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.

Sex, Gender, and Sex Hormones in Pulmonary Hypertension and Right Ventricular Failure

“…While gender does not play a clear role in human drug-and toxin-induced PAH (perhaps because of psychosocial or behavior influences), two models of drug-induced PAH predominantly affect female rodents. Specifically, administration of the anorexigen dexfenfluramine or the industrial compound 4,4′-diaminodiphenylmethane (DAPM) results in PH in female animals only (46,71). The mechanism of both drugs appears to involve increased serotonergic signaling and altered estrogen metabolism to favor pro-proliferative metabolites.…”

Gender, Estrogen, and Obliterative Lesions in the Lung

“…PCB153's effects on both endothelial cells are even more pronounced than those on E2 with respect to vasculosphere formation and vasculogenesis. Another endocrine-disrupting chemical, 4,4′-methylenedianiline, used in the synthesis of polyurethanes has been shown to increase hyperplasia of pulmonary arteries exclusively in female rats [ 62 ]. In vitro human pulmonary smooth muscle cells were shown to proliferate when exposed to 4,4′-methylenedianiline, and this was inhibited by treatment with the estrogen receptor antagonist ICI 182,780.…”

“…Anorectic drugs such as dexfenfluramine (Dfen) have been shown to induce PAH only in female mice [ 95 ]. Treatment of rats with 4,4′-methylenedianiline (DAPM) induced female-specific smooth muscle hyperplasia of the pulmonary vessels [ 62 ]. Genetic-based mouse models have also shown sex differences in PAH susceptibility.…”

Molecular Risk Factors of Pulmonary Arterial Hypertension

“…PCB153's effects on both endothelial cells are even more pronounced than E2 with respect to vasculosphere formation and vasculogenesis. Another endocrine disrupting chemical, 4,4′-methylenedianiline, used in the synthesis of polyurethanes has been shown to increase hyperplasia of pulmonary arteries exclusively in female rats (Carroll-Turpin et al, 2015).…”

“…Anorectic drugs such as dexfenfluramine (Dfen) have been shown to induce PAH in only female mice (Dempsie et al, 2013). Treatment of rats with 4, 4'-methylenedianiline (DAPM) induced female specific smooth muscle hyperplasia of the pulmonary vessels (Carroll-Turpin et al, 2015). Genetic based mouse models have also shown sex differences in PAH susceptibility.…”