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

Soluble epoxide hydrolase ( Ephx2, sEH) is a bifunctional enzyme with COOH-terminal hydrolase and NH2-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.

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Bacterial Expression and HTS Assessment of Soluble Epoxide Hydrolase Phosphatase

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057116637609 ◽

2016 ◽

Vol 21 (7) ◽

pp. 689-694 ◽

Cited By ~ 7

Author(s):

Franca-Maria Klingler ◽

Markus Wolf ◽

Sandra Wittmann ◽

Philip Gribbon ◽

Ewgenij Proschak

Keyword(s):

Phosphatase Activity ◽

High Throughput Screening ◽

Epoxide Hydrolase ◽

Physiological Role ◽

Soluble Epoxide Hydrolase ◽

Bacterial Expression ◽

Catalytic Domains ◽

Lipid Phosphatase ◽

Screening Protocol

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that possesses an epoxide hydrolase and lipid phosphatase activity (sEH-P) at two distinct catalytic domains. While the physiological role of the epoxide hydrolase domain is well understood, the consequences of the phosphatase activity remain unclear. Herein we describe the bacterial expression of the recombinant N-terminal domain of sEH-P and the development of a high-throughput screening protocol using a sensitive and commercially available substrate fluorescein diphosphate. The usability of the assay system was demonstrated and novel inhibitors of sEH-P were identified.

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Brain aromatase activity and plasma testosterone levels are elevated in aggressive male mice during early ontogeny

Developmental Brain Research ◽

10.1016/0165-3806(94)90162-7 ◽

1994 ◽

Vol 82 (1-2) ◽

pp. 185-192 ◽

Cited By ~ 22

Author(s):

J.C. Compaan ◽

J.B. Hutchison ◽

A. Wozniak ◽

A.J.H. de Ruiter ◽

J.M. Koolhaas

Keyword(s):

Early Ontogeny ◽

Plasma Testosterone ◽

Aromatase Activity ◽

Male Mice ◽

Testosterone Levels ◽

Brain Aromatase ◽

Aggressive Male

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INCREASED SENSITIVITY OF SEMINAL VESICLES TO TESTOSTERONE IN A MOUSE STRAIN WITH LOW PLASMA TESTOSTERONE LEVELS

Journal of Endocrinology ◽

10.1677/joe.0.0600145 ◽

1974 ◽

Vol 60 (1) ◽

pp. 145-148 ◽

Cited By ~ 48

Author(s):

A. BARTKE

Keyword(s):

Testosterone Propionate ◽

Seminal Vesicles ◽

Plasma Testosterone ◽

Testicular Function ◽

Androgen Deficiency ◽

Male Mice ◽

Testosterone Levels ◽

Sex Drive ◽

Testicular Weight ◽

Increased Sensitivity

SUMMARY In male mice of the C57BL/10J (C57) strain the testicular weight, sex drive and aggression are low compared with a number of other strains, indicating androgen deficiency. In contrast, DBA/2J (DBA) males were 'normal' in all studied parameters of testicular function. The weight of the seminal vesicles is similar in both strains. Plasma testosterone levels, and the responsiveness of the seminal vesicles to injected testosterone propionate in C57 and DBA animals were compared. Plasma testosterone levels were 1·3 ± 0·4 ng/ml in C57 and 4·6 ± 1·0 ng/ml in DBA mice. The increase in weight of the seminal vesicles after administration of testosterone propionate to castrated male mice was, however, considerably greater in C57 than in DBA mice. In order to restore the weight of the seminal vesicles to normal it was necessary to administer twice as much testosterone propionate to DBA than to C57 males.

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DEVELOPMENTAL PATTERNS OF PLASMA AND TESTICULAR TESTOSTERONE IN MICE FROM BIRTH TO ADULTHOOD

Acta Endocrinologica ◽

10.1530/acta.0.0890780 ◽

1978 ◽

Vol 89 (4) ◽

pp. 780-788 ◽

Cited By ~ 67

Author(s):

Ch. Jean-Faucher ◽

M. Berger ◽

M. de Turckheim ◽

G. Veyssiere ◽

Cl. Jean

Keyword(s):

Body Weight ◽

Seminal Vesicle ◽

Sex Difference ◽

Plasma Testosterone ◽

Male Mice ◽

Developmental Patterns ◽

Testosterone Levels

ABSTRACT Male mice were raised in cohabitation with females from birth to 90 days. Testosterone was measured every 10 days in plasma and testes. Sex difference in body weight was related to the pre-pubertal increase of testosterone levels in males. The weight of the seminal vesicle was positively correlated with circulating testosterone levels between 1 and 40 days but not between 50 and 90 days Testosterone concentrations in the plasma and testes were high at birth: 630 pg/ml and 58.0 ± 17.7 ng/100 mg; they subsequently decreased during the first days of life and remained low until day 20: 240 ± 110 pg/ml and 0.1 ± 0.03 ng/100 mg. The testosterone levels then increased rapidly between days 20 and 30 and especially between 30 and 40 reaching their maxima: 5770 ± 1720 pg/ml and 123.7 ± 18.3 ng/100 mg testis. This increase was transitory and testosterone levels fell after day 40. By 90 days, the testosterone levels, 440 ± 65 pg/ml and 43.2 ± 5.5 ng/100 mg testis, were comparable to those measured at birth. Plasma testosterone and age were positively correlated between 1 and 40 days, and negatively between 50 and 90 days. The first fertile matings occurred at age 40 days.

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Letrozole Protects Against Cadmium-induced Inhibition of Spermatogenesis via LHCGR and Hsd3b6 to Activate Testosterone Synthesis in Mice

10.21203/rs.3.rs-779349/v1 ◽

2021 ◽

Author(s):

Yao Yao ◽

Yangyang Wan ◽

Xiaoyun Shi ◽

Lan Guo ◽

Hui Jiang ◽

...

Keyword(s):

Sperm Quality ◽

Sperm Count ◽

Hormone Secretion ◽

Reproductive Toxicity ◽

Plasma Testosterone ◽

Control Group ◽

Rna Seq ◽

Testosterone Levels ◽

Letrozole Treatment ◽

Testosterone Synthesis

Abstract The heavy metal cadmium is believed to be one of the environmental endocrine disruptors of spermatogenesis. Cadmium-induced inhibition of spermatogenesis is associated with hormone secretion disorder. Letrozole is an aromatase inhibitor that can raise peripheral androgen levels and stimulate spermatogenesis. However, the potential protective effects of letrozole against cadmium-induced reproductive toxicity remain to be elucidated. In this study, male mice were administered CdCl2 (4 mg/kg BW) orally by gavage alone or in combination with letrozole (0.25 mg/kg BW) for 30 days. Cd exposure caused a significant decrease in body weight, sperm count, motility, vitality and plasma testosterone levels. Histopathological changes revealed extensive vacuolization and decreased spermatozoa in the lumen. However, in the Cd+letrozole group, letrozole treatment compensated for deficits in sperm parameters (count, motility, and vitality) induced by Cd. Letrozole treatment significantly increased serum testosterone levels, which were reduced by Cd. Histopathological studies revealed a systematic array of all germ cells, a preserved basement membrane and relatively less vacuolization. For mechanistic exploration, RNA-seq was used to profile alterations in gene expression in response to letrozole. Compared with that in the Cd-treated group, RNA-Seq analysis showed that 214 genes were differentially expressed in the presence of letrozole. Gene ontology (GO) enrichment analysis and KEGG signaling pathway analysis showed that steroid biosynthetic processes were the processes most affected by letrozole treatment. Furthermore, we found that the expression of the testosterone synthesis-related genes LHCGR (luteinizing hormone/choriogonadotropin receptor) and Hsd3b6 (3 beta- and steroid delta-isomerase 6) was significantly downregulated in Cd‐induced testes, but in letrozole-treated testes, these genes maintained similar expression levels as the control group. However, the transcription levels of inflammatory cytokines, such as IL-1β and IL-6, and oxidative stress-related genes (Nrf2, Nqo1, and Ho-1) showed no changes. The present study suggests that the protective potential of letrozole against Cd-induced reproductive toxicity might be due to upregulation of LHCGR and Hsd3b6, which could beneficially increase testosterone synthesis to achieve optimum protection in sperm quality and spermatogenesis.

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Role of Soluble Epoxide Hydrolase in the Sex-Specific Vascular Response to Cerebral Ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.65 ◽

2009 ◽

Vol 29 (8) ◽

pp. 1475-1481 ◽

Cited By ~ 55

Author(s):

Wenri Zhang ◽

Jeffrey J Iliff ◽

Caitlyn J Campbell ◽

Ruikang K Wang ◽

Patricia D Hurn ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Ischemia ◽

Infarct Size ◽

Epoxide Hydrolase ◽

Focal Cerebral Ischemia ◽

Soluble Epoxide Hydrolase ◽

Artery Occlusion ◽

Male Mice ◽

Key Enzyme

Soluble epoxide hydrolase (sEH), a key enzyme in the metabolism of vasodilator eicosanoids called epoxyeicosatrienoic acids (EETs), is sexually dimorphic and suppressed by estrogen. We determined if the sex difference in blood flow during focal cerebral ischemia is linked to sEH. Soluble epoxide hydrolase expression in brain, hydrolase activity in cerebral vessels, and plasma 14,15-dihydroxyeicosatrienoic acid (14,15-DHET) were determined in male and female wild-type (WT) and sEH knockout (sEHKO) mice. Male, female, and ovariectomized female WT and sEHKO mice were subjected to 2-h middle cerebral artery occlusion (MCAO) and infarct size was measured at 24 h of reperfusion. Laser—Doppler cortical perfusion during MCAO was compared among groups and differences in cortical blood flow rates were confirmed using in vivo quantitative optical microangiography. Cerebrovascular expression and activity of sEH and plasma 14,15-DHET were lower in WT female than male mice, and blood flow during MCAO was higher and infarct size was smaller in WT female compared with male mice. Sex differences in cerebral blood flow and ischemic damage were abolished after ovariectomy and were absent in sEHKO mice. We conclude that sEH is an important mechanism underlying sex-linked differences in blood flow and brain damage after cerebral ischemia.

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Age-Related Changes in Testes, Seminal Vesicles and Plasma Testosterone Levels in Male Mice

Gerontology ◽

10.1159/000212019 ◽

1974 ◽

Vol 20 (4) ◽

pp. 231-238 ◽

Cited By ~ 42

Author(s):

B.E. Eleftheriou ◽

L.A. Lucas

Keyword(s):

Seminal Vesicles ◽

Plasma Testosterone ◽

Male Mice ◽

Testosterone Levels ◽

Age Related ◽

Age Related Changes

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Postweaning Grouping as a Strategy to Reduce Singly Housed Male Mice

Animals ◽

10.3390/ani10112135 ◽

2020 ◽

Vol 10 (11) ◽

pp. 2135

Author(s):

Roger Grífols ◽

Carolina Zamora ◽

Iván Ortega-Saez ◽

Garikoitz Azkona

Keyword(s):

Social Isolation ◽

Plasma Levels ◽

Agonistic Behavior ◽

Plasma Testosterone ◽

Male Mice ◽

Laboratory Mice ◽

Testosterone Levels ◽

Behavioral Abnormalities ◽

Group Members

Rearing laboratory mice in groups is important since social isolation after weaning induces brain alterations, which entails behavioral abnormalities in adulthood. Age is an important factor when grouping males of different litters due to inter-male aggressiveness. The aim of this study was to determine whether newly weaned mice could safely be grouped with late juvenile or early and late pubescent mice, and whether cage cleaning, the number of the hosting group members and testosterone plasma levels have any influence. Newly weaned C57BL/6J, CD1, and SCID Beige male mice were systematically grouped with same strain late juvenile, early or late pubescent male mice in clean or dirty cages of 1, 2 or 3 hosting members. We also analyzed plasma testosterone levels at different postnatal days. Our result showed that only strain and hosting male’s age influence agonistic behavior toward newly weaned mice. Thus, in order not to house a recently weaned male alone, we would recommend grouping it with late juvenile same strain mice in all studied strains. In the same way, CD1 and SCID Beige pubescent mice will admit a newly weaned mouse in their group. However, we would not recommend grouping newly weaned and pubescent C57BL/6J males.

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