A mechanistic assessment of 1,3-butadiene diepoxide-induced inhibition of uterine deciduoma proliferation in pseudopregnant rats.
Butadiene diepoxide (BDE), a reactive metabolite of 1,3-butadiene that is an important industrial chemical used in synthetic rubber production causes a dose-dependent inhibition of deciduoma development in pseudopregnant Sprague-Dawley rats. This study used 4 daily i.p. BDE doses of 0.20, 0.25, 0.30, 0.35, or 0.40 to characterize mechanisms that may be responsible for the antideciduoma effect. Pseudopregnant rats were treated either before (pseudopregnancy [PPG] days 1-4) or after (PPG days 5-9) deciduoma induction by endometrial trauma with a blunt needle. Animals were killed on PPG day 9 and evaluated for serum progesterone and endometrial protein and DNA. RT-PCR was used to measure message for estrogen receptor (ER) alpha and pituitary adenylate cyclase-activating polypeptide (PACAP). Substrate zymography and Western blotting were used respectively to measure matrix metalloproteinase (MMP)-9 and inducible nitric oxide synthase. The antideciduoma effects of BDE were associated with decreases in endometrial weight, protein, and DNA, with decreases in serum progesterone, and with decreases in PACAP message and MMP-9. A reduction in NOS was identified at the highest dose of BDE. Message for estrogen receptor (ER) alpha was not affected at any dose. We conclude that the reduction in decidual proliferation was direct and appeared to be associated with either 1) a decrease in the effectiveness of the deciduogenic stimulation and/or a weakened endometrial sensitivity to the stimulus; or 2) an effect on deciduoma development. Molecular mechanisms that apparently contributed to BDE inhibition of decidual metabolism included the synthesis of protein and DNA involved in decidual growth, the synthesis and activation of a matrix metalloproteinase for degradation of the extracellular matrix that is essential for tissue remodeling during deciduoma development, and the nitric oxide/nitric oxide synthase and pituitary adenylate cyclase-activating peptide systems that are involved in promoting vasodilation and increased vascular permeability to enhance the availability of substrates for maximal deciduoma growth. The ovotoxicity of BDE, which has previously been established, may indirectly affect decidual proliferation by reducing progesterone, the preeminent endocrine regulator of deciduoma development. The findings also suggest that BDE may possess no estrogenic action since it was associated with endometrial weight loss and unaltered levels of the estrogen receptor alpha mRNA expression.
Spencer
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Health Research Center, Southern University, Baton Rouge, Louisiana 70813, USA. fitz@grant.phys.subr.edu
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Zhu
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D000818:Animals; D002070:Butadienes / Q000008:administration & dosage / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D017931:DNA Primers / Q000737:chemistry; D003656:Decidua / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha; D005260:Female; D007274:Injections, Intraperitoneal; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009929:Organ Size / Q000187:drug effects; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011247:Pregnancy; D011374:Progesterone / Q000097:blood; D011506:Proteins / Q000378:metabolism; D011555:Pseudopregnancy; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
C495403:Adcyap1 protein, rat; D002070:Butadienes; D017931:DNA Primers; D047628:Estrogen Receptor alpha; D061965:Matrix Metalloproteinase Inhibitors; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011506:Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011374:Progesterone; D004247:DNA; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D020780:Matrix Metalloproteinase 9; C031763:1,3-butadiene