Disruption of Aryl Hydrocarbon Receptor (AhR) Induces Regression of the Seminal Vesicle in Aged Male Mice

Baba, Takashi; Shima, Yuichi; Owaki, Akiko; Mimura, Junsei; Oshima, Motohiko; Fujii‐Kuriyama, Yoshiaki; Morohashi, Ken-ichirou

doi:10.1159/000117714

Cited by 47 publications

(37 citation statements)

References 63 publications

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“…A previous study found that the loss of AhR causes reduced fertility in male mice and that regression of the seminal vesicles was responsible for this phenotype in the aged AhR −/− male mice (11). We found reduced fertility in young AhR −/− male mice measured by number of pups in a litter.…”

Section: Low Fertility Of Young Ahr-deficient Male Mice With No Changsupporting

confidence: 59%

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Dysregulation of Notch and ERα signaling in AhR^−/−male mice

Huang

Butler

Miao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The aryl hydrocarbon receptor (AhR) is now recognized as an important physiological regulator in the immune and reproductive systems, and in the development of the liver and vascular system. AhR regulates cell cycle, cell proliferation, and differentiation through interacting with other signaling pathways, like estrogen receptor α (ERα), androgen receptor (AR), and Notch signaling. In the present study, we investigated Notch and estrogen signaling in AhR−/− mice. We found low fertility with degenerative changes in the testes, germ cell apoptosis, and a reduced number of early spermatids. There was no change in aromatase, AR, ERα, or ERβ expression in the testis and no detectable change in serum estrogen levels. However, expression of Notch receptors (Notch1 and Notch3) and their target Hairy and Enhancer of Split homolog 1 (HES1) was reduced. In addition, the testosterone level was slightly reduced in the serum. In the mammary fat pad, AhR appeared to regulate estrogen signaling because, in AhR−/− males, there was significant growth of the mammary ducts with high expression of ERα in the ductal epithelium. The enhanced mammary ductal growth appears to be related to overexpression of ERα accompanied by a high proliferation index, whereas the reduced fertility appears to be related defects in Notch signaling that leads to reduced expression of HES1 and, consequently, early maturation of spermatocytes and a depletion of primary spermatids. Previous reports have indicated that AhR pathway is associated with infertility in men. Our results provide a mechanistic explanation for this defect.

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Section: Low Fertility Of Young Ahr-deficient Male Mice With No Changsupporting

confidence: 59%

“…Previous studies on the role of AhR in reproduction in male mice revealed that seminal vesicles were regressed in the aged AhR −/− male mice (11). In the present study, we found no such regression in young or old AhR −/− male mice, but nonetheless fertility was reduced and there was marked growth of mammary ducts.…”

contrasting

confidence: 67%

Dysregulation of Notch and ERα signaling in AhR^−/−male mice

Huang

Butler

Miao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Other mechanisms may involve altered hormonal signaling as developmental exposure to dioxins inhibit sex steroid biosynthesis by suppressing activity of testicular STAR protein [76]. Male mice with AhR knockout (AhR(−/−)) have impaired testosterone synthesis in Leydig cells and low sperm counts [77]. Furthermore, dioxin-activated AhR/ARNT can recruit estrogen receptor and co-activator p300 to estrogen-responsive elements (EREs), leading to transactivation and estrogenic effects in the absence of estrogenic ligand [78].…”

Section: Mechanisms Of Epigenetic Reprograming By Dioxinsmentioning

confidence: 99%

Spermatogenesis disruption by dioxins: Epigenetic reprograming and windows of susceptibility

Pilsner

Parker

Sergeyev

et al. 2017

Reproductive Toxicology

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Dioxins are a group of highly persistent chemicals that are generated as by-products of industrial and natural processes. Reduction in sperm counts is among the most sensitive endpoints of dioxin toxicity. The exact mechanism by which dioxins reduce sperm counts is not known. Recent data implicate the role of epididymal factors rather than disruption of spermatogenesis. Studies reviewed here demonstrate that dioxins induce the transfer of environmental conditions to the next generation via male germline following exposures during the window of epigenetic reprogramming of primordial germ cells. Increased incidence of birth defects in offspring of male veterans exposed to dioxin containing, Agent Orange, suggest that dioxins may induce epigenomic changes in male germ cells of adults during spermatogenesis. This is supported by recent animal data that show that environmental conditions can cause epigenetic dysregulation in sperm in the context of specific windows of epigenetic reprogramming during spermatogenesis.

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“…Common features of the AhR −/− mice are decreased liver size, hepatic portal fibrosis, and decreased constitutive expression of drug metabolizing enzymes such a P4501A1 and 1B1 (10). In the AhR mice produced in the Bradfield laboratory, seminal vesicle weight was higher than that of WT mice at postnatal day 35 (11), whereas in the AhR −/− mice produced in the Fujii-Kuriyama laboratory, seminal vesicles were reported to regress in an age-dependent manner (12). To date no abnormalities in the metabolism of purines or excretion of urate have been reported in AhR −/− mice and variable effects on the immune system have been reported in the three AhR −/− strains.…”

mentioning

confidence: 99%

Uric acid stones in the urinary bladder of aryl hydrocarbon receptor (AhR) knockout mice

Butler

Inzunza

Suzuki

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The aryl hydrocarbon receptor (AhR) knockout mice raised in the laboratory of Fujii-Kuriyama have been under investigation for several years because of the presence in their urinary bladder of large, yellowish stones. The stones are composed of uric acid and become apparent in the bladders as tiny stones when mice are 10 wk of age. By the time the mice are 6 mo of age, there are usually two or three stones with diameters of 3-4 mm. The urate concentration in the serum was normal but in the urine the concentration was 40-50 mg/dL, which is 10 times higher than that in the WT littermates. There were no apparent histological pathologies in the kidney or joints and the levels of enzymes involved in elimination of purines were normal. The source of the uric acid was therefore judged to be from degradation of nucleic acids due to a high turnover of cells in the bladder itself. The bladder was fibrotic and the luminal side of the bladder epithelium was filled with eosinophilic granules. There was loss of E-cadherin between some epithelial cells, with an enlarged submucosal area filled with immune cells and sometimes invading epithelial cells. We hypothesize that in the absence of AhR there is loss of detoxifying enzymes, which leads to accumulation of unconjugated cytotoxins and carcinogens in the bladder. The presence of bladder toxins may have led to the increased apoptosis and inflammation as well as invasion of epithelial cells in the bladders of older mice.

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Disruption of Aryl Hydrocarbon Receptor (AhR) Induces Regression of the Seminal Vesicle in Aged Male Mice

Cited by 47 publications

References 63 publications

Dysregulation of Notch and ERα signaling in AhR^−/−male mice

Dysregulation of Notch and ERα signaling in AhR^−/−male mice

Spermatogenesis disruption by dioxins: Epigenetic reprograming and windows of susceptibility

Uric acid stones in the urinary bladder of aryl hydrocarbon receptor (AhR) knockout mice

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Disruption of Aryl Hydrocarbon Receptor (AhR) Induces Regression of the Seminal Vesicle in Aged Male Mice

Cited by 47 publications

References 63 publications

Dysregulation of Notch and ERα signaling in AhR−/−male mice

Dysregulation of Notch and ERα signaling in AhR−/−male mice

Spermatogenesis disruption by dioxins: Epigenetic reprograming and windows of susceptibility

Uric acid stones in the urinary bladder of aryl hydrocarbon receptor (AhR) knockout mice

Contact Info

Product

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Dysregulation of Notch and ERα signaling in AhR^−/−male mice

Dysregulation of Notch and ERα signaling in AhR^−/−male mice