Teratological Evaluation of Azinphos-Methyl in Rat Fetuses

Azinphos-methyl이 랫트 태아에 미치는 기형학적 연구

This study was carried out to investigate the teratological potential of azinphos-methyl in the rat fetuses and to establish the nature of the effects on organogenesis and intrauterine development. The Sprague-Dawley female rats (180-210g) without previous litter were used in this study. Azinphos-methyl dosages of 0.094mg/kg, 0.4mg/kg, 1.5mg/kg were selected based on the acute intragastric $LD_{50}$ of 15mg/kg in the rat. Azinphos-methyl in water (Treatment Group), non-treatment control (Negative Control), water control (Sham Control), were administered by oral route and aqueous solution of acetyl salicylic acid (Positive Control) was administered by gavage at rate of 10 ml/kg of body weight from day 6 through 15. The results obtained were summarized as follows. 1. Decreased body weight of dams was observed in animals treated with aspirin and azinphos-methyl 1.5 mg/kg from day 7 through 14. (P<0.01) 2. There was an apparent decrement in the absolute liver weight in the azinphos-methyl 1.5 mg/kg treated group (P<0.05). However, the absolute and relative kidney weight in aspirin group (P<0.05, P<0.01) and the absolute and relative ovary weight in aspirin, azinphos-methyl treatment groups (P<0.01, P<0.05) were increased. 3. Decreased protein contents of dam's liver was observed in the aspirin and high dose azinphos-methyl treated group of animals (P<0.01). 4. The number of male-female ratio per dam increased in azinphos-methyl 1.5 mg/kg group but there was an apparent decrement in the body weight of fetuses in aspirin and high dose azinphos-methyl group (P<0.01, P<0.05). Total immature and resorbed fetuses were increased in aspirin group and the number of dead fetuses were also increased in azinphos-methyl 1.5mg/kg treated group of animals. (P<0.01, P<0.05). 5. In soft tissue defects, diaphragmatic hernia in diaphragm, anophthalmia, enlarged olfactory bulb, hydrocephalus, absence of third and lateral ventricle in skull, hydronephrosis in kidney, atrophy of left ventricle wall, enlarged apex in heart were observed. Especially, defects of diaphragm, heart and eye ball showed peak incidences in the high dose azinphosmethyl and aspirin group. (P<0.01). 6. Variations in the ossification patterns of skull, sternebrae, tail, forelimbs and hindlimbs showed peak incidences in the aspirin and high dose azinphos-methyl group. (P<0.01). 7. In the developmental indices of offspring, the mortality of aspirin and azinphos-methyl 1.5mg/kg treated group was higher than that of negative control. And, there was an apparent decrement in the body weight of fetuses (P<0.01) and considerable differences were obtained in pivoting, development of fur, auditory function, vision, quadrupled muscle development and testes descent in aspirin and azinphos-methyl 1.5mg/kg group. (P<0.01).

azinphos-methyl을 S.D.랫트에 투여하여 기형이 유발되는지의 여부와 태아의 기관형성 및 자궁내에서 태아의 발달에 미치는 영향을 알아보기 위하여 무처치의 negative control군, 수도물을 경구투여한 sham control군, 이미 기형효과가 있는 것으로 알려진 aspirin투여의 positive control군, 그리고 azinphosmethyl 0.094 mg/kg, 0.4 mg/kg 및 1.5mg/kg 투여군으로 나누어 각군 30마리씩으로, 임신 6~15일 사이에 경구투여한 결과는 다음과 같다. 즉, 모체의 체중증가율은 임신 7~14일, 즉 약물투여기에 aspirin 투여군과 azinphos-methyl 1.5mg/kg 투여군에서 현저한 감소를 보였다(p<0.01). 모체의 장기무게는 azinphos-methyl 1.5mg/kg 투여군에서 간장의 절대무게비가 유의성(p<0.05) 있는 감소를 보였으며, 신장의 절대 및 상대무게비는 aspirin군에서 (p<0.05, p<0.01), 또 난소의 절대 및 상대무게비는 aspirin 투여군(p<0.01)과 azinphos-methyl 전처치군(p<0.05)에서 유의성 있게 증가하였다. 모체 간장의 단백질량은 aspirin과 azinphos-methyl 1.5mg/kg 투여군에서 현저히 감소되었다(p<0.01). 모체의 배아와 태자에 대한 관찰 결과 azinphos-methyl 1.5mg/kg 투여군에서 암수의 비율에 있어 현저하게 증가(p<0.01) 했으며, 체중은 aspirin과 azinphos-methyl 1.5mg/kg 투여군에서 고도의 유의성(p<0.01) 있게 감소하였고, azinphos-methyl 0.4 mg/kg 투여군에서도 현저하게 감소하였다(p<0.05). 그리고 미숙태자와 흡수태자는 aspirin군에서, 죽은 태자수는 azinphos-methyl 1.5mg/kg 투여군에서 유의성 있게 증가하였다(p<0.05, p<0.01). 태자의 장기에서 나타난 기형은 aspirin과 azinphos-methyl 1.5mg/kg 투여군 공히 횡경막에서 횡격막 천공, 두부에서 무안구증, olfactory bulb의 확장, 수두뇌, 그리고 3뇌실과 측뇌실의 결손, 심장에서 좌심실벽 위축, 심첨확장 등이 유의성(P<0.01, P<0.05) 있게 관찰되었으며, 특히 횡경막, 심장 및 안구등에 높은 기형발생율을 보였다. 또 태자의 골화지연은 두개골에서 후두골, 접형골, 구개, 흉골에서 4번째 흉골편, 검상돌기, 척추에서 경추, 흉추, 미추, 전${\cdot}$후지골, 중족골에서 관찰되었다. 한편, 자연 분만시킨 태자의 사망율은 azinphos-methyl 1.5mg/kg 투여군에서 negative control군에 비해 고도의 유의성(p<0.01) 있게 높음을 알 수 있었으며, 체중도 역시 현저하게(p<0.01) 감소하였고, 발육지표중 pivoting, 체모형성, 청각능력, 시각능력, 사지근육 발달정도 및 고환하강시기 등에서 고도의 유의성(p<0.01)이 관찰되었다.