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Embryonic oxidative stress as a mechanism of teratogenesis with special emphasis on diabetic embryopathy
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Abstracts / Reproductive Toxicology 24 (2007) 57–80
Embryonic oxidative stress as a mechanism of teratogenesis with special emphasis on diabetic embryopathy
Effect of Pinellia ternata extract on fetal development of rats
Asher Ornoy
Sunhee Shin, Dongsun Park, Jeong Hee Jeon, Sang-Yoon Nam, Young Won Yun, Yun-Bae Kim ∗
Laboratory of Teratology, Department of Anatomy and Cell Biology, Hebrew University-Hadassah Medical School, and Israeli Ministry of Health, Jerusalem, Israel
College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, South Korea
Reactive oxygen species (ROS) are involved in the etiology of numerous diseases including cardiovascular diseases and diabetes mellitus. There is evidence that several teratogens affect the developing embryo by increasing its oxidative stress and, because of its relatively weak antioxidant defense, especially at the early stages of organogenesis, result in severe embryonic damage. This mechanism seems to operate in diabetes-induced embryonic damage as well as in the mechanism of teratogenicity caused by ionizing radiation, hypoxia, alcohol and cocaine use and cigarette smoking. We studied the role of oxidative stress in diabetic induced embryopathy, both in vivo and in vitro. Under diabetic condition there was a significant decrease in the activity of endogenous antioxidant enzymes and of vitamins C and E in the embryos and their yolk sacs. The lowest activity was observed in the malformed experimental embryos when compared to experimental embryos without anomalies. Similar results were obtained in the Cohen Diabetic rats, where the diabetic prone (CDs) rats were unable to increase their antioxidant enzyme activity in spite of the diabetes. Studies performed by other investigators show similar results. Human and animal studies show that the main mechanism of fetal damage induced by high levels of ionizing irradiation, cocaine and alcohol abuse, hypoxia and cigarette smoking is also by increased embryonic oxidative stress. Similarly, several drugs exert their teratogenic activity via embryonic oxidative stress. Abnormal placentation may also cause enhanced placental oxidative stress, resulting in embryonic death, preeclampsia or congenital anomalies. Inability of the developing embryo to cope with that stress may result in embryonic death and/or congenital anomalies. Animal studies also show that a variety of antioxidants are effective in decreasing the damaging effects of heightened oxidative stress induced by teratogens. Effective antioxidants, which might also be of clinical use, include vitamins C and E, carotenoids, folic acid, as well as synthetic products. Appropriate clinical studies with antioxidants in pregnancies of high risk to develop oxidative stress are needed, since non-toxic antioxidants might prove an efficient and inexpensive way to reduce the rate of some serious and sometimes fatal congenital anomalies.
The effect of extract of Pinellia ternata, one of the mostwidely used plants in Oriental medicine, on fetal development was investigated in rats. Pregnant Sprague–Dawley rats were orally administered with the Pinellia extract (20, 200 or 2000 mg/kg) from 6 to 15 of gestation. On day 20 of gestation, the maternal and fetal abnormalities were examined under Caesarian section. There were neither clinical signs, nor changes in body weight gain, feed and water consumptions, fertility parameters, placental and organ weights in Pinellia-treated dams. However, the Pinellia extract at high doses (200–2000 mg/kg) caused visceral abnormalities of fetuses. That is, the rates of ureteric dilatation and renal malposition significantly increased in a dose-dependent manner, leading to 33.3% visceral malformations (15.7% in control group) and to 15.8% variations (4.3% in control group) following treatment with 2000 mg/kg of Pinellia extract. In addition, the Pinellia extract remarkably enhanced the rates of skeletal malformations and variations of fetuses, resulting in asymmetric alignment of ribs (11.1%), dumbbell ossification of thoracic centrum (5.0%) and 14th supernumerary ribs (12.1%) in a high dose (2000 mg/kg). Interestingly, mRNA of catalase, glutathione peroxidase, transforming growth factor, p53, c-fos and bcl-2 were affected by treatment of Pinellia extract. Taken together, it is proposed that maternal exposure to high doses of Pinellia extract might cause fetal abnormalities by influencing the expression of antioxidant, growth factor, apoptosis and tumor-related genes.
Keywords: Antioxidants; Oxidative stress; Diabetes; Hypoxia; Alcohol; Cocaine; Ionizing radiation; Cigarette smoking doi:10.1016/j.reprotox.2007.04.052
Keywords: Pinellia ternate; Fetal abnormalities; Gene expression doi:10.1016/j.reprotox.2007.04.053 Effects of adrenalectomy and aryl hydrocarbon receptor antagonists on teratogenicity of 2,3,7,8-tetrachlorodibenzop-dioxin in C57BL/6J mice Dongsun Park, Sunhee Shin, Jeong Hee Jeon, Ja Young Jang, Byong-il Choi, Yun-Bae Kim ∗ College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, South Korea Effects of adrenalectomy and aryl hydrocarbon receptor (AhR) antagonists, ␣-naphthoflavone and resveratrol, on the reproductive toxicity and fetal malformations induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were investigated in mice. Pregnant C57BL/6J mice were bilaterally adrenalectomized on gestational day (GD) 7 or orally administered with ␣-naphthoflavone (5 mg/kg) or resveratrol (50 mg/kg) on
Abstracts / Reproductive Toxicology 24 (2007) 57–80
Embryonic oxidative stress as a mechanism of teratogenesis with special emphasis on diabetic embryopathy
Effect of Pinellia ternata extract on fetal development of rats
Asher Ornoy
Sunhee Shin, Dongsun Park, Jeong Hee Jeon, Sang-Yoon Nam, Young Won Yun, Yun-Bae Kim ∗
Laboratory of Teratology, Department of Anatomy and Cell Biology, Hebrew University-Hadassah Medical School, and Israeli Ministry of Health, Jerusalem, Israel
College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, South Korea
Reactive oxygen species (ROS) are involved in the etiology of numerous diseases including cardiovascular diseases and diabetes mellitus. There is evidence that several teratogens affect the developing embryo by increasing its oxidative stress and, because of its relatively weak antioxidant defense, especially at the early stages of organogenesis, result in severe embryonic damage. This mechanism seems to operate in diabetes-induced embryonic damage as well as in the mechanism of teratogenicity caused by ionizing radiation, hypoxia, alcohol and cocaine use and cigarette smoking. We studied the role of oxidative stress in diabetic induced embryopathy, both in vivo and in vitro. Under diabetic condition there was a significant decrease in the activity of endogenous antioxidant enzymes and of vitamins C and E in the embryos and their yolk sacs. The lowest activity was observed in the malformed experimental embryos when compared to experimental embryos without anomalies. Similar results were obtained in the Cohen Diabetic rats, where the diabetic prone (CDs) rats were unable to increase their antioxidant enzyme activity in spite of the diabetes. Studies performed by other investigators show similar results. Human and animal studies show that the main mechanism of fetal damage induced by high levels of ionizing irradiation, cocaine and alcohol abuse, hypoxia and cigarette smoking is also by increased embryonic oxidative stress. Similarly, several drugs exert their teratogenic activity via embryonic oxidative stress. Abnormal placentation may also cause enhanced placental oxidative stress, resulting in embryonic death, preeclampsia or congenital anomalies. Inability of the developing embryo to cope with that stress may result in embryonic death and/or congenital anomalies. Animal studies also show that a variety of antioxidants are effective in decreasing the damaging effects of heightened oxidative stress induced by teratogens. Effective antioxidants, which might also be of clinical use, include vitamins C and E, carotenoids, folic acid, as well as synthetic products. Appropriate clinical studies with antioxidants in pregnancies of high risk to develop oxidative stress are needed, since non-toxic antioxidants might prove an efficient and inexpensive way to reduce the rate of some serious and sometimes fatal congenital anomalies.
The effect of extract of Pinellia ternata, one of the mostwidely used plants in Oriental medicine, on fetal development was investigated in rats. Pregnant Sprague–Dawley rats were orally administered with the Pinellia extract (20, 200 or 2000 mg/kg) from 6 to 15 of gestation. On day 20 of gestation, the maternal and fetal abnormalities were examined under Caesarian section. There were neither clinical signs, nor changes in body weight gain, feed and water consumptions, fertility parameters, placental and organ weights in Pinellia-treated dams. However, the Pinellia extract at high doses (200–2000 mg/kg) caused visceral abnormalities of fetuses. That is, the rates of ureteric dilatation and renal malposition significantly increased in a dose-dependent manner, leading to 33.3% visceral malformations (15.7% in control group) and to 15.8% variations (4.3% in control group) following treatment with 2000 mg/kg of Pinellia extract. In addition, the Pinellia extract remarkably enhanced the rates of skeletal malformations and variations of fetuses, resulting in asymmetric alignment of ribs (11.1%), dumbbell ossification of thoracic centrum (5.0%) and 14th supernumerary ribs (12.1%) in a high dose (2000 mg/kg). Interestingly, mRNA of catalase, glutathione peroxidase, transforming growth factor, p53, c-fos and bcl-2 were affected by treatment of Pinellia extract. Taken together, it is proposed that maternal exposure to high doses of Pinellia extract might cause fetal abnormalities by influencing the expression of antioxidant, growth factor, apoptosis and tumor-related genes.
Keywords: Antioxidants; Oxidative stress; Diabetes; Hypoxia; Alcohol; Cocaine; Ionizing radiation; Cigarette smoking doi:10.1016/j.reprotox.2007.04.052
Keywords: Pinellia ternate; Fetal abnormalities; Gene expression doi:10.1016/j.reprotox.2007.04.053 Effects of adrenalectomy and aryl hydrocarbon receptor antagonists on teratogenicity of 2,3,7,8-tetrachlorodibenzop-dioxin in C57BL/6J mice Dongsun Park, Sunhee Shin, Jeong Hee Jeon, Ja Young Jang, Byong-il Choi, Yun-Bae Kim ∗ College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, South Korea Effects of adrenalectomy and aryl hydrocarbon receptor (AhR) antagonists, ␣-naphthoflavone and resveratrol, on the reproductive toxicity and fetal malformations induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were investigated in mice. Pregnant C57BL/6J mice were bilaterally adrenalectomized on gestational day (GD) 7 or orally administered with ␣-naphthoflavone (5 mg/kg) or resveratrol (50 mg/kg) on