Xenoestrogens Ethinyl Estradiol and Zearalenone Cause Precocious Puberty in Female Rats via Central Kisspeptin Signaling
Xenoestrogens from synthetic or natural origin represent an increasing risk of disrupted endocrine functions including the physiological activity of the hypothalamo-pituitary-gonad axis. Ethinyl estradiol (EE2) is a synthetic estrogen used in contraceptive pills, whereas zearalenone (ZEA) is a natur...
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| Veröffentlicht in: | Endocrinology (Philadelphia) 2015-11, Vol.156 (11), p.3996-4007 |
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| creator | Kriszt, Rókus Winkler, Zsuzsanna Polyák, Ágnes Kuti, Dániel Molnár, Csilla Hrabovszky, Erik Kalló, Imre Szőke, Zsuzsanna Ferenczi, Szilamér Kovács, Krisztina J |
| description | Xenoestrogens from synthetic or natural origin represent an increasing risk of disrupted endocrine functions including the physiological activity of the hypothalamo-pituitary-gonad axis. Ethinyl estradiol (EE2) is a synthetic estrogen used in contraceptive pills, whereas zearalenone (ZEA) is a natural mycoestrogen found with increasing prevalence in various cereal crops. Both EE2 and ZEA are agonists of estrogen receptor-α and accelerate puberty. However, the neuroendocrine mechanisms that are responsible for this effect remain unknown. Immature female Wistar rats were treated with EE2 (10 μg/kg), ZEA (10 mg/kg), or vehicle for 10 days starting from postnatal day 18. As a marker of puberty, the vaginal opening was recorded and neuropeptide and related transcription factor mRNA levels were measured by quantitative real time PCR and in situ hybridization histochemistry. Both ZEA and EE2 accelerated the vaginal opening, increased the uterine weight and the number of antral follicles in the ovary, and resulted in the increased central expression of gnrh. These changes occurred in parallel with an earlier increase of kiss1 mRNA in the anteroventral and rostral periventricular hypothalamus and an increased kisspeptin (KP) fiber density and KP-GnRH appositions in the preoptic area. These changes are compatible with a mechanism in which xenoestrogens overstimulate the developmentally unprepared reproductive system, which results in an advanced vaginal opening and an enlargement of the uterus at the periphery. Within the hypothalamus, ZEA and EE2 directly activate anteroventral and periventricular KP neurons to stimulate GnRH mRNA. However, GnRH and gonadotropin release and ovulation are disrupted due to xenoestrogen-mediated inhibitory KP signaling in the arcuate nucleus. |
| doi_str_mv | 10.1210/en.2015-1330 |
| format | Article |
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Ethinyl estradiol (EE2) is a synthetic estrogen used in contraceptive pills, whereas zearalenone (ZEA) is a natural mycoestrogen found with increasing prevalence in various cereal crops. Both EE2 and ZEA are agonists of estrogen receptor-α and accelerate puberty. However, the neuroendocrine mechanisms that are responsible for this effect remain unknown. Immature female Wistar rats were treated with EE2 (10 μg/kg), ZEA (10 mg/kg), or vehicle for 10 days starting from postnatal day 18. As a marker of puberty, the vaginal opening was recorded and neuropeptide and related transcription factor mRNA levels were measured by quantitative real time PCR and in situ hybridization histochemistry. Both ZEA and EE2 accelerated the vaginal opening, increased the uterine weight and the number of antral follicles in the ovary, and resulted in the increased central expression of gnrh. These changes occurred in parallel with an earlier increase of kiss1 mRNA in the anteroventral and rostral periventricular hypothalamus and an increased kisspeptin (KP) fiber density and KP-GnRH appositions in the preoptic area. These changes are compatible with a mechanism in which xenoestrogens overstimulate the developmentally unprepared reproductive system, which results in an advanced vaginal opening and an enlargement of the uterus at the periphery. Within the hypothalamus, ZEA and EE2 directly activate anteroventral and periventricular KP neurons to stimulate GnRH mRNA. However, GnRH and gonadotropin release and ovulation are disrupted due to xenoestrogen-mediated inhibitory KP signaling in the arcuate nucleus.</description><identifier>ISSN: 0013-7227</identifier><identifier>EISSN: 1945-7170</identifier><identifier>DOI: 10.1210/en.2015-1330</identifier><identifier>PMID: 26248220</identifier><language>eng</language><publisher>United States: Endocrine Society</publisher><subject>17β-Estradiol ; Animals ; Arcuate nucleus ; Arcuate Nucleus of Hypothalamus - drug effects ; Arcuate Nucleus of Hypothalamus - metabolism ; Cereal crops ; Contraceptives ; Estrogen receptors ; Estrogens ; Estrogens - pharmacology ; Estrogens, Non-Steroidal - pharmacology ; Ethinyl Estradiol - pharmacology ; Ethinylestradiol ; Female ; Females ; Follicles ; Gene expression ; Gene Expression - drug effects ; Gonadotropin-releasing hormone ; Gonadotropin-Releasing Hormone - genetics ; Gonadotropin-Releasing Hormone - metabolism ; Gonadotropins ; Gonadotropins - metabolism ; Histochemistry ; Hybridization ; Hypothalamus ; Hypothalamus - cytology ; Hypothalamus - drug effects ; Hypothalamus - metabolism ; In Situ Hybridization ; Kiss1 protein ; Kisspeptins - genetics ; Kisspeptins - metabolism ; Microscopy, Confocal ; Neuroendocrine system ; Neurons - drug effects ; Neurons - metabolism ; Ovulation ; Pituitary ; Pituitary (anterior) ; Preoptic area ; Puberty ; Rats, Wistar ; Receptors, G-Protein-Coupled - genetics ; Receptors, G-Protein-Coupled - metabolism ; Receptors, Kisspeptin-1 ; Reproductive system ; Reverse Transcriptase Polymerase Chain Reaction ; Sex hormones ; Sexual Maturation - drug effects ; Signal Transduction - drug effects ; Signal Transduction - genetics ; Uterus ; Uterus - drug effects ; Uterus - growth & development ; Uterus - metabolism ; Vagina ; Xenobiotics - pharmacology ; Xenoestrogens ; Zearalenone ; Zearalenone - pharmacology</subject><ispartof>Endocrinology (Philadelphia), 2015-11, Vol.156 (11), p.3996-4007</ispartof><rights>Copyright © 2015 by the Endocrine Society</rights><rights>Copyright © 2015 by the Endocrine Society 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c433t-fde441b5abcf6b9a5c57620583c441e823ffa1947594388e3f224b44ecaeb3da3</citedby><cites>FETCH-LOGICAL-c433t-fde441b5abcf6b9a5c57620583c441e823ffa1947594388e3f224b44ecaeb3da3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26248220$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kriszt, Rókus</creatorcontrib><creatorcontrib>Winkler, Zsuzsanna</creatorcontrib><creatorcontrib>Polyák, Ágnes</creatorcontrib><creatorcontrib>Kuti, Dániel</creatorcontrib><creatorcontrib>Molnár, Csilla</creatorcontrib><creatorcontrib>Hrabovszky, Erik</creatorcontrib><creatorcontrib>Kalló, Imre</creatorcontrib><creatorcontrib>Szőke, Zsuzsanna</creatorcontrib><creatorcontrib>Ferenczi, Szilamér</creatorcontrib><creatorcontrib>Kovács, Krisztina J</creatorcontrib><title>Xenoestrogens Ethinyl Estradiol and Zearalenone Cause Precocious Puberty in Female Rats via Central Kisspeptin Signaling</title><title>Endocrinology (Philadelphia)</title><addtitle>Endocrinology</addtitle><description>Xenoestrogens from synthetic or natural origin represent an increasing risk of disrupted endocrine functions including the physiological activity of the hypothalamo-pituitary-gonad axis. Ethinyl estradiol (EE2) is a synthetic estrogen used in contraceptive pills, whereas zearalenone (ZEA) is a natural mycoestrogen found with increasing prevalence in various cereal crops. Both EE2 and ZEA are agonists of estrogen receptor-α and accelerate puberty. However, the neuroendocrine mechanisms that are responsible for this effect remain unknown. Immature female Wistar rats were treated with EE2 (10 μg/kg), ZEA (10 mg/kg), or vehicle for 10 days starting from postnatal day 18. As a marker of puberty, the vaginal opening was recorded and neuropeptide and related transcription factor mRNA levels were measured by quantitative real time PCR and in situ hybridization histochemistry. Both ZEA and EE2 accelerated the vaginal opening, increased the uterine weight and the number of antral follicles in the ovary, and resulted in the increased central expression of gnrh. These changes occurred in parallel with an earlier increase of kiss1 mRNA in the anteroventral and rostral periventricular hypothalamus and an increased kisspeptin (KP) fiber density and KP-GnRH appositions in the preoptic area. These changes are compatible with a mechanism in which xenoestrogens overstimulate the developmentally unprepared reproductive system, which results in an advanced vaginal opening and an enlargement of the uterus at the periphery. Within the hypothalamus, ZEA and EE2 directly activate anteroventral and periventricular KP neurons to stimulate GnRH mRNA. However, GnRH and gonadotropin release and ovulation are disrupted due to xenoestrogen-mediated inhibitory KP signaling in the arcuate nucleus.</description><subject>17β-Estradiol</subject><subject>Animals</subject><subject>Arcuate nucleus</subject><subject>Arcuate Nucleus of Hypothalamus - drug effects</subject><subject>Arcuate Nucleus of Hypothalamus - metabolism</subject><subject>Cereal crops</subject><subject>Contraceptives</subject><subject>Estrogen receptors</subject><subject>Estrogens</subject><subject>Estrogens - pharmacology</subject><subject>Estrogens, Non-Steroidal - pharmacology</subject><subject>Ethinyl Estradiol - pharmacology</subject><subject>Ethinylestradiol</subject><subject>Female</subject><subject>Females</subject><subject>Follicles</subject><subject>Gene expression</subject><subject>Gene Expression - drug effects</subject><subject>Gonadotropin-releasing hormone</subject><subject>Gonadotropin-Releasing Hormone - genetics</subject><subject>Gonadotropin-Releasing Hormone - metabolism</subject><subject>Gonadotropins</subject><subject>Gonadotropins - metabolism</subject><subject>Histochemistry</subject><subject>Hybridization</subject><subject>Hypothalamus</subject><subject>Hypothalamus - cytology</subject><subject>Hypothalamus - drug effects</subject><subject>Hypothalamus - metabolism</subject><subject>In Situ Hybridization</subject><subject>Kiss1 protein</subject><subject>Kisspeptins - genetics</subject><subject>Kisspeptins - metabolism</subject><subject>Microscopy, Confocal</subject><subject>Neuroendocrine system</subject><subject>Neurons - drug effects</subject><subject>Neurons - metabolism</subject><subject>Ovulation</subject><subject>Pituitary</subject><subject>Pituitary (anterior)</subject><subject>Preoptic area</subject><subject>Puberty</subject><subject>Rats, Wistar</subject><subject>Receptors, G-Protein-Coupled - genetics</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Receptors, Kisspeptin-1</subject><subject>Reproductive system</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Sex hormones</subject><subject>Sexual Maturation - drug effects</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - genetics</subject><subject>Uterus</subject><subject>Uterus - drug effects</subject><subject>Uterus - growth & development</subject><subject>Uterus - metabolism</subject><subject>Vagina</subject><subject>Xenobiotics - pharmacology</subject><subject>Xenoestrogens</subject><subject>Zearalenone</subject><subject>Zearalenone - pharmacology</subject><issn>0013-7227</issn><issn>1945-7170</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc9LHDEUx0NR6mp78ywBD_bgaJKX2Zk5yrL-QKFiWyheQibzZo3MJmMyI93_vll2W6HYU8jjw4fve19CDjk744Kzc3RngvE84wDsA5nwSuZZwQu2QyaMccgKIYo9sh_jc_pKKeEj2RNTIUsh2IT8-onOYxyCX6CLdD48Wbfq6DxNdGN9R7Vr6CPqoLsEOqQzPUak9wGNN9aPkd6PNYZhRa2jl7hMGH3QQ6SvVtMZuqTp6K2Nscd-SMg3u3C6s27xiey2uov4efsekB-X8--z6-zu69XN7OIuMxJgyNoGpeR1rmvTTutK5yYvpoLlJZg0x1JA2-q0c5FXEsoSoRVC1lKi0VhDo-GAfNl4--BfxrSpWtposOu0wxRf8XSfShQMIKHH_6DPfgwpblTAgU0BqiJP1OmGMsHHGLBVfbBLHVaKM7VuRKFT60bUupGEH22lY73E5i_8p4IEnGwAP_b_U2VbFWxIdI03wTrsA8b4lvLdAL8BxWykNg</recordid><startdate>201511</startdate><enddate>201511</enddate><creator>Kriszt, Rókus</creator><creator>Winkler, Zsuzsanna</creator><creator>Polyák, Ágnes</creator><creator>Kuti, Dániel</creator><creator>Molnár, Csilla</creator><creator>Hrabovszky, Erik</creator><creator>Kalló, Imre</creator><creator>Szőke, Zsuzsanna</creator><creator>Ferenczi, Szilamér</creator><creator>Kovács, Krisztina J</creator><general>Endocrine Society</general><general>Oxford University Press</general><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>7QG</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>201511</creationdate><title>Xenoestrogens Ethinyl Estradiol and Zearalenone Cause Precocious Puberty in Female Rats via Central Kisspeptin Signaling</title><author>Kriszt, Rókus ; Winkler, Zsuzsanna ; Polyák, Ágnes ; Kuti, Dániel ; Molnár, Csilla ; Hrabovszky, Erik ; Kalló, Imre ; Szőke, Zsuzsanna ; Ferenczi, Szilamér ; Kovács, Krisztina J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c433t-fde441b5abcf6b9a5c57620583c441e823ffa1947594388e3f224b44ecaeb3da3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>17β-Estradiol</topic><topic>Animals</topic><topic>Arcuate nucleus</topic><topic>Arcuate Nucleus of Hypothalamus - drug effects</topic><topic>Arcuate Nucleus of Hypothalamus - metabolism</topic><topic>Cereal crops</topic><topic>Contraceptives</topic><topic>Estrogen receptors</topic><topic>Estrogens</topic><topic>Estrogens - pharmacology</topic><topic>Estrogens, Non-Steroidal - pharmacology</topic><topic>Ethinyl Estradiol - pharmacology</topic><topic>Ethinylestradiol</topic><topic>Female</topic><topic>Females</topic><topic>Follicles</topic><topic>Gene expression</topic><topic>Gene Expression - drug effects</topic><topic>Gonadotropin-releasing hormone</topic><topic>Gonadotropin-Releasing Hormone - genetics</topic><topic>Gonadotropin-Releasing Hormone - metabolism</topic><topic>Gonadotropins</topic><topic>Gonadotropins - metabolism</topic><topic>Histochemistry</topic><topic>Hybridization</topic><topic>Hypothalamus</topic><topic>Hypothalamus - cytology</topic><topic>Hypothalamus - drug effects</topic><topic>Hypothalamus - metabolism</topic><topic>In Situ Hybridization</topic><topic>Kiss1 protein</topic><topic>Kisspeptins - genetics</topic><topic>Kisspeptins - metabolism</topic><topic>Microscopy, Confocal</topic><topic>Neuroendocrine system</topic><topic>Neurons - drug effects</topic><topic>Neurons - metabolism</topic><topic>Ovulation</topic><topic>Pituitary</topic><topic>Pituitary (anterior)</topic><topic>Preoptic area</topic><topic>Puberty</topic><topic>Rats, Wistar</topic><topic>Receptors, G-Protein-Coupled - genetics</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Receptors, Kisspeptin-1</topic><topic>Reproductive system</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Sex hormones</topic><topic>Sexual Maturation - drug effects</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - genetics</topic><topic>Uterus</topic><topic>Uterus - drug effects</topic><topic>Uterus - growth & development</topic><topic>Uterus - metabolism</topic><topic>Vagina</topic><topic>Xenobiotics - pharmacology</topic><topic>Xenoestrogens</topic><topic>Zearalenone</topic><topic>Zearalenone - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kriszt, Rókus</creatorcontrib><creatorcontrib>Winkler, Zsuzsanna</creatorcontrib><creatorcontrib>Polyák, Ágnes</creatorcontrib><creatorcontrib>Kuti, Dániel</creatorcontrib><creatorcontrib>Molnár, Csilla</creatorcontrib><creatorcontrib>Hrabovszky, Erik</creatorcontrib><creatorcontrib>Kalló, Imre</creatorcontrib><creatorcontrib>Szőke, Zsuzsanna</creatorcontrib><creatorcontrib>Ferenczi, Szilamér</creatorcontrib><creatorcontrib>Kovács, Krisztina J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Endocrinology (Philadelphia)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kriszt, Rókus</au><au>Winkler, Zsuzsanna</au><au>Polyák, Ágnes</au><au>Kuti, Dániel</au><au>Molnár, Csilla</au><au>Hrabovszky, Erik</au><au>Kalló, Imre</au><au>Szőke, Zsuzsanna</au><au>Ferenczi, Szilamér</au><au>Kovács, Krisztina J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Xenoestrogens Ethinyl Estradiol and Zearalenone Cause Precocious Puberty in Female Rats via Central Kisspeptin Signaling</atitle><jtitle>Endocrinology (Philadelphia)</jtitle><addtitle>Endocrinology</addtitle><date>2015-11</date><risdate>2015</risdate><volume>156</volume><issue>11</issue><spage>3996</spage><epage>4007</epage><pages>3996-4007</pages><issn>0013-7227</issn><eissn>1945-7170</eissn><abstract>Xenoestrogens from synthetic or natural origin represent an increasing risk of disrupted endocrine functions including the physiological activity of the hypothalamo-pituitary-gonad axis. Ethinyl estradiol (EE2) is a synthetic estrogen used in contraceptive pills, whereas zearalenone (ZEA) is a natural mycoestrogen found with increasing prevalence in various cereal crops. Both EE2 and ZEA are agonists of estrogen receptor-α and accelerate puberty. However, the neuroendocrine mechanisms that are responsible for this effect remain unknown. Immature female Wistar rats were treated with EE2 (10 μg/kg), ZEA (10 mg/kg), or vehicle for 10 days starting from postnatal day 18. As a marker of puberty, the vaginal opening was recorded and neuropeptide and related transcription factor mRNA levels were measured by quantitative real time PCR and in situ hybridization histochemistry. Both ZEA and EE2 accelerated the vaginal opening, increased the uterine weight and the number of antral follicles in the ovary, and resulted in the increased central expression of gnrh. These changes occurred in parallel with an earlier increase of kiss1 mRNA in the anteroventral and rostral periventricular hypothalamus and an increased kisspeptin (KP) fiber density and KP-GnRH appositions in the preoptic area. These changes are compatible with a mechanism in which xenoestrogens overstimulate the developmentally unprepared reproductive system, which results in an advanced vaginal opening and an enlargement of the uterus at the periphery. Within the hypothalamus, ZEA and EE2 directly activate anteroventral and periventricular KP neurons to stimulate GnRH mRNA. However, GnRH and gonadotropin release and ovulation are disrupted due to xenoestrogen-mediated inhibitory KP signaling in the arcuate nucleus.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>26248220</pmid><doi>10.1210/en.2015-1330</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Journals@Ovid Complete; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | 17β-Estradiol Animals Arcuate nucleus Arcuate Nucleus of Hypothalamus - drug effects Arcuate Nucleus of Hypothalamus - metabolism Cereal crops Contraceptives Estrogen receptors Estrogens Estrogens - pharmacology Estrogens, Non-Steroidal - pharmacology Ethinyl Estradiol - pharmacology Ethinylestradiol Female Females Follicles Gene expression Gene Expression - drug effects Gonadotropin-releasing hormone Gonadotropin-Releasing Hormone - genetics Gonadotropin-Releasing Hormone - metabolism Gonadotropins Gonadotropins - metabolism Histochemistry Hybridization Hypothalamus Hypothalamus - cytology Hypothalamus - drug effects Hypothalamus - metabolism In Situ Hybridization Kiss1 protein Kisspeptins - genetics Kisspeptins - metabolism Microscopy, Confocal Neuroendocrine system Neurons - drug effects Neurons - metabolism Ovulation Pituitary Pituitary (anterior) Preoptic area Puberty Rats, Wistar Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Receptors, Kisspeptin-1 Reproductive system Reverse Transcriptase Polymerase Chain Reaction Sex hormones Sexual Maturation - drug effects Signal Transduction - drug effects Signal Transduction - genetics Uterus Uterus - drug effects Uterus - growth & development Uterus - metabolism Vagina Xenobiotics - pharmacology Xenoestrogens Zearalenone Zearalenone - pharmacology |
| title | Xenoestrogens Ethinyl Estradiol and Zearalenone Cause Precocious Puberty in Female Rats via Central Kisspeptin Signaling |
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