• Biomolecules & Therapeutics
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• 제25권5호
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• pp.545-552
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• 2017

Increasing concern is being given to the association between risk of cancer and exposure to low-dose bisphenol A (BPA), especially in young-aged population. In this study, we investigated the effects of repeated oral treatment of low to high dose BPA in juvenile Sprague-Dawley rats. Exposing juvenile rats to BPA (0, 0.5, 5, 50, and 250 mg/kg oral gavage) from post-natal day 9 for 90 days resulted in higher food intakes and increased body weights in biphasic dose-effect relationship. Male mammary glands were atrophied at high dose, which coincided with sexual pre-maturation of females. Notably, proliferative changes with altered cell foci and focal inflammation were observed around bile ducts in the liver of all BPA-dosed groups in males, which achieved statistical significance from 0.5 mg/kg (ANOVA, Dunnett's test, p<0.05). Toxicokinetic analysis revealed that systemic exposure to BPA was greater at early age (e.g., 210-fold in $C_{max}$, and 26-fold in AUC at 50 mg/kg in male on day 1 over day 90) and in females (e.g., 4-fold in $C_{max}$ and 1.6-fold in AUC at 50 mg/kg vs. male on day 1), which might have stemmed from either age- or gender-dependent differences in metabolic capacity. These results may serve as evidence for the association between risk of cancer and exposure to low-dose BPA, especially in young children, as well as for varying toxicity of xenobiotics in different age and gender groups.

• Toxicological Research
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• 제16권2호
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• pp.163-172
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• 2000

Recently, there is a worldwide concern that a great number of man-made chemicals have a hormone-like action both in humans and in animals. DECD is developing screening programs using validated test systems to determine whether certain substances may have an effect in humans. In the present study. the establishment oj repeated-dose toxicity test method was tried. Flutamide. an anti-androgenic agent. was administered by gavage to Sprague-Dawley rats for 28 days at dose levels of 0. 0.5. 3 and 18 mg/kg body weight (10-15 rats/sex/group) to examine the effects on general findings. especially reproductive and endocrine parameters. Clinical signs. body weights, food consumption, and sexual cycle were checked and measured. For the gross and microscopic examinations. 10 rats/sex/group were sacrificed at the end of dosing period and the remaining animals of control and high dose groups (5 each) were sacrificed after 14 days recovery. Examinations for hematology and clinical chemistry were carried out at necropsy. There were no treatment-related changes in clinical signs. body weights, food consumption. gross necropsy. hematology and clinical chemistry at all doses of both sexes. The period and regularity of sexual cycle were not adversely affected at all doses by the test agent. At 18 mg/kg. both decreased weights of prostate, seminal vesicle and epididymis in males and increased weights of spleen and thymus in females were observed. In addition, decreased number of spermatids and sperms. increased serum testosterone concentration and increased incidence (100%) of interstitial cell hyperplasia were seen in males. At 18 mg/kg of the recovery group. decreased prostate weight. reduced sperm count and increased incidence (20%) of interstitial cell hyperplasia in males and increased thymus weight in females were observed. At 3 mg/kg. reduced sperm count was found. There were no adverse effects on parameters examined at 0.5 mg/kg of both sexes. The results suggested that the potential target organs of flutamide may be accessory sexual glands including testes for males and spleen and thymus for females. Taken together. this test method was found to be a useful screening test system for endocrine disrupting chemicals.

• 한국환경보건학회지
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• 제41권3호
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• pp.147-162
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• 2015

Objectives: The objective of this review was to summarize the primary role of three representative endocrine axes in aquatic vertebrates and discuss the effects on endocrine systems and their interactions in teleost fish after exposure to environmental contaminants. Methods: We summarized individual traits and mechanisms for hormonal and transcriptional interactions between the hypothalamic-pituitary-gonad (HPG), hypothalamic-pituitary-thyroid (HPT), and hypothalamic-pituitary-adrenal (HPA) axes in fish. We also provided a brief discussion on the effects of nonylphenol-induced toxicity on endocrine systems and their interactions in fish as a demonstration of holistic explanation. Results: Currently-available data showed that thyroid dysfunction is associated with reproductive toxicity due to changes in steroidogenic gene expressions and sex hormone levels as well as gonad glands in fish. As an example, we demonstrated that exposure to nonylphenol could induce estrogenicity in male fish by decreasing thyroid hormones, which contributes to increased aromatase expression. Although the mechanisms are complicated and involved in multiple ways, a number of studies have shown that sex steroids influence the HPT axis or the HPA axis in fish, indicating bi-directional crosstalk. Critically missing is information on the primary target or toxicity mechanisms of environmental contaminants among the three endocrine axes, so further studies are needed to explore those possibilities. Conclusions: This review highlights the interactions between the HPG, HPT, and HPA axes in fish in order to better understand how these endocrine systems could interact with each other in situations of exposure to endocrine disrupting chemicals.

• 한국산업보건학회지
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• 제30권3호
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• pp.270-279
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• 2020

Objective: The aim of this study was to propose revision of the occupational exposure limit(OEL) for 1-Bromopropane(1-BP) following a review of the appropriateness of the standard in light of increasing epidemiological data and handling risk. Materials and Methods: The results of toxicity and epidemiologic investigations for 1-BP and agencies' OELs were compared and reviewed through a literature review. In order to investigate the status of 1-BP handling in South Korea, data from work environment actual condition survey results and work environment measurement results were used. Results: The toxicity of 1-BP, such as central nervous system(CNS) damage, peripheral neuropathy, hematological adverse effects, and developmental and reproductive toxicity(male and female) has been reported. ACGIH recommends 0.1 ppm as a TLV-TWA value, but the OEL of South Korea stands at 25 ppm, which is 250 times higher than the TLV-TWA. Although 1-BP is a specially managed substance under the Industrial Safety and Health Law, the currently applied OEL cannot be said to be a safe level based on the results of epidemiological studies to date. In a work environment measurement in 2017, the total number of samples was 626, which were derived from 78 industries, and the average concentration was 1.173 ppm(standard deviation 2.88). Conclusions: To protect the health of workers handling 1-BP, estimated to be 780 in South Korea, it is necessary to strengthen the OEL(TWA) to a level of 0.3 ppm(lower than the 0.34 ppm with known toxic effects), which is believed to be safe as a result of epidemiological investigation. "Skin" notation should be recommended.

• 한국환경보건학회:학술대회논문집
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• 한국환경보건학회 2004년도 International Conference Global Environmental Problems and their Health Consequences
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• pp.185-187
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• 2004

The co-administration of BPA and BBP induced slow weight gain compared with single administration in dams. Also, such mixture induced low neonatal body weights in next generation. The dams treated with BPA and BBP showed significant organ weight changes in liver, spleen exposed during lactational periods. But the dams exposed during lactational periods showed significant organ weight changes not only in liver, spleen but also in kidney, uterus and ovary. The F1 female rats exposed during lactation periods showed significant organ weight changes in liver, spleen, ovary. The F1 male rats showed significant organ weight changes in liver, kidney, epididymis, vesicular glands, prostate. However no clear synergistic effects of BPA and BBP could be found. Estrogen receptor ${\alpha}$ expression by BPA and BBP in the uterus(dam, F1 female) and testis(F1 male) were studied. There was no significant different $ER{\alpha}$ expression pattern between control and treated groups. But $ER{\alpha}$ expression were increased in F1 male testis and female uterus. F1 male showed distinct $ER{\alpha}$ expression, especially in the group of lactational combined exposure. Synergistic $ER{\alpha}$ expression was found by combined treatment of BPA and BBP.

• Biomolecules & Therapeutics
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• 제12권1호
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• pp.43-48
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• 2004

The present study was carried out to investigate the potential acute toxicity of CKD-602 by a single intravenous dose in Sprague-Dawley rats. Ten males females were used in each test groups: a vehicle control, 34.7, 4l.7, 50.0, 60.0 and 72.0 mg/kg groups, and were given different single intravenous doses of CKD-602 to the test animals. Mortalities, clinical findings, and body weight changes were monitored for the 14-day period following the administration. At the end of l4-day observation period, all animals were sacrificed and complete gross postmortem examinations were performed. One, 1, 2, 8 and 9 cases of deaths occurred in the male dose groups of 34.7, 41.7, 50.0, 60.0 and 72.0 mg/kg, respectively, and 1, 5 and 9 cases in the female dose groups 50.0, 60.0 and 72.0 mg/kg, respectively. An increase in the incidence of clinical signs such as alopecia, skin pallor skin ulcerations, emaciation and change of fecal material was found in the both sexes of all treatment groups. A decrease or Suppression in the body weight was also observed in a dose-dependent manner. In autopsy, male and/or female rats of the treatment groups showed treatment-related gross findings such as splenomegaly, atrophy of the testis, epididymis, seminal vesicles, ovary, uterus and thymus which were dose-dependent in incidence and severity. Based on these results, it was concluded that a single intravenous injection of CKD-602 to rats caused significant toxicities in gastrointestinal, hematopoietic, and reproductive systems. The $LD_{50}$ value was 53.8 (95% confidence limit: 48.5~60.6) mg/kg for males and 60.l (95% confidence limit: 55.3~65.8) mg/kg for females. The $LD_{10}$ value was 39.9 (95% confidence limit: 3l.7~44.8) mg/kg for males and 50.3 (95% confidence limit: 40.6~54.8) mg/kg for females.

• 환경생물
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• 제27권4호
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• pp.323-333
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• 2009

파라벤은 p-하이드록시 벤조산(p-hydroxybenzoic acid)의 알킬에스테르로, 비교적 빠르게 흡수, 대사 및 배설되는 살균성 보존제로 식품, 화장품, 약품 등에 널리 사용되고 있다. 실제 인체는 파라벤 복합물에 노출된다. 파라벤의 안전성에 관한 연구결과들에 대한 고찰 결과 파라벤 종류에 따라 다양한 독성종말점을 대상으로 파라벤의 급성, 아급성 및 만성독성 영향은 비교적 적은 것으로 나타났다. 파라벤은 에스트로젠 유사활성을 가지며 화장품을 통한 경피흡수를 통해 유방암과의 상관성이 보고되었으나, 이와 상반된 견해도 있다. 파라벤의 항안드로젠성은 남성생식기계의 장애를 유발할 수 있으나 이와 상반된 견해도 있다. 파라벤은 정자의 미토콘드리아 기능 및 남성호르몬 생성을 저해할 수 있으나 이와 상반된 견해도 있다. 배아발달에는 독성이 없는 것으로 나타났다. 세포독성으로는 세포용혈, 미토콘드리아 막투과성 변화, 세포사멸 등을 유발할 수 있다. 수환경에서 파라벤은 환경에스트로젠으로 작동하여 어류에서 내분비장애 효과를 발휘한다. 결론적으로 파라벤은 저독성물질로 분류할 수 있으나, 인체 및 수생동물들에서 파라벤의 노출경로 및 농도, 사용기간 등에 따른 독성과 내분비계장애 효과에 대하여는 다양한 종말점을 대상으로 좀 더 구체적인 독성자료들이 요구된다.

• Reproductive and Developmental Biology
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• 제35권4호
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• pp.441-447
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• 2011

The study aim is to investigate the free radicals scavenging and spermatogenic potentials, as well as to analyze any reproductive toxicity of ethanolic extract of Mucuna prureins (M. pruriens) Linn. in spermatozoa, under different dosages in normal male rat. Normal rats were randomly selected and suspension of the extract was administered orally at the dosages of 150, 200 and 250 mg/kg body weight of the different groups of male rats (n=6) once in a day for 60 days and grouped as group II, III and IV respectively. Saline treated rats served as control -group I. On the $60^{th}$ day the animals were sacrificed and the epididymal sperm were subjected to various analyses like level of ROS production, LPO, enzymatic and non enzymatic antioxidant, morphology, morphometry, chromosomal integrity and DNA damage. Results showed significant reduction in ROS production and peroxidation and significant increase in both enzymic and non-enzymic antioxidants in all concentration treated groups when compared with control. Results from all the drug treated groups showed good sperm morphology, increased sperm count and motility. There was no DNA damage and showed normal chromosomal integrity even in 250 mg/kg dose. When compared with control all the three extract treated groups showed increased ROS scavenging activity. However, group II (200 mg/kg) showed significant changes in all the parameters. From the present study it was confirmed that the M. pruriens has potential to improve the sperm qualitatively and quantitatively through scavenging the excess ROS with any adverse side effects. These observations suggest that ethanolic seed extract of M. pruriens may serve as anti-oxidant that can exploit to treat the oxidative stress mediated male factor infertility.

• Toxicological Research
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• 제14권2호
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• pp.143-149
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• 1998

This study was carried out to evaluate the testicular toxicity of 2-bromopropane (2-BP), which recently caused occupational intoxication on the reproductive and hematopoietic system in Koreans, using light microscopy, immunohistochemistry and flow cytometry. 10 weeks old male Sprague-Dawley (SD) rats were treated with 0.5 g/㎏/day of 2-BP orally for 8 consecutive weeks. The testes of the rats were vascularly perfused with Karnovsky's solution or immersed in Bouin's solution, embedded in plastic and evaluated with light microscopy. And relative proportions of haploid, diploid, and tetra-ploid states of DNA ploidy in the testicular cell suspensions of the SD rats were examined by flow cytometry. 2-BP induced severe testicular atrophy, depletion and degeneration of spermatogonia, spermatocytes, and spermatids and mild hyperplasia of Leydig cells without significant morphological changes. The Leydig cell hyperplasia was confirmed by immunohistochemistry using proliferating cell nuclear antigen (PCNA). The immunopositive cells against PCNA were observed in the nuclei oj some interstitial cells. Relative proportions of haploid states of DNA ploidy decreased in the atrophic testicular cell suspensions comparing with those of the control. In conclusion, 2-BP induced testicular atrophy with Leydig cell hyperplasia as examined by histopathology, immunohistochemistry and DNA flow cytometry.

• 한국발생생물학회지:발생과생식
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• 제24권1호
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• pp.1-17
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• 2020

Phthalates and those metabolites have long history in industry and suspected to have deficient effects in development and reproduction. These are well-known anti-androgenic chemicals and many studies have examined the effects of these compounds on male reproduction as toxins and endocrine disruptors. Uterus is a key organ for proper embryo development, successful reproduction, and health of eutherian mammals including women. To understand the effects of the phthalate, the horizontal approach with a whole group of phthalate is best but the known phthalates are huge and all is not uncovered. Di-(2-ethylhexyl) phthalate (DEHP) is the most common product of plasticizers in polymer products and studied many groups. Although, there is limited studies on the effects of phthalates on the female, a few studies have proved the endocrine disrupting characters of DEHP or phthalate mixture in female. An acute and high dose of DEHP has adverse effects on uterine histological characters. Recently, it has been revealed that a chronical low-dose exposing of DEHP works as endocrine disrupting chemicals (EDC). DEHP can induce various cellular responses including the expression regulation of steroid hormone receptors, transcription factors, and paracrine factors. Interestingly, the response of uterus to DEHP is not monotonous and the exposed female has various phenotypes in fertility. These suggest that the exposing of DEHP may causes of histological modification in uterus and of disease in female such as endometriosis, hyperplasia, and myoma in addition to developmental and reproductive toxicity.