Karen Bedard and Karl-Heinz Krause

272 KAREN BEDARD AND KARL-HEINZ KRAUSE
(56). Yet, the conclusion that NOX5 is the spermatozoa
NADPH oxidase is premature for the following reasons.
First, in situ hybridization showed NOX5 mRNA only in
very early stages of spermatogenesis, in particular
pachytene spermatocytes; the NOX5 protein might be
expressed in mature spermatozoa, but this has not been
demonstrated. Second, although NOX5 is found in many
mammalian species, it is not found in rodents, while
rodent spermatozoa have also been reported to generate
ROS. This apparent discrepancy might be explained by
the possible expression of NOX2 and its subunits in
mouse spermatozoa (816).
NOX-derived ROS might be important for maturation
of spermatocyte maturation or the function of mature
spermatocytes. During spermatogenesis, up to 75% of developing
spermatocytes are eliminated through apoptosis
(65). In analogy with apoptosis in other cell types (in
particular neurons and hepatocytes), NOX enzymes might
be involved in the mechanisms of apoptosis. Another
interesting hypothesis is a potential role for NOX enzymes
in cell proliferation and differentiation during spermatogenesis;
however, this possibility has not been studied.
More data are available on the function of ROS in regulation
of activation and function of mature spermatocytes
(18, 572). It has been suggested that NOX-derived ROS
regulated acrosome formation and capacitation, the final
steps in sperm maturation (20, 49, 190, 191, 364, 662, 663).
Finally, NOX enzymes are involved in the respiratory
burst that occurs during fertilization (364, 957); in the case of
sea urchin eggs, the burst is mediated through the DUOX
homolog Udx1. This respiratory burst is thought to prevent
the entry of supernumerary sperms through the stabilization
of the fertilization envelope. The biochemical mechanism of
this stabilization involves dityrosine cross-linking of proteins
within the fertilization envelope. Two important points
should, however, be considered in this context.
1) Most of the studies on this topic were performed
in nonmammalian systems. While mammalian strategies
to block polyspermy are often similar to those applied by
nonmammals (288), the ROS-dependent stabilization of
the fertilization envelope through dityrosine cross-link
has to our knowledge not been reported in mammals.
2) The NOX-dependent ROS generation during fertilization
is generally attributed to the eggs; whether there is
a role for sperm-dependent ROS generation is not clear.
Excessive ROS generation might also be implicated
in sperm pathology. Male infertility has been linked to
excessive ROS generation (18). In male-factor infertility,
oxidative stress is thought to affect the fluidity of the
sperm plasma membrane, and ROS-induced DNA damage
may accelerate the process of germ cell apoptosis, leading
to the decline in sperm counts (13). In line with the
janus-faced function of ROS in spermatocyte physiology
and pathophysiology, there are reports that antioxidants
Physiol Rev VOL 87 JANUARY 2007 www.prv.org
may prevent oxidative damage to sperm (612) but may be
detrimental to sperm development at high levels (867).
In summary, there is now little doubt about the
importance of ROS in sperm development and function,
and the implication of a spermatocyte NOX enzyme
(NOX5, possibly another NOX family member in rodents)
is likely.
2. Prostate
Little is known about ROS generation by cells of
the prostate, although it is clear that NOX enzymes are
expressed. NOX1 and NOX2 were found in total mRNA
from prostate (55, 353, 454, 841). NOX5 was described
in prostate cancer cell lines and in prostatic adenocarcinomas
(103). In response to castration, upregulation
of NOX1, NOX2, and NOX4 has been described in the
rat prostate (859), indicating a hormonal control of
NOX expression.
The physiological function of ROS generation in
prostate cells is little understood, but may be related to
cell growth (103). The possible role of ROS in prostate
cancer development has received particular attention, because
the consumption of the tomato-derived antioxidant
lycopene is associated with a decreased prostate cancer
risk (282). Both NOX1 and NOX5 have been associated
with prostate cancer (103, 546). As in other types of
cancer, ROS might be involved in carcinogenesis through
ROS-dependent DNA damage or through ROS-dependent
regulation of cell growth. Interestingly, NOX1-mediated
ROS generation decreases P-glycoprotein levels in prostate
cancer cell lines (940), raising the question of
whether NOX-derived ROS generation might prevent multidrug
resistance.
3. Ovary
Within the ovary, generation of ROS has mainly been
described for the corpus luteum at regression and in response
to prostaglandin F2� (38, 75, 748, 786). The expression
of NOX2, NOX4, and NOX5 has been reported in ovaries
(143). NOX2 expression might be due to leukocytes, and
indeed, it has been suggested that neutrophil NOX2 participates
in corpus luteum ROS generation (610).
ROS may lead to cell cycle arrest and apoptosis in vitro,
a mechanism that can be limiting for in vitro fertilization
(140). However, in vivo, a role for NOX-derived ROS in
meiotic maturation of oocytes has been suggested, as maturation
was prevented by apocynin and diphenyleneiodonium
(226). Angiogenesis in the context of follicular development
might also involve NOX-derived ROS (12).
4. Uterus, placenta, and preeclampsia
A) UTERUS. ROS generation by the endometrial epithelium
was observed already more than 20 years ago, and an
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