Ethylene glycol developmental toxicity: unraveling the roles of glycolic acid and metabolic acidosis.
This study sought to determine the relative roles of glycolic acid (GA), a toxicologically important metabolite of ethylene glycol (EG), and metabolic acidosis in causing developmental toxicity in Sprague-Dawley rats. To tease apart these two interrelated factors, we developed an experimental approach in which high blood glycolate levels could be achieved, in either the presence or absence of metabolic acidosis. Initially, rats previously implanted with a carotid artery cannula were given, on gestation day (gd) 10, 40.3 mmol/kg (2500 mg/kg) of EG via gavage, 8.5 mmol/kg (650 mg/kg) of GA via gavage, 8.5 mmol/kg (833 mg/kg) of sodium glycolate (NaG; pH 7.4) via subcutaneous (sc) injection, or distilled water via gavage (control). Peak serum glycolate was nearly identical (8.4-8.8 mM) in the EG, GA, and NaG groups and, as expected, EG and GA caused a metabolic acidosis, but acid base balance was normal with NaG. Subsequently, these treatments were given on gd 6-15 to groups of 25 time-mated rats, followed by fetal evaluation on gd 21. EG and GA decreased fetal body weights and caused a similar spectrum of developmental effects, including numerous axial skeleton malformations. NaG treatment also caused slight decreases in fetal body weight, increases in skeletal variations, and totally malformed fetuses. These results indicate that glycolate, in the absence of metabolic acidosis, can cause the most sensitive of EG's developmental effects, whereas metabolic acidosis appears to interact with glycolate at very high doses to markedly enhance teratogenesis. These results support previous studies, which indicated that glycolate is the proximate developmental toxicant for EG, and that GA toxicokinetic parameters can be used to define a quantitative, physiologically based threshold for EG-induced developmental effects.
Carney
E W
EW
Health and Environmental Research Laboratories, The Dow Chemical Company, Midland, Michigan 48674, USA.
Freshour
N L
NL
Dittenber
D A
DA
Dryzga
M D
MD
D000138:Acidosis / Q000139:chemically induced*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000002:abnormalities / Q000187:drug effects; D019855:Ethylene Glycol / Q000378:metabolism* / Q000633:toxicity; D005260:Female; D005333:Fetus / Q000002:abnormalities* / Q000187:drug effects; D006016:Glycolates / Q000097:blood / Q000633:toxicity*; D007641:Keratolytic Agents / Q000097:blood / Q000633:toxicity; D008297:Male; D008431:Maternal-Fetal Exchange / Q000187:drug effects*; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000633:toxicity; D013997:Time Factors
D006016:Glycolates; D007641:Keratolytic Agents; D013723:Teratogens; C031149:glycolic acid; D019855:Ethylene Glycol