Interaction between oviductal epithelial cells and
spermatozoa underlies a systems biology
approach to treating infertility
The requirement of both sexes to have perfectly functioning
gametes exponentially increases the possibilities for failure
and makes the diagnosis of infertility especially dif
cult. Sys-
tems biology is an emerging approach to a paradigm that con-
cerns itself with the complex interactions between biological
systems and their local environment. In general, the aim is to
understand the properties and relationships between cells, tis-
sues, and organisms together within the context of a complete
system. For example, the purposeful movement of spermatozoa
from themaletothefemalereproductive tract shouldbeconsid-
ered not in isolation but rather as a complex interrelationship.
Spermatozoa undergo numerous physiologic posttesticu-
lar changes that optimize their ability to successfully fertilize
an oocyte; however, much is unknown regarding the milieu in
which these events take place. The notion that spermatozoa
interact with the local environment is not a new concept. In-
deed, the ability of spermatozoa to fertilize naturally is ac-
quired during passage through the epididymis
. The
biochemical changes that occur during this epididymal inter-
action include improved structural rigidity, altered lectin-
binding properties, and phospholipid and lipid composition,
as well as glycoprotein content
. All of these modi
contribute to the ability of spermatozoa to adhere to the oo-
cyte and to subsequently achieve fertilization.
Unfortunately, not all posttesticular changes are bene
cial. Accumulation of reactive oxygen species (ROS) evokes
spermatozoa membrane lipid peroxidation, with resultant al-
terations in sperm morphology and motility
. Moreover,
seminal ROS levels are increased in the presence of varico-
celes, leading to elevations in DNA fragmentation, impaired
fertilization potential, and lower pregnancy rates after assis-
ted reproduction
. Although varicocele repair has been
shown to reduce ROS and decrease sperm DNA damage, other
forms of treatment have not been effective
Knowledge of how the oviduct interacts with spermato-
zoa is equivocal. Spermatozoa can remain in the oviduct for
several days by binding to epithelial cells, thus sustaining fer-
tility by delaying capacitation. Moreover, previous work has
found that coculture of oviductal cells with spermatozoa
maintains viability and motility while improving IVF rates
. The work by Huang et al. published in this issue of
and Sterility
presents a series of experiments that illus-
trates how oviductal epithelial cells function to protect sper-
matozoa from oxidative damage.
In brief, extracted membrane proteins from a previously
characterized oviductal epithelial cell line (OE-E6/E7) were
found to bind the heads of spermatozoa, whereas the control tro-
phoblast cell line (TEV-1) exhibited no binding. In cases where
cantly reduced amount of OE-E6/E7 cell membrane pro-
teins were bound, early sperm capacitation occurred. The authors
also analyzed the effects of oxidative stress on spermatozoa as
evoked by H
. Damage to sperm motility parameters and
lipid peroxidation were reduced after pretreatment with
OE-E6/E7 membrane proteins. Moreover, OE-E6/E7 membrane
proteins signi
cantly suppressed H
-evoked DNA damage, in-
hibited the H
-induced elevations in ROS, and signi
increased the activities of spermatozoal superoxide dismutase
(SOD) and glutathione peroxidase (GPx) levels
As such, this study illustrates that oviductal epithelial
cells interact with spermatozoa in a bene
cial way by protect-
ing them from oxidative damage as well as preserving motility
and DNA integrity
. The elevations in SOD and GPx after
exposure to OE-E6/E7 membrane proteins suggest that this in-
teraction results in some type of signal transduction with re-
sultant cellular changes within the spermatozoa itself.
Perhaps these experiments are just the tip of the proverbial
iceberg? Consider that elevations of SOD are associated with
higher sperm motility, and patients with lower levels of sper-
matozoal SOD and GPx have abnormalities in sperm counts
and motility
. What happens to the sperm of these patients
in the presence of their female partner's oviductal epithelial
cells? Is function improved or, perhaps, worsened to the point
where conception is impossible? How can it even be known?
We are thus forced to contemplate the possibility that, in the
face of these types of interactions, the semen analysis is
even more inadequate than previously thought. If spermato-
zoa can be modi
ed by oviductal epithelial cells, how can
these interactions be predicted and, if incompatible, treated?
Other provocative ideas are brought to the forefront when
contemplating a systems biology approach to the treatment of
infertility. Are some oviductal epithelial membrane proteins
more effective than others at nurturing spermatozoa? Can
they be isolated? Can they be used in an in vitro setting to im-
prove IVF outcomes? How can these
ndings be used in the
treatment of patients with varicocele-associated elevations
in seminal ROS? Are freshly isolated epithelial cells more ef-
fective than the cultured OE-E6/E7 cell line used in the exper-
iments by Huang et al.
? By beginning the process of
understanding human fertility in a systems approach, we
can start to devise investigations, and even treatments, that
simultaneously address the complex relationships between
male and female reproductive function.
Jason R. Kovac, M.D., Ph.D.
Larry I. Lipshultz, M.D.
Scott Department of Urology, Baylor College of Medicine,
Houston, Texas
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VOL. 99 NO. 5 / APRIL 2013