Potential hazards to embryo implantation: A human endometrial in vitro model to identify unwanted antigestagenic actions of chemicals.
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Potential hazards to embryo implantation: A human endometrial in vitro model to identify unwanted antigestagenic actions of chemicals. / Fischer, L; Deppert, Wolfgang; Pfeifer, D; Stanzel, S; Weimer, M; Hanjalic-Beck, A; Stein, A; Straßer, M; Zahradnik, H P; Schaefer, W R.
in: TOXICOL APPL PHARM, Jahrgang 260, Nr. 3, 3, 2012, S. 232-240.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Potential hazards to embryo implantation: A human endometrial in vitro model to identify unwanted antigestagenic actions of chemicals.
AU - Fischer, L
AU - Deppert, Wolfgang
AU - Pfeifer, D
AU - Stanzel, S
AU - Weimer, M
AU - Hanjalic-Beck, A
AU - Stein, A
AU - Straßer, M
AU - Zahradnik, H P
AU - Schaefer, W R
PY - 2012
Y1 - 2012
N2 - Embryo implantation is a crucial step in human reproduction and depends on the timely development of a receptive endometrium. The human endometrium is unique among adult tissues due to its dynamic alterations during each menstrual cycle. It hosts the implantation process which is governed by progesterone, whereas 17?-estradiol regulates the preceding proliferation of the endometrium. The receptors for both steroids are targets for drugs and endocrine disrupting chemicals. Chemicals with unwanted antigestagenic actions are potentially hazardous to embryo implantation since many pharmaceutical antiprogestins adversely affect endometrial receptivity. This risk can be addressed by human tissue-specific in vitro assays. As working basis we compiled data on chemicals interacting with the PR. In our experimental work, we developed a flexible in vitro model based on human endometrial Ishikawa cells. Effects of antiprogestin compounds on pre-selected target genes were characterized by sigmoidal concentration-response curves obtained by RT-qPCR. The estrogen sulfotransferase (SULT1E1) was identified as the most responsive target gene by microarray analysis. The agonistic effect of progesterone on SULT1E1 mRNA was concentration-dependently antagonized by RU486 (mifepristone) and ZK137316 and, with lower potency, by 4-nonylphenol, bisphenol A and apigenin. The negative control methyl acetoacetate showed no effect. The effects of progesterone and RU486 were confirmed on the protein level by Western blotting. We demonstrated proof of principle that our Ishikawa model is suitable to study quantitatively effects of antiprogestin-like chemicals on endometrial target genes in comparison to pharmaceutical reference compounds. This test is useful for hazard identification and may contribute to reduce animal studies.
AB - Embryo implantation is a crucial step in human reproduction and depends on the timely development of a receptive endometrium. The human endometrium is unique among adult tissues due to its dynamic alterations during each menstrual cycle. It hosts the implantation process which is governed by progesterone, whereas 17?-estradiol regulates the preceding proliferation of the endometrium. The receptors for both steroids are targets for drugs and endocrine disrupting chemicals. Chemicals with unwanted antigestagenic actions are potentially hazardous to embryo implantation since many pharmaceutical antiprogestins adversely affect endometrial receptivity. This risk can be addressed by human tissue-specific in vitro assays. As working basis we compiled data on chemicals interacting with the PR. In our experimental work, we developed a flexible in vitro model based on human endometrial Ishikawa cells. Effects of antiprogestin compounds on pre-selected target genes were characterized by sigmoidal concentration-response curves obtained by RT-qPCR. The estrogen sulfotransferase (SULT1E1) was identified as the most responsive target gene by microarray analysis. The agonistic effect of progesterone on SULT1E1 mRNA was concentration-dependently antagonized by RU486 (mifepristone) and ZK137316 and, with lower potency, by 4-nonylphenol, bisphenol A and apigenin. The negative control methyl acetoacetate showed no effect. The effects of progesterone and RU486 were confirmed on the protein level by Western blotting. We demonstrated proof of principle that our Ishikawa model is suitable to study quantitatively effects of antiprogestin-like chemicals on endometrial target genes in comparison to pharmaceutical reference compounds. This test is useful for hazard identification and may contribute to reduce animal studies.
KW - Adult
KW - Humans
KW - Female
KW - Cells, Cultured
KW - Oligonucleotide Array Sequence Analysis
KW - Blotting, Western
KW - Reverse Transcriptase Polymerase Chain Reaction/methods
KW - RNA, Messenger/metabolism
KW - Toxicity Tests/methods
KW - Embryo Implantation/drug effects
KW - Endocrine Disruptors/toxicity
KW - Endometrium/drug effects/metabolism
KW - Hormone Antagonists/toxicity
KW - Pharmaceutical Preparations/adverse effects
KW - Progesterone/metabolism/pharmacology
KW - Sulfotransferases/genetics
KW - Adult
KW - Humans
KW - Female
KW - Cells, Cultured
KW - Oligonucleotide Array Sequence Analysis
KW - Blotting, Western
KW - Reverse Transcriptase Polymerase Chain Reaction/methods
KW - RNA, Messenger/metabolism
KW - Toxicity Tests/methods
KW - Embryo Implantation/drug effects
KW - Endocrine Disruptors/toxicity
KW - Endometrium/drug effects/metabolism
KW - Hormone Antagonists/toxicity
KW - Pharmaceutical Preparations/adverse effects
KW - Progesterone/metabolism/pharmacology
KW - Sulfotransferases/genetics
M3 - SCORING: Journal article
VL - 260
SP - 232
EP - 240
JO - TOXICOL APPL PHARM
JF - TOXICOL APPL PHARM
SN - 0041-008X
IS - 3
M1 - 3
ER -
