The objective of this study was to determine the incidence of DNA fragmentation in human sperm, and to correlate any detected DNA damage with semen analysis parameters and fertilization rates in in vitro fertilization (IVF). A total of 298 semen samples were collected from men in the infertility program at The Toronto Hospital. For each sample, the percentage of sperm with DNA fragmentation was determined using the method of terminal deoxynucleotidyl transferase-mediated dUTP-biotin end-labeling (TUNEL) and fluorescence-activated cell sorting. The percentage of sperm with fragmented DNA was less than 4% in the majority of samples but ranged from 5% to 40% in approximately 27% of the samples. A negative correlation was found between the percentage of DNA fragmentation and the motility, morphology, and concentration of the ejaculated sperm. In 143 IVF samples, a significant negative association was also found between the percentage of sperm with DNA fragmentation and fertilization rate (p = 0.008) and embryo cleavage rate (p = 0.01). In addition, 35 men who smoked demonstrated an increased percentage of sperm with fragmented DNA (4.7 +/- 1.2%) as compared to 78 nonsmokers (1.1 +/- 0.2%; p = 0.01). These results demonstrate a negative association between semen analysis parameters and sperm with fragmented DNA. Since extremely poor semen samples are the indication for intracytoplasmic sperm injection, there is a high likelihood that sperm with fragmented DNA may be selected by chance and used for oocyte injection, resulting in poor fertilization and/or cleavage rates.
Polycyclic aromatic hydrocarbons (PAHs) are toxic chemicals released into the environment by fossil fuel combustion. Moreover, a primary route of human exposure to PAHs is tobacco smoke. Oocyte destruction and ovarian failure occur in PAH-treated mice, and cigarette smoking causes early menopause in women. In many cells, PAHs activate the aromatic hydrocarbon receptor (Ahr), a member of the Per-Arnt-Sim family of transcription factors. The Ahr is also activated by dioxin, one of the most intensively studied environmental contaminants. Here we show that an exposure of mice to PAHs induces the expression of Bax in oocytes, followed by apoptosis. Ovarian damage caused by PAHs is prevented by Ahr or Bax inactivation. Oocytes microinjected with a Bax promoter-reporter construct show Ahr-dependent transcriptional activation after PAH, but not dioxin, treatment, consistent with findings that dioxin is not cytotoxic to oocytes. This difference in the action of PAHs versus dioxin is conveyed by a single base pair flanking each Ahr response element in the Bax promoter. Oocytes in human ovarian biopsies grafted into immunodeficient mice also accumulate Bax and undergo apoptosis after PAH exposure in vivo. Thus, Ahr-driven Bax transcription is a novel and evolutionarily conserved cell-death signaling pathway responsible for environmental toxicant-induced ovarian failure.
Female reproductive capacity declines dramatically in the fourth decade of life as a result of an age-related decrease in oocyte quality and quantity. The primary causes of reproductive aging and the molecular factors responsible for decreased oocyte quality remain elusive. Here, we show that aging of the female germ line is accompanied by mitochondrial dysfunction associated with decreased oxidative phosphorylation and reduced Adenosine tri-phosphate (ATP) level. Diminished expression of the enzymes responsible for CoQ production, Pdss2 and Coq6, was observed in oocytes of older females in both mouse and human. The age-related decline in oocyte quality and quantity could be reversed by the administration of CoQ10. Oocyte-specific disruption of Pdss2 recapitulated many of the mitochondrial and reproductive phenotypes observed in the old females including reduced ATP production and increased meiotic spindle abnormalities, resulting in infertility. Ovarian reserve in the oocyte-specific Pdss2-deficient animals was diminished, leading to premature ovarian failure which could be prevented by maternal dietary administration of CoQ10. We conclude that impaired mitochondrial performance created by suboptimal CoQ10 availability can drive age-associated oocyte deficits causing infertility.
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