Dysregulation of Notch and ERα signaling in AhR-/- male mice.
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.
Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204.
Bo
B
Huang
Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204.
Ryan
R
Butler
Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204.
Yifei
Y
Miao
Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204.
Yubing
Y
Dai
Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204.
Wanfu
W
Wu
Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204.
Wen
W
Su
Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
Yoshiaki
Y
Fujii-Kuriyama
Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204.
Margaret
M
Warner
Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204; Center for Medical Innovations, Department of Biosciences and Nutrition, Karolinska Institutet, Novum 141 86, Sweden jgustafsson@uh.edu.
Jan-Åke
JÅ
Gustafsson
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001141:Aromatase / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency*; D015415:Biomarkers; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005260:Female; D005298:Fertility / Q000235:genetics; D017353:Gene Deletion; D015870:Gene Expression; D005854:Germ Cells / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency*; D051880:Receptors, Notch / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013090:Spermatocytes / Q000378:metabolism; D013737:Testis / Q000378:metabolism
D001141:Aromatase; D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011944:Receptors, Androgen; D018336:Receptors, Aryl Hydrocarbon; D051880:Receptors, Notch; D011980:Receptors, Progesterone; C484722:Ahr protein, mouse
aryl hydrocarbon receptor; germ cell apoptosis; low fertility; mammary gland; testosterone
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