DYSMORPHOGENIC EFFECTS OF IVOMEC IN MOUSE EMBRYOS IN VITRO

Abstract

Iverm ectin is an antiparasitic agent used in animals and humans and is often administered as a 1% solution (Ivomec, Merck) dissolved in propylene glycol and glycerol formal. Ivermectin alone produces minor adverse reactions in humans and farm animals, but mice are particularly sensitive to the drug, demonstrating neurotoxicity in adults and malformations in offspring at relatively low maternal doses. Ivom ec and its constituent solvents, propylene glycol and glycerol formal, have not been previously examined for their direct effect on embryonic development. In this study the in vitro method of whole-embryo culture was used to expose early-som ite mouse embryos to Ivomec, propylene glycol, and glycerol formal. Pure iverm ectin could not be obtained from the manufacturer and thus could not be evaluated individually. Ivomec was added to the culture medium to achieve ivermectin concentrations of 0, 5, 10, 25, and 50 ug/ ml. Controls for each group were exposed to propylene glycol and glycerol formal (no ivermectin) at the same concentrations as Ivomec-treated embryos. Em bryos were also exposed individually to propylene glycol and glycerol formal at the same concentrations used earlier: 0, 114, and 228 ug/ m l (propylene glycol) and 0, 21, 42, 104, and 208 ug/ ml (glycerol form al). Embryonic m orphology, heart rate, somite num bers, and protein levels were evaluated after 24 h in culture. Ivomec produced malform ations in early-som ite m ouse embryos in vitro in a fairly dose-dependent m anner, with malformation rates of 14% at 5 ug/ ml, 44% at 10 ug/ m l, 40% at 25 ug/ ml, and 88% at 50 ug/ m l, compared to 3% in normal controls. Corresponding controls treated with both solvents together dem onstrated a similar response, with malformation rates of 20%, 25%, 30%, and 79%, respectively, suggesting that propylene glycol and/ or glycerol formal may be largely responsible for the observed effects. When studied individually, propylene glycol was dysm orphogenic only at 228 ug/ m l, whereas glycerol form al produced dose-dependent m alform ations at 21 ug/ m l. Therefore, glycerol form al may be largely responsible for the dysm orphogenic effects of Ivom ec, but the mechanisms responsible for these effects are not yet understood.