) decreased embryonic and VYS cysteine content by 54% and 83%, respectively, after 24 h. Acetaminophen alters the spatial distribution of LMWT in rat conceptuses, particularly with respect to cysteine. The mobilization of cysteine following chemical insult may influence the ability of conceptal cells to maintain normal GSH status due to reduced availability of cysteine for de novo GSH synthesis.
Beck
M J
MJ
Toxicology Program, Department of Environmental Health Sciences, The University of Michigan, Ann Arbor, Michigan 48109-2029, USA.
McLellan
C
C
Lightle
R L
RL
Philbert
M A
MA
Harris
C
C
D000082:Acetaminophen / Q000008:administration & dosage / Q000494:pharmacology*; D000284:Administration, Oral; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism*; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D005453:Fluorescence; D005978:Glutathione / Q000378:metabolism*; D006651:Histocytochemistry; D008099:Liver / Q000378:metabolism; D010663:Phenylmercury Compounds; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013194:Staining and Labeling; D013997:Time Factors; D014018:Tissue Distribution
D018712:Analgesics, Non-Narcotic; D010663:Phenylmercury Compounds; D000082:Acetaminophen; D005978:Glutathione; D003545:Cysteine; C031504:mercury orange