TY - JOUR
T1 - Estrogen actions in the male reproductive system involve estrogen response element-independent pathways
AU - Weiss, Jeffrey
AU - Bernhardt, Miranda L.
AU - Laronda, Monica M.
AU - Hurley, Lisa A.
AU - Glidewell-Kenney, Christine
AU - Pillai, Suresh
AU - Tong, Minghan
AU - Korach, Kenneth S.
AU - Jameson, J. Larry
PY - 2008/12
Y1 - 2008/12
N2 - The estrogen receptor-α (ERα) acts through multiple pathways, including estrogen response element (ERE)-dependent (classical) and ERE-independent (nonclassical) mechanisms. We previously created a mouse model harboring a two-amino-acid mutation of the DNA-binding domain (E207A, G208A) that precludes direct binding of ERα to an ERE. After crossing heterozygous mutant mice with an ERα knockout (ERKO) line, it was possible to assess the degree of physiological rescue by the isolated ERα nonclassical allele (-/AA; AA) when compared with ERKO mice (-/-) and to wild type (+/+; WT). In male ERKO mice up to 8 months of age, testosterone levels were high, although LH levels were similar to WT. Testosterone was normal in the AA mice, indicating that the AA allele rescues the enhanced testosterone biosynthesis in ERKO mice. Male ERKO mice exhibited distention of the seminiferous tubules as early as 2-3 months of age as a consequence of decreased water resorption in the efferent ducts. By 3-4 months of age, ERKO mice had impaired spermatogenesis in approximately 40% of their tubules, and sperm counts and motility declined in association with the histological changes. In the AA mice, histological defects were greatly reduced or absent, and sperm counts and motility were rescued. Levels of aquaporins 1 and 9, which contribute to water uptake in the efferent ducts, were reduced in ERKO mice and partially or fully rescued in AA mice, whereas another water transporter, sodium-hydrogen exchanger-3, was decreased in both ERKO and AA mice. We conclude that non-ERE-dependent estrogen pathways are sufficient to rescue the defective spermatogenesis observed in ERKO mice and play a prominent role in ERα action in the testis, including pathways that regulate water resorption and androgen biosynthesis.
AB - The estrogen receptor-α (ERα) acts through multiple pathways, including estrogen response element (ERE)-dependent (classical) and ERE-independent (nonclassical) mechanisms. We previously created a mouse model harboring a two-amino-acid mutation of the DNA-binding domain (E207A, G208A) that precludes direct binding of ERα to an ERE. After crossing heterozygous mutant mice with an ERα knockout (ERKO) line, it was possible to assess the degree of physiological rescue by the isolated ERα nonclassical allele (-/AA; AA) when compared with ERKO mice (-/-) and to wild type (+/+; WT). In male ERKO mice up to 8 months of age, testosterone levels were high, although LH levels were similar to WT. Testosterone was normal in the AA mice, indicating that the AA allele rescues the enhanced testosterone biosynthesis in ERKO mice. Male ERKO mice exhibited distention of the seminiferous tubules as early as 2-3 months of age as a consequence of decreased water resorption in the efferent ducts. By 3-4 months of age, ERKO mice had impaired spermatogenesis in approximately 40% of their tubules, and sperm counts and motility declined in association with the histological changes. In the AA mice, histological defects were greatly reduced or absent, and sperm counts and motility were rescued. Levels of aquaporins 1 and 9, which contribute to water uptake in the efferent ducts, were reduced in ERKO mice and partially or fully rescued in AA mice, whereas another water transporter, sodium-hydrogen exchanger-3, was decreased in both ERKO and AA mice. We conclude that non-ERE-dependent estrogen pathways are sufficient to rescue the defective spermatogenesis observed in ERKO mice and play a prominent role in ERα action in the testis, including pathways that regulate water resorption and androgen biosynthesis.
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U2 - 10.1210/en.2008-0122
DO - 10.1210/en.2008-0122
M3 - Article
C2 - 18719025
AN - SCOPUS:57349117645
VL - 149
SP - 6198
EP - 6206
JO - Endocrinology
JF - Endocrinology
SN - 0013-7227
IS - 12
ER -