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: Michelle Carroll-Turpin, Valeria Hebert, Tanya Chotibut, Heather Wensler, Dallas Krentzel, Kurt James Varner, Brendan R Burn, Yi-Fan Chen, Fleurette Abreo, Tammy Renee Dugas
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 147 Issue 1 Pg. 235-45 (Sep 2015) ISSN: 1096-0929 [Electronic] United States
• PMID: 26116029 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Aniline Compounds
• Endocrine Disruptors
• Endothelin-1
• Estrogens
• RNA-Binding Proteins
• Receptors, Estrogen
• Sert1 protein, rat
• Nitric Oxide
• Serotonin
• 4,4'-diaminodiphenylmethane

Topics

• Aniline Compounds (toxicity)
• Animals
• Endocrine Disruptors (toxicity)
• Endothelin-1 (metabolism)
• Epithelial Cells (drug effects, metabolism)
• Estrogens (metabolism)
• Female
• Hypertension, Pulmonary (metabolism, pathology)
• Hypertrophy, Right Ventricular (chemically induced, pathology)
• Male
• Muscle, Smooth, Vascular (drug effects, metabolism)
• Nitric Oxide (metabolism)
• Pulmonary Artery (metabolism, pathology)
• RNA-Binding Proteins (biosynthesis, genetics)
• Rats
• Rats, Sprague-Dawley
• Receptors, Estrogen (drug effects)
• Serotonin (metabolism)
• Sex Characteristics