Infertility observed in reproductive toxicity study of N-acetyl-L-cysteine in rats.
The toxic effects of i.v. administration of N-acetyl-l-cysteine (NAC), a component of parenteral nutrition solutions, on fertility and embryonic development were investigated in SD male and female rats at doses of 100, 300, and 1000 mg kg-1 day-1. Infertility was observed in females in the 1000-mg/kg group throughout the period from before mating to embryogenesis. No effect of NAC on the reproductive ability of the male rats was seen. The oocytes and embryos were assessed morphologically to clarify the cause of the effects of NAC. The unfertilized oocytes (UO) recovered from the ampullae of the uterine tubes and Gestational Day (GD) 1 and 2 embryos recovered from the oviducts or uterus of the rats that received NAC i.v. at a dosage of 1000 mg kg-1 day-1 for more than 1 wk before mating were assessed morphologically by stereomicroscopy. In addition, the thickness of the zona pellucida (ZP) was calculated by morphometric evaluation of the UO. Fewer UO were collected in the NAC group than in the control (nontreatment) group. Interestingly, ZP-lacking or partially ZP-lacking oocytes were observed in the NAC group, and the morphometric evaluation of the UO showed thinning of the ZP. The number of embryos in each animal was markedly decreased on GD1, and no embryos were recovered on GD2 in the NAC group. The oocytes that had ZP affected by NAC treatment were abnormal or nonviable. The findings of the present study suggest that changes in the ZP are related to the infertility associated with NAC.
Harada
Miwa
M
Division of Pharmacology, Drug Safety and Metabolism, Otsuka Pharmaceutical Factory, Inc., 115 Tateiwa, Muya-cho, Naruto, Tokushima 772-8601, Japan. haradamw@otsukakj.co.jp
Kishimoto
Koji
K
Furuhashi
Tadakazu
T
Naito
Kazuyosi
K
Nakashima
Yoshifumi
Y
Kawaguchi
Yoshiro
Y
Hiraoka
Isao
I
D000111:Acetylcysteine / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D007247:Infertility, Female / Q000139:chemically induced*; D008297:Male; D009865:Oocytes / Q000187:drug effects / Q000473:pathology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D015044:Zona Pellucida / Q000187:drug effects / Q000473:pathology
D000111:Acetylcysteine