title: 4,4'-Methylenedianiline Alters Serotonergic Transport in a Novel, Sex-Specific Model of Pulmonary Arterial Hypertension in Rats.
abstract: Pulmonary arterial hypertension (PAH) is a cardiovascular disorder characterized by elevated pulmonary artery pressure as a result of arterial wall thickening. Patients are 3-4 times more likely to be women than men. This gender discrepancy demonstrates a need for an animal model with similar sex differences. 4,4'-Methylenedianiline (DAPM) is an aromatic amine used industrially in the synthesis of polyurethanes. Chronic, intermittent treatment of male and female rats with DAPM resulted in medial hyperplasia of pulmonary arterioles, exclusively in females, coupled to increases in pulmonary arterial pressures. Significant increases in plasma levels of endothelin-1 (ET-1) and serotonin, but decreases in nitrite [Formula: see text], were observed in females treated with DAPM. A decrease was observed in the serum ratio of the estrogen metabolites 2-hydroxyestradiol (2-OHE1)/16α-hydroxyestrogen (16α-OHE1). In females, ET-1,[Formula: see text] , and 2-OHE1/16α-OHE1 were significantly correlated with peak pressure gradient, an indirect measure of pulmonary arterial pressure. Expression of the serotonin transport protein (SERT) was significantly higher in the arteries of DAPM-treated females. In vitro, DAPM induced human pulmonary vascular smooth muscle cell proliferation and serotonin uptake, both of which were inhibited by treatment with the estrogen receptor antagonist ICI 182,780 or the selective serotonin reuptake inhibitor fluoxetine. DAPM also induced the release of serotonin from human pulmonary endothelial cells in culture, which is blocked by ICI 182,780. Taken together, this suggests that DAPM-mediated dysregulation of serotonin transport is estrogen-receptor dependent. Thus, DAPM-induced PAH pathology may be a new tool to clarify the sex selectivity of PAH disease pathogenesis.
authors.affiliation: *Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130;
authors.forename: Michelle
authors.initials: M
authors.lastname: Carroll-Turpin
authors.affiliation: *Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130;
authors.forename: Valeria
authors.initials: V
authors.lastname: Hebert
authors.affiliation: *Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130;
authors.forename: Tanya
authors.initials: T
authors.lastname: Chotibut
authors.affiliation: *Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130;
authors.forename: Heather
authors.initials: H
authors.lastname: Wensler
authors.affiliation: *Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130;
authors.forename: Dallas
authors.initials: D
authors.lastname: Krentzel
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans 70112;
authors.forename: Kurt James
authors.initials: KJ
authors.lastname: Varner
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans 70112;
authors.forename: Brendan R
authors.initials: BR
authors.lastname: Burn
authors.affiliation: Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana 70803; and.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Chen
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center, Shreveport 71130.
authors.forename: Fleurette
authors.initials: F
authors.lastname: Abreo
authors.affiliation: *Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130; tammydugas@lsu.edu.
authors.forename: Tammy Renee
authors.initials: TR
authors.lastname: Dugas
mesh_terms: D000814:Aniline Compounds / Q000633:toxicity*; D000818:Animals; D052244:Endocrine Disruptors / Q000633:toxicity; D019332:Endothelin-1 / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology*; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology*; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism*; D012727:Sex Characteristics; D001559:Benzhydryl Compounds
chemical_list: D000814:Aniline Compounds; D052244:Endocrine Disruptors; D019332:Endothelin-1; D004967:Estrogens; D009569:Nitric Oxide; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; D012701:Serotonin; C482440:Sert1 protein, rat; C009505:4,4'-diaminodiphenylmethane; D001559:Benzhydryl Compounds
keywords: 4,4′-methylenedianiline; estrogen receptor; pulmonary arterial hypertension; serotonin; serotonin transporter