Maternal and developmental toxicity in mice by aminophenylnorharman, formed from norharman and aniline.
9-(4'-Aminophenyl)-9H-pyrido [3,4-b] indole (aminophenylnorharman, APNH) is a novel mutagenic heterocyclic amine, produced by the reaction of norharman with aniline in the presence of S9 mix. In the present study, the maternal and developmental toxicity of APNH were investigated in ICR mice administered oral doses of 0, 0.625, 1.25, 2.5 or 5 mg/kg/day on gestational days (GD) 6 through 15 or 0, 5, 10, or 20 mg/kg on GD 12. Maternal and foetal parameters were evaluated on day 18 of gestation. Foetuses of dams treated on GD 6-15 were examined for external and skeletal malformations and variations, and foetuses of dams treated on GD 12 were inspected for cleft palate. Maternal death occurred when APNH was administered at 5 mg/kg/day on GD 6-15. No significant decrease in body weight gain during the administration period was observed at doses of 2.5 mg/kg/day or less when applied on GD 6-15. Adverse changes in general condition of dams were observed in the groups treated at doses of 2.5 mg/kg/day and above on GD 6-15, whereas no adverse effects on dams were noted even when APNH was applied at a fairly high dose on GD 12. Intracytoplasmic vacuolation in hepatocytes, necrosis of proximal tubular epithelial cells and desquamation of necrotic epithelial cells in the tubular lumen were observed in dams treated with APNH at 2.5 or 5 mg/kg/day on GD 6-15. Increased preimplantation loss was observed at 5 mg/kg/day and post-implantation loss was observed at 2.5 mg/kg/day and above when applied on GD 6-15, or at 20 mg/kg when applied on GD 12. Foetal body weight was decreased by APNH in a dose-dependent manner. The frequency of external malformations (cleft palate) was significantly increased in the group treated with APNH at 2.5 mg/kg/ day on GD 6-15 compared to the controls. However, there were no foetuses with cleft palate even when APNH was given at 20 mg/kg on GD 12. No significant increases in skeletally malformed foetuses were found in any APNH-treated group. The frequency of lumbar ribs was increased dose dependently. This study demonstrated the developmental toxicity of a mutagenic compound, APNH, in mice at maternally toxic doses, and that cleft palate observed in term foetuses resulted from the adverse effect of APNH on the maternal environment during organogenesis. More detailed studies are warranted to assess the possible risks to pregnant women from exposure to APNH.
Naga
T
T
Department of Life Science, Faculty of Science and Technology, Kinki University, Osaka, Japan. nagaot@kb3.so-net.ne.jp
Yoshimura
S
S
Totsuka
Y
Y
Wakabayashi
K
K
D000814:Aniline Compounds / Q000737:chemistry; D000818:Animals; D002243:Carbolines; D002972:Cleft Palate / Q000139:chemically induced; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects; D006247:Harmine / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D008813:Mice, Inbred ICR; D009153:Mutagens / Q000008:administration & dosage / Q000633:toxicity; D011247:Pregnancy; D011725:Pyridines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000633:toxicity*
D000814:Aniline Compounds; D002243:Carbolines; D007211:Indoles; D009153:Mutagens; D011725:Pyridines; D006247:Harmine; C010262:norharman; C421010:9-(4'-aminophenyl)-9H-pyrido(3,4-b)indole; C023650:aniline