Knockout of the transcription factor NRF2 disrupts spermatogenesis in an age-dependent manner.
Oxidative stress occurs when generation of reactive oxygen species (ROS) overwhelms antioxidant defenses. Oxidative stress has been associated with male infertility. The transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2) regulates basal and inducible transcription of genes encoding enzymes important for protection against ROS. We hypothesized that deletion of the Nrf2 gene causes testicular and epididymal oxidative stress, which disrupts spermatogenesis. Our results show that male Nrf2(-/-) mice have decreased fertility compared to wild-type and heterozygous littermates, due to accumulating seminiferous tubule damage with increasing age. Testicular sperm head counts, epididymal sperm counts, and epididymal sperm motility in 2-month-old Nrf2(-/-) males did not differ from those of wild-type littermates; however, by age 6 months, Nrf2(-/-) males had 44% lower testicular sperm head counts, 65% lower epididymal sperm counts, and 66% lower epididymal sperm motility than wild-type males. Two- to 4-month-old Nrf2(-/-) males had elevated levels of testicular and epididymal lipid peroxidation and testicular germ cell apoptosis, and decreased levels of antioxidants, compared to wild-type males. These results provide evidence that oxidative stress has deleterious effects on the testis and epididymis and demonstrate a critical role for the transcription factor NRF2 in preventing oxidative disruption of spermatogenesis.
Nakamura
Brooke N
BN
Department of Medicine, University of California at Irvine, Irvine, CA 92617, USA.
Lawson
Gregory
G
Chan
Jefferson Y
JY
Banuelos
Jésus
J
Cortés
Mabel M
MM
Hoang
Yvonne D
YD
Ortiz
Laura
L
Rau
Bogdan A
BA
Luderer
Ulrike
U
D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018450:Disease Progression; D007248:Infertility, Male / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013076:Sperm Count; D013081:Sperm Motility / Q000235:genetics; D013091:Spermatogenesis / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D014157:Transcription Factors