Chronic Toxicity and Reversibility of Antifertility Effect of Immunization against Gonadotropin-Releasing Hormone in Male Rats and Rabbits
The chronic systemic toxicity of immunization with gonadotropin-releasing hormone, conjugated to tetanus toxoid (GnRH-TT), was investigated in male rats and rabbits in order to start Phase I clinical trials. Groups of rats and rabbits were immunized with GnRH-TT dissolved in aqueous adjuvant. The an...
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| creator | Kumar, Narender Savage, Toyin DeJesus, William Tsong, Y. Y. Didolkar, A. Sundaram, K. |
| description | The chronic systemic toxicity of immunization with gonadotropin-releasing hormone, conjugated to tetanus toxoid (GnRH-TT), was investigated in male rats and rabbits in order to start Phase I clinical trials. Groups of rats and rabbits were immunized with GnRH-TT dissolved in aqueous adjuvant. The antigen was administered at weeks 0, 4, and 8, followed by boosters to maintain high antibody titers. At termination (8–9 months after first immunization), twenty rats and ten rabbits exhibiting the highest mean anti-GnRH titers and all the controls were selected for complete toxicological evaluation. In the rat study, a castrated control group was included for comparison with the immunized group. The hematological and serum chemistry parameters of immunized rats and rabbits were not affected in a significant manner. Most of the changes in serum chemistry of immunized rats were also found in castrated rats, indicating that the changes are most likely due to the withdrawal of androgenic support. The weights of the testes, epididymides, and sex accessory glands were lower in all immunized animals. There was significant atrophy of the germinal epithelium, which, however, sustained a population of Sertoli cells, spermatogonia, and pachytene spermatocytes. Other morphological changes in the prostate, seminal vesicles, pituitary, and mammary gland reflected the effect of androgen withdrawal. The decrease in the weight of liver, kidney, and heart seen in the immunized rats was also present in castrated rats and was not associated with any histopathological changes. The reversibility of immunization-induced infertility was investigated by mating the rats with normal females. Four months after the start of immunization, 9 out of 10 immunized rats were infertile whereas by nine months, all rats had regained fertility. Thus, it is concluded that immunization with GnRH-TT had no systemic toxicological effects in the adult male rats and rabbits for the period studied. The results also indicated that the GnRH-TT immunization had an antifertility effect in male rats. Fertility was restored following cessation of immunization and decline in anti-GnRH antibody titers. |
| doi_str_mv | 10.1093/toxsci/53.1.92 |
| format | Article |
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Y. ; Didolkar, A. ; Sundaram, K.</creator><creatorcontrib>Kumar, Narender ; Savage, Toyin ; DeJesus, William ; Tsong, Y. Y. ; Didolkar, A. ; Sundaram, K.</creatorcontrib><description>The chronic systemic toxicity of immunization with gonadotropin-releasing hormone, conjugated to tetanus toxoid (GnRH-TT), was investigated in male rats and rabbits in order to start Phase I clinical trials. Groups of rats and rabbits were immunized with GnRH-TT dissolved in aqueous adjuvant. The antigen was administered at weeks 0, 4, and 8, followed by boosters to maintain high antibody titers. At termination (8–9 months after first immunization), twenty rats and ten rabbits exhibiting the highest mean anti-GnRH titers and all the controls were selected for complete toxicological evaluation. In the rat study, a castrated control group was included for comparison with the immunized group. The hematological and serum chemistry parameters of immunized rats and rabbits were not affected in a significant manner. Most of the changes in serum chemistry of immunized rats were also found in castrated rats, indicating that the changes are most likely due to the withdrawal of androgenic support. The weights of the testes, epididymides, and sex accessory glands were lower in all immunized animals. There was significant atrophy of the germinal epithelium, which, however, sustained a population of Sertoli cells, spermatogonia, and pachytene spermatocytes. Other morphological changes in the prostate, seminal vesicles, pituitary, and mammary gland reflected the effect of androgen withdrawal. The decrease in the weight of liver, kidney, and heart seen in the immunized rats was also present in castrated rats and was not associated with any histopathological changes. The reversibility of immunization-induced infertility was investigated by mating the rats with normal females. Four months after the start of immunization, 9 out of 10 immunized rats were infertile whereas by nine months, all rats had regained fertility. Thus, it is concluded that immunization with GnRH-TT had no systemic toxicological effects in the adult male rats and rabbits for the period studied. The results also indicated that the GnRH-TT immunization had an antifertility effect in male rats. Fertility was restored following cessation of immunization and decline in anti-GnRH antibody titers.</description><identifier>ISSN: 1096-6080</identifier><identifier>ISSN: 1096-0929</identifier><identifier>EISSN: 1096-0929</identifier><identifier>DOI: 10.1093/toxsci/53.1.92</identifier><identifier>PMID: 10653526</identifier><identifier>CODEN: TOSCF2</identifier><language>eng</language><publisher>Cary, NC: Oxford University Press</publisher><subject>Animals ; Biological and medical sciences ; Blood Chemical Analysis ; Body Weight - drug effects ; Contraceptive Agents, Male - toxicity ; Female ; Fertility - drug effects ; GnRH ; Gonadotropin-Releasing Hormone - blood ; Gonadotropin-Releasing Hormone - immunology ; Gonadotropin-Releasing Hormone - toxicity ; Hematologic Tests ; Hormones. Endocrine system ; Immunization ; Male ; Medical sciences ; Organ Size - drug effects ; Pharmacology. Drug treatments ; pituitary response ; Rabbits ; Rats ; Recovery of Function ; reversibility ; Testosterone - blood ; tetanus toxin ; Tetanus Toxin - toxicity ; toxicity ; Toxicity Tests</subject><ispartof>Toxicological sciences, 2000-01, Vol.53 (1), p.92-92</ispartof><rights>2000 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c429t-cb5ebc72f546e7487e5d27a276f7bf5cee393264008ef646e862df100542bbca3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,4024,27923,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1374609$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10653526$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kumar, Narender</creatorcontrib><creatorcontrib>Savage, Toyin</creatorcontrib><creatorcontrib>DeJesus, William</creatorcontrib><creatorcontrib>Tsong, Y. Y.</creatorcontrib><creatorcontrib>Didolkar, A.</creatorcontrib><creatorcontrib>Sundaram, K.</creatorcontrib><title>Chronic Toxicity and Reversibility of Antifertility Effect of Immunization against Gonadotropin-Releasing Hormone in Male Rats and Rabbits</title><title>Toxicological sciences</title><addtitle>Toxicol. Sci</addtitle><description>The chronic systemic toxicity of immunization with gonadotropin-releasing hormone, conjugated to tetanus toxoid (GnRH-TT), was investigated in male rats and rabbits in order to start Phase I clinical trials. Groups of rats and rabbits were immunized with GnRH-TT dissolved in aqueous adjuvant. The antigen was administered at weeks 0, 4, and 8, followed by boosters to maintain high antibody titers. At termination (8–9 months after first immunization), twenty rats and ten rabbits exhibiting the highest mean anti-GnRH titers and all the controls were selected for complete toxicological evaluation. In the rat study, a castrated control group was included for comparison with the immunized group. The hematological and serum chemistry parameters of immunized rats and rabbits were not affected in a significant manner. Most of the changes in serum chemistry of immunized rats were also found in castrated rats, indicating that the changes are most likely due to the withdrawal of androgenic support. The weights of the testes, epididymides, and sex accessory glands were lower in all immunized animals. There was significant atrophy of the germinal epithelium, which, however, sustained a population of Sertoli cells, spermatogonia, and pachytene spermatocytes. Other morphological changes in the prostate, seminal vesicles, pituitary, and mammary gland reflected the effect of androgen withdrawal. The decrease in the weight of liver, kidney, and heart seen in the immunized rats was also present in castrated rats and was not associated with any histopathological changes. The reversibility of immunization-induced infertility was investigated by mating the rats with normal females. Four months after the start of immunization, 9 out of 10 immunized rats were infertile whereas by nine months, all rats had regained fertility. Thus, it is concluded that immunization with GnRH-TT had no systemic toxicological effects in the adult male rats and rabbits for the period studied. The results also indicated that the GnRH-TT immunization had an antifertility effect in male rats. Fertility was restored following cessation of immunization and decline in anti-GnRH antibody titers.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood Chemical Analysis</subject><subject>Body Weight - drug effects</subject><subject>Contraceptive Agents, Male - toxicity</subject><subject>Female</subject><subject>Fertility - drug effects</subject><subject>GnRH</subject><subject>Gonadotropin-Releasing Hormone - blood</subject><subject>Gonadotropin-Releasing Hormone - immunology</subject><subject>Gonadotropin-Releasing Hormone - toxicity</subject><subject>Hematologic Tests</subject><subject>Hormones. Endocrine system</subject><subject>Immunization</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Organ Size - drug effects</subject><subject>Pharmacology. Drug treatments</subject><subject>pituitary response</subject><subject>Rabbits</subject><subject>Rats</subject><subject>Recovery of Function</subject><subject>reversibility</subject><subject>Testosterone - blood</subject><subject>tetanus toxin</subject><subject>Tetanus Toxin - toxicity</subject><subject>toxicity</subject><subject>Toxicity Tests</subject><issn>1096-6080</issn><issn>1096-0929</issn><issn>1096-0929</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpN0U9vFCEYBnBibGxtvXo0HIy32fJngJ1js6m7NW1q1taYXgjDvFR0BlZgzdaP4Kd2NrNRT5CHHy_JA0KvKZlR0vDzEnfZ-nPBZ3TWsGfoZExlRRrWPD_sJZmTY_Qy52-EUCpJ8wIdUyIFF0yeoN-LrykGb_Fd3HnryxM2ocNr-Akp-9b3-yQ6fBGKd5DKFFw6B7bs86th2Ab_yxQfAzaPxodc8DIG08WS4saHag09mOzDI17FNMQA2Ad8Y3rAa1Py9JppW1_yGTpyps_w6rCeovv3l3eLVXV9u7xaXFxXtmZNqWwroLWKOVFLUPVcgeiYMkxJp1onLABvOJM1IXNwcjRzyTpHCRE1a1tr-Cl6N83dpPhjC7nowWcLfW8CxG3WVNVKEa5GOJugTTHnBE5vkh9MetKU6H37empfC66pbth44c1h8rYdoPuPT3WP4O0BmGxN75IJ1ud_jqt6_KCRVRPzucDu77FJ37VUXAm9-vKgb8SnDx8_Pyz1mv8BV1Wg2Q</recordid><startdate>200001</startdate><enddate>200001</enddate><creator>Kumar, Narender</creator><creator>Savage, Toyin</creator><creator>DeJesus, William</creator><creator>Tsong, Y. Y.</creator><creator>Didolkar, A.</creator><creator>Sundaram, K.</creator><general>Oxford University Press</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>200001</creationdate><title>Chronic Toxicity and Reversibility of Antifertility Effect of Immunization against Gonadotropin-Releasing Hormone in Male Rats and Rabbits</title><author>Kumar, Narender ; Savage, Toyin ; DeJesus, William ; Tsong, Y. Y. ; Didolkar, A. ; Sundaram, K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c429t-cb5ebc72f546e7487e5d27a276f7bf5cee393264008ef646e862df100542bbca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood Chemical Analysis</topic><topic>Body Weight - drug effects</topic><topic>Contraceptive Agents, Male - toxicity</topic><topic>Female</topic><topic>Fertility - drug effects</topic><topic>GnRH</topic><topic>Gonadotropin-Releasing Hormone - blood</topic><topic>Gonadotropin-Releasing Hormone - immunology</topic><topic>Gonadotropin-Releasing Hormone - toxicity</topic><topic>Hematologic Tests</topic><topic>Hormones. Endocrine system</topic><topic>Immunization</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Organ Size - drug effects</topic><topic>Pharmacology. Drug treatments</topic><topic>pituitary response</topic><topic>Rabbits</topic><topic>Rats</topic><topic>Recovery of Function</topic><topic>reversibility</topic><topic>Testosterone - blood</topic><topic>tetanus toxin</topic><topic>Tetanus Toxin - toxicity</topic><topic>toxicity</topic><topic>Toxicity Tests</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kumar, Narender</creatorcontrib><creatorcontrib>Savage, Toyin</creatorcontrib><creatorcontrib>DeJesus, William</creatorcontrib><creatorcontrib>Tsong, Y. Y.</creatorcontrib><creatorcontrib>Didolkar, A.</creatorcontrib><creatorcontrib>Sundaram, K.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Toxicological sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kumar, Narender</au><au>Savage, Toyin</au><au>DeJesus, William</au><au>Tsong, Y. Y.</au><au>Didolkar, A.</au><au>Sundaram, K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chronic Toxicity and Reversibility of Antifertility Effect of Immunization against Gonadotropin-Releasing Hormone in Male Rats and Rabbits</atitle><jtitle>Toxicological sciences</jtitle><addtitle>Toxicol. Sci</addtitle><date>2000-01</date><risdate>2000</risdate><volume>53</volume><issue>1</issue><spage>92</spage><epage>92</epage><pages>92-92</pages><issn>1096-6080</issn><issn>1096-0929</issn><eissn>1096-0929</eissn><coden>TOSCF2</coden><abstract>The chronic systemic toxicity of immunization with gonadotropin-releasing hormone, conjugated to tetanus toxoid (GnRH-TT), was investigated in male rats and rabbits in order to start Phase I clinical trials. Groups of rats and rabbits were immunized with GnRH-TT dissolved in aqueous adjuvant. The antigen was administered at weeks 0, 4, and 8, followed by boosters to maintain high antibody titers. At termination (8–9 months after first immunization), twenty rats and ten rabbits exhibiting the highest mean anti-GnRH titers and all the controls were selected for complete toxicological evaluation. In the rat study, a castrated control group was included for comparison with the immunized group. The hematological and serum chemistry parameters of immunized rats and rabbits were not affected in a significant manner. Most of the changes in serum chemistry of immunized rats were also found in castrated rats, indicating that the changes are most likely due to the withdrawal of androgenic support. The weights of the testes, epididymides, and sex accessory glands were lower in all immunized animals. There was significant atrophy of the germinal epithelium, which, however, sustained a population of Sertoli cells, spermatogonia, and pachytene spermatocytes. Other morphological changes in the prostate, seminal vesicles, pituitary, and mammary gland reflected the effect of androgen withdrawal. The decrease in the weight of liver, kidney, and heart seen in the immunized rats was also present in castrated rats and was not associated with any histopathological changes. The reversibility of immunization-induced infertility was investigated by mating the rats with normal females. Four months after the start of immunization, 9 out of 10 immunized rats were infertile whereas by nine months, all rats had regained fertility. Thus, it is concluded that immunization with GnRH-TT had no systemic toxicological effects in the adult male rats and rabbits for the period studied. The results also indicated that the GnRH-TT immunization had an antifertility effect in male rats. Fertility was restored following cessation of immunization and decline in anti-GnRH antibody titers.</abstract><cop>Cary, NC</cop><pub>Oxford University Press</pub><pmid>10653526</pmid><doi>10.1093/toxsci/53.1.92</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological and medical sciences Blood Chemical Analysis Body Weight - drug effects Contraceptive Agents, Male - toxicity Female Fertility - drug effects GnRH Gonadotropin-Releasing Hormone - blood Gonadotropin-Releasing Hormone - immunology Gonadotropin-Releasing Hormone - toxicity Hematologic Tests Hormones. Endocrine system Immunization Male Medical sciences Organ Size - drug effects Pharmacology. Drug treatments pituitary response Rabbits Rats Recovery of Function reversibility Testosterone - blood tetanus toxin Tetanus Toxin - toxicity toxicity Toxicity Tests |
| title | Chronic Toxicity and Reversibility of Antifertility Effect of Immunization against Gonadotropin-Releasing Hormone in Male Rats and Rabbits |
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