Alteration in plasma testosterone levels in male mice lacking soluble epoxide hydrolase

Abstract

Soluble epoxide hydrolase (Ephx2, sEH) is a bifunctional enzyme with COOH-terminal hydrolase and NH(2)-terminal phosphatase activities. sEH converts epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), and the phosphatase activity is suggested to be involved in cholesterol metabolism. EETs participate in a wide range of biological functions, including regulation of vascular tone, renal tubular transport, cardiac contractility, and inflammation. Inhibition of sEH is a potential approach for enhancing the biological activity of EETs. Therefore, disruption of sEH activity is becoming an attractive therapeutic target for both cardiovascular and inflammatory diseases. To define the physiological role of sEH, we characterized a knockout mouse colony lacking expression of the Ephx2 gene. Lack of sEH enzyme is characterized by elevation of EET to DHET ratios in both the linoleate and arachidonate series in plasma and tissues of both female and male mice. In male mice, this lack of expression was also associated with decreased plasma testosterone levels, sperm count, and testicular size. However, this genotype was still able to sire litters. Plasma cholesterol levels also declined in this genotype. Behavior tests such as anxiety-like behavior and hedonic response were also examined in Ephx2-null and WT mice, as all can be related to hormonal changes. Null mice showed a level of anxiety with a decreased hedonic response. In conclusion, this study provides a broad biochemical, physiological, and behavioral characterization of the Ephx2-null mouse colony and suggests a mechanism by which sEH and its substrates may regulate circulating levels of testosterone through cholesterol biosynthesis and metabolism.

Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance

“…Mice with targeted disruption in exon 1 of the Ephx2 gene (19), were back-crossed onto a C57BL6 (Jackson Laboratories) genetic background an additional ten generations prior to use in this study (20,43). Mice were placed either on standard chow diet or a HFD (SI Text).…”

The Pharmacology of the Cytochrome P450 Epoxygenase/Soluble Epoxide Hydrolase Axis in the Vasculature and Cardiovascular Disease

“…The activity of the lipid phosphatase has been associated with the metabolism of lysophosphatidic acid Oguro and Imaoka, 2012), peroxisome proliferator-activated receptor (PPAR) activity, the isoprenoid/cholesterol biosynthesis pathway, and cholesterol-related disorders (Enayetallah et al, 2008). Indeed, in addition to demonstrating enhanced circulating EET levels (Sinal et al, 2000), male sEH 2/2 mice exhibit decreased plasma cholesterol and testosterone levels (Luria et al, 2009). Moreover, the isoprenoid pyro-and monophosphates that are reported to be substrates for the N-terminal domain of the enzyme (Tran et al, 2005; are also used for isoprenylation of small G proteins involved in multiple cell signaling pathways, especially those linked to redox stress and inflammation (Kovacs et al, 2002).…”

“…Soluble epoxide hydrolase. The sEH has a complicated relationship with cholesterol and sEH 2/2 mice demonstrate lower levels of plasma cholesterol than wild-type mice (Enayetallah et al, 2008;Luria et al, 2009), a finding apparently explained by reduced hepatic expression of the 3-hydroxy-3-methylglutaryl-CoA, which is rate limiting for cholesterol synthesis (Enayetallah et al, 2008). However, a group of human subjects suffering from familial hypercholesterolemia that was linked to a polymorphism of the Ephx2 gene (Arg287Glu substitution) demonstrated increased, rather than decreased, plasma cholesterol levels (Sato et al, 2004).…”

Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers

“…Male Swiss Webster mice from Charles River Laboratory and sEH knockout mice in a C57BL6 background raised at University of California, Davis weighing 35-40 g and aged 5-6 months were used for this study. A colony of the sEH knockout mouse strain has been maintained at the "Mouse Biology Program" facility of the University of California, Davis, under standard rearing conditions as described previously (Luria et al, 2009). The sEH knockout mouse strain has a targeted disruption in exon 1 of the Ephx2 gene and was obtained from Dr. Christopher J. Sinal (National Cancer Institute, Bethesda, MD) (Miyata et al, 1999;Sinal et al, 2000).…”