Potential Estrogenic and Antiandrogenic Effects of Permethrin in Rats

KIM, Soon-Sun,LEE, Rhee-Da,LIM, Kwon-Jo,KWACK, Seung-Jun,RHEE, Gyu-Seek,SEOK, Ji-Hyun,LEE, Geun-Shik,AN, Beum-Soo,JEUNG, Eui-Bae,PARK, Kui-Lea 家畜繁殖硏究所 2005 Journal of Reproduction and Development Vol.51 No.2

<P>Many environmental chemicals including pesticides have been reported to possess hormonal activities, and thus are classified as endocrine disruptors. Permethrin, a synthetic pyrethroid insecticide, is used worldwide, which provides potential environmental exposure. However, relatively few studies have reported on hormonal activities, particularly estrogenic and androgenic activities of permethrin, and the results of these studies are in some respects contradictory. Therefore, this study investigated the potential estrogenic and androgenic activities of permethrin <I>in vitro</I> and <I>in vivo</I>. We conducted an uterine Calbindin-D<SUB>9k</SUB> (CaBP-9k) gene expression assay and an uterotrophic assay for estrogenic activity, and a Hershberger assay for androgenic activity. The CaBP-9k gene, one of the intracellular calcium binding proteins, is estrogen-responsive in the uterus. The rat uterotrophic and Hershberger assays are generally used as <I>in vivo</I> short-term screening assays for detecting the estrogenic and androgenic activities of chemicals, although these assays are still being validated by the Organization for Economic Cooperation and Development (OECD). Northern blot analysis showed the induction of uterine CaBP-9k mRNA level in response to permethrin as well as co-administration of permethrin with E2. In the uterotrophic assay using 18-day-old female rats, subcutaneous treatments with permethrin (10 to 800 mg/kg) for three days increased relative uterine wet weights, and E2-induced uterine weights. These effects were statistically significant at 800 and 200 mg/kg, respectively. Moreover, permethrin-induced uterine weights were inhibited by the co-administration of ICI 182,780, an antiestrogen. In the Hershberger assay, the administration of permethrin orally to testosterone propionate-treated castrated male rats led to statistically significant reductions in androgen-dependent sex accessory tissue (ventral prostate, seminal vesicles, levator ani and bulbocavernosus muscles, Cowper's gland and glans penis) weights at all doses tested (10, 50 and 100 mg/kg). These results suggest that permethrin might have estrogen-like effects on female rats, but antiandrogen-like effects on males.</P>

Phytochemical Characterization of Vitex negundo Leaves: a Potent Antiandrogenic and Antioxidant Agent

Jayapal Sharath,Rafi Ahmed Shahin Taj,Mahadevaiah Bhagya 한국생약학회 2022 Natural Product Sciences Vol.28 No.3

This study was conducted to characterise phytochemicals and to explore the biological activities of Vitex negundo leaves. The washed, course powder of V. negundo leaves were extracted with different solvents of increasing polarity. All the extracts were characterized and biological activities were compared. The results revealed that the ethanolic and cold water extracts showed the presence of all phytochemicals studied except protein compared to other extracts. Further, the quantitative estimation of phytochemicals showed that the ethanolic extract had highest yield and maximum amount of total polyphenols, flavonoids, and alkaloids with the least amount of tannins compared to other extracts studied. Furthermore, the highest total polyphenol content corresponds with the potent biological activities. Indeed, in vitro antioxidant and antisteroidogenic activities were highest in the ethanolic extract than others. To conclude, the present study is the first to report the characterization and antiandrogenic property of V. negundo leaf extracts. The ethanolic extract of V. negundo leaves can be used as an antioxidant and antiandrogenic agent. Hence, it can be considered for the treatment of hyperandrogenic conditions like polycystic ovary syndrome, etc.

Antispermatogenic and antiandrogenic activities of various extracts of Melia azedarach Linn. seeds in albino rats

Patil, Sharanabasappa A.,Malashetty, Vijaykumar B.,Patil, Saraswati B. Kyung Hee Oriental Medicine Research Center 2003 Oriental pharmacy and experimental medicine Vol.3 No.3

Petroleum ether, chloroform and ethanol extracts of the seeds of Melia azedarach Linn. administered orally to male rats at the dose level of 25 mg/100 g body weight for 48 days showed antispermatogenic activity, as the number of spermatocytes, spermatids and spermatozoa was decreased. The total cholesterol content was increased while protein and glycogen contents were decreased. The acid phosphatase content was also decreased while that of alkaline phosphatase increased. At the same time the weight of caput and cauda epididymis, prostate gland, seminal vesicle and Levator Ani muscle was decreased indicating its antiandrogenic property. Of the three extracts, the petroleum ether extract was more potent in its antispermatogenic and antiandrogenic activities and did not produce any sings of toxicity upto a dose of 25 mg/100 g body weight oral administration. After subjecting it to preliminary phytochemical screening the petroleum ether extract showed positive tests for steroids and saponins.

A Study of the Endocrine Disrupting Activity of Phthalate Esters using Human Cancer Cell Lines

Han, Sang-Kuk 木浦海洋大學校 2002 論文集 Vol.10 No.1

Phthalate esters have recently been added to the list of chemicals which mimic the female hormone estrogen. However, they have been tested for estrogenic activity only to a very small extent. In this study, therefore, we test to estrogenic and androgenic agonists and antagonists of phthalate esters by E-Screen and A-Screen bioassay. In the E-Screen assay, butylbenzyl phthalate (BBP), di-n-butyl phthalate (DBP), diethyl phthalate (DEP), and di-2-ethylhexyl phthalate (DEHP) showed all weakly estrogenic activity, comparing with β-estradiol-17-acetate (E₂) as positive control. Also, all of them stimulated maximally the proliferation of MCF-7 cells at a concentration of 10 μM. Other phthalate esters tested not showed estrogenic activity. In the A-Screen assay, all of phthalate esters tested showed no androgen agonistic activity. However, BBP and DBP were antiandrogenics in the antagonist assay. Our results demonstrate that hormone mimicking chemicals can have multiple hormonal activities, which may make it difficult to interpret their mechanisms of action in vivo.

‘화학적 거세’에 관한 쟁점과 논의

이희경 한국보호관찰학회 2012 보호관찰 Vol.12 No.1

최근 법무부 치료감호심의위원회는 2010년 7월 23일 「성폭력범죄자의 성충동 약물치 료에 관한 법률」이 제정된 이래 처음으로 성충동 약물치료 명령을 결정하여 국내에서는 최초로 ‘화학적 거세’가 시행될 예정이다. 이러한 화학적 거세의 시행을 앞두고 성충동치 료약물의 효능과 부작용에 관한 문제, 성폭력범죄자의 인권침해 문제, 이중처벌금지의 원칙 위반 여부에 관한 문제 등 ‘화학적 거세’에 관한 주요쟁점이 논의되고 있다. 많은 연구들이 MPA나 CPA 등의 성충동치료약물을 투여했을 때 성폭력범죄의 발생률 이 낮아졌다는 보고를 하고 있으며, 성충동약물치료의 효과를 높이기 위해서는 약물투여 와 함께 심리치료프로그램도 병행해야 한다고 한다. 물론 성충동 약물치료의 경우 그 부 작용의 가능성이 있다는 연구도 보고되어 인권침해의 논란이 야기되고 있다. 그러나 아 동성폭력범죄에 대한 재범을 방지하고 성폭력범죄자의 사회복귀를 촉진하기 위한 동법 의 성충동약물치료는, 약물의 부작용으로 인한 성폭력범죄자에 대한 위해가 있을 수는 있다고 하더라도 생명에 위협을 초래하는 정도는 아니고 평생 지속될 수 있는 아동에 대한 성폭력범죄의 피해를 막기 위한 공공의 이익보다는 크다고 할 수는 없으므로, 성폭 력범죄자의 신체를 훼손당하지 않을 권리와 자기결정권 등의 인권을 침해하는 것이 아 니다. 또한 화학적 거세가 형벌이 아니라 장래 범죄의 예방을 위한 보안처분이라고 할 것이 므로 이중처벌금지의 원칙에 반하는 것도 아니다. 다만, 현행법은 만 16세 미만자에 대 한 성폭력범죄자에 대해서도 약물치료를 가능하게 하고 있지만, 화학적 거세를 규정하는 법률의 제정 이유가 아동성기호증환자 등에 의한 것이거나 성인에 대한 방어능력이 없 어 범행대상이 쉽게 되어 재범률이 특히 높은 만 13세 미만의 아동에 대한 성폭력범죄 의 피해를 방지하기 위한 것이었으므로, 성충동약물치료명령의 대상자를 본래 동법의 법 률안에서 규정하고 있던 바대로 만 13세 미만의 아동에 대한 성폭력범죄를 저지른 성도 착증환자로 개정해야 한다.

Third-line Hormonal Therapy to Treat Prostate Cancer Relapse after Initial and Second-line Hormonal Therapy: Report of 52 Cases and Literature Review

Matsumoto, Kazuhiro,Hagiwara, Masayuki,Hayakawa, Nozomi,Tanaka, Nobuyuki,Ito, Yujiro,Maeda, Takahiro,Ninomiya, Akiharu,Nagata, Hirohiko,Nakamura, So Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.8

The aim of this study was to evaluate the efficacy of third-line combined androgen blockade (CAB) therapy for castration-resistant prostate cancer that relapsed after primary and second-line CAB. We retrospectively reviewed the medical records of 52 patients who received first-, second-, and third-line CAB therapy (medical or surgical castration, plus steroidal antiandrogen of chlormadinone acetate, or nonsteroidal antiandrogen of flutamide or bicalutamide). For cumulative analysis, we searched the PubMed database and identified a total of 50 cases published in English. Including our cases, this provided a total of 102 cases for analysis. In our study cohort, 11 cases (21.2%) achieved more than 50% reduction of serum prostate-specific antigen (PSA) on initiation of third-line CAB. We found that third-line CAB with nonsteroidal antiandrogen after second-line CAB with steroidal antiandrogen exhibited favorable results, with a positive response in six of 13 patients (46.2%). Cumulative analysis findings were comparable. Regarding the timing of third-line CAB administration, 15 patients had started at a PSA equal to or less than 4.0 ng/ml, and eight of them (53.3%) showed a positive response to treatment, compared to only three of 37 patients (8.1%) whose PSA at the initiation of third-line therapy was higher than 4.0 ng/ml (p<0.001). We conclude that third-line CAB with nonsteroidal antiandrogen would be particularly useful for patients whose cancer progressed after second-line CAB with steroidal antiandrogen. The timing of treatment seems to be important because the higher the PSA at the start of third-line therapy, the lower the PSA response rate.

Influence of Androgen Deprivation Therapy on the Uptake of PSMA-Targeted Agents: Emerging Opportunities and Challenges

Martin K. Bakht,오소원,윤혜원,천기정,곽철,강건욱 대한핵의학회 2017 핵의학 분자영상 Vol.51 No.3

Prostate-specific membrane antigen (PSMA) is an attractive target for both diagnosis and therapy because of its high expression in the vast majority of prostate cancers. Development of small molecules for targeting PSMA is important for molecular imaging and radionuclide therapy of prostate cancer. Recent evidence implies that androgendeprivation therapy increase PSMA-ligand uptake in some cases. The reported upregulations in PSMA-ligand uptake after exposure to second-generation antiandrogens such as enzalutamide and abiraterone might disturb PSMA-targeted imaging for staging and response monitoring of patients undergoing treatment with antiandrogen-based drugs. On the other hand, second-generation antiandrogens are emerging as potential endoradio-/chemosensitizers. Therefore, the enhancement of the therapeutic efficiency of PSMA-targeted theranostic methods can be listed as a new capability of antiandrogens. In this manuscript, we will present what is currently known about the mechanism of increasing PSMA uptake following exposure to antiandrogens. In addition, we will discuss whether these above-mentioned antiandrogens could play the role of endoradio-/chemosensitizers in combination with the well-established PSMA-targeted methods for pre-targeting of prostate cancer.

Benzyldihydroxyoctenone, a Novel Nonsteroidal Antiandrogen, Shows Differential Apoptotic Induction in Prostate Cancer Cells in Response to Their Androgen Responsiveness

( Hye Won Suh ),( Ha Lim Oh ),( Chul Hoon Lee ) 한국미생물 · 생명공학회 2011 Journal of microbiology and biotechnology Vol.21 No.5

The molecular mechanisms of apoptotic induction by benzyldihydroxyoctenone (BDH), a nonsteroidal antiandrogen, isolated from the culture broth of Streptomyces sp., have been previously published in prostate cancer LNCaP cells. Apoptotic induction of BDH-treated LNCaP cells was associated with downregulation of Bcl-xL that caused, in turn, cytochrome c release from mitochondria, and activation of procaspases and specific proteolytic cleavage of poly(ADP-ribose) polymerase (PARP). The purpose of the present study was to investigate the patterns of apoptotic induction by BDH in non-prostate, ovarian cancer PA-1 (androgen-independent and -insensitive) cells and prostate cancer cells with different androgen responsiveness, such as C4-2 (androgen-independent and -sensitive), 22Rv1 (androgen-dependent and -low sensitive), and LNCaP (androgen-dependent and -high sensitive) cells. We found that BDH-treated LNCaP cell proliferation was significantly inhibited in a time-dependent manner and induced apoptosis via downregulation of the androgen receptor (AR) and prostate-specific antigen (PSA), as well as antiapoptotic Bcl-xL protein. However, the levels of BDH-mediated apoptotic induction and growth inhibition in 22Rv1 cells were apparently lower than those of LNCaP cells. In contrast, the induction of apoptosis and antiproliferative effect in BDH-treated non-prostate cancer PA-1 and hormone refractory C4-2 cells were not detectable and marginal, respectively. Therefore, BDH-mediated differential apoptotic induction and growth inhibition in a cell type seem to be obviously dependent on its androgen responsiveness; primarily on androgen-dependency, and then on androgensensitivity.

Long-Lasting Antiandrogen Withdrawal Syndrome in Castration-Resistant Prostate Cancer: Three Cases With Complete Response

김상진,류재현,김윤범,정태영 대한비뇨기종양학회 2018 대한비뇨기종양학회지 Vol.16 No.1

This is a case report of 3 patients who had a dramatic and long-term complete response after antiandrogen withdrawal. All 3 patients were diagnosed with advanced or metastatic prostate cancer with a high prostate-specific antigen (PSA) level. For all patients, we started combined androgen blockade as androgen deprivation therapy and the PSA concentration decreased to <0.1 ng/mL, but then started to increase. After discontinuation of antiandrogen the PSA concentration decreased again and has remained below the limit of sensitivity for more than 1 year in all 3 patients.

Long-Lasting Antiandrogen Withdrawal Syndrome in Castration-Resistant Prostate Cancer

Sang Jin Kim,Jae Hyun Ryu,Yun Beom Kim,Tae Young Jung 대한비뇨기종양학회 2018 대한비뇨기종양학회지 Vol.16 No.1

This is a case report of 3 patients who had a dramatic and long-term complete response after antiandrogen withdrawal. All 3 patients were diagnosed with advanced or metastatic prostate cancer with a high prostate-specific antigen (PSA) level. For all patients, we started combined androgen blockade as androgen deprivation therapy and the PSA concentration decreased to <0.1 ng/mL, but then started to increase. After discontinuation of antiandrogen the PSA concentration decreased again and has remained below the limit of sensitivity for more than 1 year in all 3 patients.