• 미생물학회지
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• 제43권3호
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• pp.151-158
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• 2007

유전자치료W터의 주입시 생식세포를 통한 다음 세대로의 전달 가능성은 안전성 측면에서 관심을 중대시키고 있다. 특히 전립선암이나 난소암의 치료시 바이러스를 생식기관에 인접한 부위에 주입하여야 하므로 그 가능성이 높다. 따라서 본 연구에서는 유전자치료에 많이 이용되는 아데노바이러스를 매개로하여 tumor suppressor 유전자인 p53을 발현하는 아데노바이러스 벡터를 제조하여 이를 투여시 생식장기를 포함한 주요장기조직에의 분포와 germ cell을 통한 차세대로의 전달 가능성 등의 생식독성을 조사하였다. In vivo biodistribution study를 위하여 $Ad-CMV-{\beta}-gal$흑은 Ad-CMV-p53를 마우스 암 수의 복강에 주사한 후 생식장기를 포함한 주요 장기에서 아데노바이러스 유래 DNA검출 및 RNA발현 여부를PCR과 RT-PCR로 각각 확인하였다. 그 결과 간 및 비장과 같은 일반 장기에서도 주입한 외부유전자의 DNA가 검출되거나RNA가 발현되었을 뿐만 아니라, 정낭, 전립선, 부고환, 난소 및 자궁 등의 생식장기에서도 주입한 외부유전자가 검출되거나 발현되는 것으로 나타났다. Real-time PCR을 이용하여 각 장기에서의 투여된 아데노바이러스 벡터는 시간 의존적으로 감소되는 것을 정량하였다. Ad-CMV-p53를 암 수 마우스의 난소와 고환에 각각 직접 주사하여 교배시킨 후 그 후세대의 DNA를 분리하여 주입한 아데노바이러스 유래의 DNA를 검색한 결과, 어떠한 차세대에서도 주입한 아데노바이러스 유래의 DNA가 검출되지 않았다. 한편 생식장기에서의 PCR및 RT-PCR signal유래 vector의 위치를 확인하기 위해 매우 감도가 높은 in-situ PCR로 조사한 결과 고환의 경우 간질조직으로의 전달은 일어나나 정세관 내에는 아데노바이러스 벡터가 전달되지 않으며, 난소에서도 아데노바이러스벡터는 난포내의 난자에 전달되지 않고 기질조직에 존재하는 것으로 확인되었다. 결론적으로 복제 능력 이 결여된 아데노바이러스를 매개로 한 유전자치료제는 생식 장기에서 검출되더라도 다음 세대로 전달될 가능성은 대단히 낮음을 제시한다.

• 한국독성학회:학술대회논문집
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• 한국독성학회 2002년도 Molecular and Cellular Response to Toxic Substances
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• pp.149-150
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• 2002

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most potent halogenated aromatic hydrocarbon congener that induces expression of several genes including CYP1A. Exposure to TCDD results in many toxic actions such as carcinogenesis, hepatotoxicity, immune suppression, reproductive toxicity and developmental toxicity.(omitted)

• Toxicological Research
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• 제32권4호
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• pp.327-335
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• 2016

This study aimed to evaluate the potential toxicity and safety of ethyl hydrogen adipate (EHA) by determining its effect on the reproductive function and development of Sprague-Dawley (SD) rats at dose levels of 0 (control), 200, 400, and 800 mg/kg/day. One male and five females of the 800 mg/kg/day died. Body weight loss was observed in the males of the 800 mg/kg/day and in females of the 400 and 800 mg/kg/day. In addition, mating indices decreased and pre-implantation loss rates increased in parental animals of the 400 and 800 mg/kg/day. The gestation index decreased in the male and female rats of the 800 mg/kg/day. Moreover, the body weight of the pups from the 800 mg/kg/day group decreased on post-parturition day 4. These results indicated that the no-observed-adverse-effect level of EHA for parental males and females was 400 mg/kg/day and 200 mg/kg/day, respectively, and that for pups was 400 mg/kg/day.

• 한국수정란이식학회:학술대회논문집
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• 한국수정란이식학회 2002년도 국제심포지엄
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• pp.110-110
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• 2002

Rapidly progressive interstitial renal fibrosis has recently been reported in young women who have been on a slimming regimen including chinese herbs. Aristolochic acid, suspected as the causal factor of this renal disease, is a well known carcinogen. It has been known that Madouling (Aristolochiae fructus) contains aristolochic acid. The objective of this study was to investigate the effects of Madouling, Madouling-tang, which are the extract mixture from 10 different chinese herbs including Madouling, and aristolochic acid on reproductive and developmental toxicity. Female rats were administered orally with the extracts of Madouling, madouling-tang, and aristolochic acid from 14 days before mating to day 17 of gestation. Madouling (8mg/kg) decreased fertility in the 8mg/kg group, but Madouling-tang and aristolochic acids did not. Significant decrease of mean fetal body weights were observed in the 16mg/kg group of aristolochic acids. External, visceral and skeletal malformation of fetuses were not observed with treatment. Histopathological examination showed the discrete damage of kidney in the 8mg/kg group of Madouling and 16mg/kg groups of aristolochic acid. In whole embryo culture, Madouling and Madouling-tang caused the retardation of growth and development of embryo in the dose of 1 $\mu$g/ml and 0.02 $\mu\textrm{g}$/kg, respectively while aristolochic acids showed the similar effect in the dose of 300 $\mu\textrm{g}$/kg. These results indicate that Madouling, up to 0.05mg/kg (prescription dose to human) has no adverse effects on the fertility, reproduction and development of Sprague-Dawley rats.

• Toxicological Research
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• 제20권2호
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• pp.131-136
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• 2004

3-Monochloro-1,2-propanediol(3-MCPD) is a toxic compound, often present in different foods containing acid hydrolyzed(AH) protein, like seasonings and savory food products. The purpose of the present study was to investigate the effects of 3-MCPD on male fertility, sperm and testosterone secretion. In vivo male fertility test was performed for observing the adverse effects of 3-MCPD on the function of male reproductive system and pregnancy outcome. 0.01, 0.05, 0.25, 1 and 5 mg/kg b.w. of 3-MCPD was given daily by gavage to groups of 15 adult male SD rats for 4 weeks. At the end of pre-treatment period, males were mated overnight with normal females. Following morning, males demonstrating successful induction of pregnancy were sacrificed on that day to assess sperm parameters and histopathology of reproductive organs. The resulting pregnant females were sacrificed on day 20 of gestation to evaluate pregnancy outcome. As a result, four-week paternal administration with 3-MCPD resulted in adverse effects on male fertility and pregnancy outcome without remarkable histopathological changes in testes and epididymides; sperm motility, copulation index and fertility index were markedly decreased in the treated group and numbers of live fetuses showed steep dose-response curves. Also, spermatogenesis was investigated in this experiment. However, no effect was observed on production of sperm in testes treated with 3-MCPD for 4 weeks. Hormone assay was performed for observing the effects of 3-MCPD on testosterone and luteinizing hormone (LH) in blood and testes of male SD rats and cultured primary Leydig cell. In result, significant changes of related hormones did not observed by treatment of 3-MCPD. These results indicated that paternal treatment with 3-MCPD induced spermatotoxic effect, which caused an antifertility on male.

• Biomolecules & Therapeutics
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• 제6권1호
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• pp.82-88
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• 1998

LBO0014, a new recombinant human erythropoietin, was at dose levels of 0, 120, 600, and 3,000 IU/kg/day administered intravenously to pregnant Sprague-Dawley rats during the organogenetic period. All dams were subjected to caesarean section on day 20 of pregnancy, Effects of test substance on dams and embryonic development of Fl fetuses were examined. No treatment-related changes in clinical signs, body weight, and food consumption were observed at all doses tested. At necropsy spleen enlargement was found at 3,000 lU/kg. There was an ulcrease in the spleen weight at 600 and 3,0007/kg. Developmental toxicity was evident as increased resorptions at 3,000 lU/kg. At 600 and 3,000 RJ/kg, retarded ossification of fetuses occurred at an incidence of 31.3% and 64.7%, respectively. In addition, there was a delay in ossification of sternebrae and sacrocaudal vertebrae at 600 and 3,000 lU/kg. A decrease in the number of metacarpi and metatarsi was also seen at 3,000 nJ/kg. The results show that the no observed adverse effect dose level (NOAEL) for material toxicity was over 3,000 IU/kg/day and the NOAEL for developmental toxicity was 120 IU/kg/day.

• Toxicological Research
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• 제19권2호
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• pp.123-131
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• 2003

This study was carried out to assess the combined repeated dose, reproduction and developmental toxicities of benzoyl peroxide for OECD SIDS (Screening Information Data Set) program. Male and female Sprague-Dawley rats were exposed to benzoyl peroxide at dose levels of 0, 250, 500 and 1,000 mg/kg/day for 29 days for males and for 41-51 days for females. No deaths were found in all animals including control group during exposure period. No hematological effects attributable to benzoyl peroxide were observed in all treated groups. Significant decrease in the weight of testes and epididymis were observed in males at 1,000 mg/kg/day. In females at 1,000 mg/kg/day, slight histopathological effects in uterus such as epithelial vacuolation or hyperplasia were observed. No treatment-related changes in precoital time and rate of copulation, fertility and gestation period were noted in all treated groups. There was no evidence of teratogenic effect of benzoyl peroxide, but body weight of pups at 1,000 mg/kg/day was significantly decreased. NOAEL for combined repeated dose and reproduction/developmental toxicity was 500 mg/kg/day.

• Biomolecules & Therapeutics
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• 제6권2호
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• pp.151-158
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• 1998

Aspalatone, a new antithrombotic agent, was administered orally to pregnant Sprague-Dawley rats during the organogenetic period at dose levels of 0, 20, 100 and 500 mg/kg/day. All dams were subjected to caesarean section on day 20 of pregnancy. Effects of test substance on dams and embryonic development of F1 fetuses were examined There were treatment-related decreases in body weight and food consumption in the 500 mg/kg group. There was a increase in the spleen weight in the 100 and 500 mg/kg groups. Develo-pmental toxicity was evident as decreased fetal body weights and increased fetal malformations in the 500 mg/ kg group. External and skeletal malformations of fetuses occurred at an incidence of 1 and 8.2%, respectively. In addition, there was a delay in ossification of sternebrae and sacrocaudal vertebrae in the 500 mg/kg group. The results show that the no observed adverse effect dose level (NOAEL) for maternal toxicity was 20 mg/kg/ day and for developmental toxicity was 100 mg/kg/day.

• Clinical and Experimental Reproductive Medicine
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• 제50권1호
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• pp.26-33
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• 2023

Objective: Human exposure to multiple xenobiotics, over various developmental windows, results in adverse health effects arising from these concomitant exposures. Humans are widely exposed to bisphenol A, and acetaminophen is the most commonly used over-the-counter drug worldwide. Bisphenol A is a well-recognized male reproductive toxicant, and increasing evidence suggests that acetaminophen is also detrimental to the male reproductive system. The recent recognition of male reproductive system dysfunction in conditions of suboptimal reproductive outcomes makes it crucial to investigate the contributions of toxicant exposures to infertility and sub-fertility. We aimed to identify toxicity in the male reproductive system at the mitochondrial level in response to co-exposure to bisphenol A and acetaminophen, and we investigated whether melatonin ameliorated this toxicity. Methods: Male Wistar rats were divided into six groups (n=10 each): a control group and groups that received melatonin, bisphenol A, acetaminophen, bisphenol A and acetaminophen, and bisphenol A and acetaminophen with melatonin treatment. Results: Significantly higher lipid peroxidation was observed in the testicular mitochondria and sperm in the treatment groups than in the control group. Levels of glutathione and the activities of catalase, glutathione peroxidase, glutathione reductase, and manganese superoxide dismutase decreased significantly in response to the toxicant treatments. Likewise, the toxicant treatments significantly decreased the sperm count and motility, while significantly increasing sperm mortality. Melatonin mitigated the adverse effects of bisphenol A and acetaminophen. Conclusion: Co-exposure to bisphenol A and acetaminophen elevated oxidative stress in the testicular mitochondria, and this effect was alleviated by melatonin.

• 대한약학회:학술대회논문집
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• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
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• pp.294.1-294.1
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• 2002

The effects of estradiol and its metabolites on the regulation of CYP1A1 expression. K.E. Joung and Y.Y. Sheen College of Pharmacy, Ewha womans University, Seoul. 120-750, Korea 2, 3.7.8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most potent halogenated aromatic hydrocarbon congener that induces expression of several genes including CYP1A1. Exposure to TCDD results in many toxic actions such as carcinogenesis, hepatotoxicity. immune suppression. and reproductive and developmental toxicity. (omitted)