Review Article

Reactive Oxygen Species Generation and Use of

Antioxidants during In Vitro Maturation of Oocytes
Mozafar Khazaei, Ph.D.#, Faranak Aghaz, M.Sc.#*

)HUWLOLW\DQG,QIHUWLOLW\5HVHDUFK&HQWHU.HUPDQVKDK8QLYHUVLW\RI0HGLFDO6FLHQFHV.HUPDQVKDK,UDQ

Abstract
In vitro maturation (IVM) is emerging as a popular technology at the forefront of
fertility treatment and preservation. However, standard in vitro culture (IVC) con-
ditions usually increase reactive oxygen species (ROS), which have been implicat-
ed as one of the major causes for reduced embryonic development. It is well-known
that higher than physiological levels of ROS trigger granulosa cell apoptosis and
thereby reduce the transfer of nutrients and survival factors to oocytes, which leads
to apoptosis. ROS are neutralized by an elaborate defense system that consists of
enzymatic and non-enzymatic antioxidants. The balance between ROS levels and
antioxidants within IVM media are important for maintenance of oocytes that de-
velop to the blastocyst stage. The effects of antioxidant supplementation of IVM
media have been studied in various mammalian species. Therefore, this article re-
views and summarizes the effects of ROS on oocyte quality and the use of antioxi-
dant supplementations for IVM, in addition to its effects on maturation rates and
further embryo development.

Keywords: Oxidative Stress, Reactive Oxygen Species, Antioxidant, In Vitro Maturation

Citation: Khazaei M, Aghaz F. Reactive oxygen species generation and use of antioxidants during in vitro
maturation of oocytes. Int J Fertil Steril. 2017; 11(2): 63-70. doi: 10.22074/ijfs.2017.4995.

Introduction 5). Therefore, the in vitro advancement of an oocyte

In vitro embryo production (IVEP) allows the pro-
duction of a high and inexpensive number of em-
bryos to conduct basic research and apply emerging
biotechnologies such as cloning and transgenesis.
IVEP is a three-step methodology that comprises the
following procedures: i. In vitro maturation (IVM)
of oocytes recovered directly from follicles, ii. In
vitro fertilization (IVF) or co-incubation of capaci-
tated spermatozoa with in vitro matured oocytes,
and iii. In vitro culture (IVC) of zygotes up to the
blastocyst stage. According to reports, IVM is the
key factor that determines the proportion of oocytes
which develop to the blastocyst stage.
,90RIRRF\WHVLVDFRPSOH[SURFHVVLQÀXHQFHG
by the interplay of regulatory factors that include
gonadotrophins and a growing list of secreted mol-
ecules, the biochemical state of the oocyte, and in-
teractions between the oocyte and cumulus cells (1-
from the diplotene stage of prophase I [germinal
vesicle (GV)] to metaphase II (MII), along with cy-
toplasmic maturation that encloses a broad set of
VWLOOLOOGH¿QHGFHOOXODUHYHQWVDUHHVVHQWLDOIRUIHUWL-
lization and early development of the embryo (6-8).
Although substantial progress has been made to
LPSURYHWKHHI¿FLHQF\RIDQ,90SURWRFROKRZ-
ever, there is a lack of consistency in the success
rate of conventional in vitro matured oocytes com-
pared to in vivo matured oocytes. Multiple factors
likely contribute to the overall poor quality of in
vitro matured oocytes. One of the important fac-
tors may be oxidative stress (OS). The generation
of pro-oxidants such as reactive oxygen species
(ROS) is an invariable phenomenon in the culture
FRQGLWLRQ,WLVSRVVLEOHWKDW26DOVRLQÀXHQFHVRR-
cyte development in vitro. On the other hand, ROS
are considered signal molecules in oocyte physi-

Received: 16 Jul 2016, Accepted: 9 Oct 2016

*Corresponding Address: P.O.Box: 6714869914, Fertility and
Infertility Research Center, Kermanshah University of Medical
Sciences, Kermanshah, Iran Royan Institute
#
The two authors equally contributed to this article. International Journal of Fertility and Sterility
Email: faranak_aghaz@yahoo.com
Vol 11, No 2, Jul-Sep 2017, Pages: 63-70

63

ology and their impact on maturation promoting
factor (MPF) destabilization has recently been re-
ported (9-11).
Oocyte protection against ROS may play impor-
tant roles in pre-implantation embryonic develop-
ment. On the other hand, antioxidants are ROS
scavengers, thereby helping to maintain the oo-
cyte’s oxidant/antioxidant balance. The effects of
antioxidant supplementation to IVM media have
Khazaei and Aghaz
2[LGDWLYHVWUHVVDQG in vitroPDWXUDWLRQ
Under physiological conditions, the oocytes are
major sources of ROS because they use oxygen
to produce energy through mitochondrial oxida-
tive phosphorylation. Their ROS production is
increased during IVM when compared to in vitro
maturation (13, 29). Increased levels of ROS be-
yond the physiological range that may lead to OS
can result in deterioration in oocyte quality and
been studied in various mammalian species (12-
14). Our purpose was to incorporate the role of
ROS in oocyte physiology, impact of OS in down-
fall of oocyte quality (15, 16), and the role of en-
zymatic as well as non-enzymatic antioxidants in
reducing ROS levels and deterioration of oocyte
quality under IVC conditions. This review article
summarized the effects of ROS, the use of anti-
oxidant supplementations for IVM, and its effects
on maturation rates. In this systematic review, we
used IVM, OS, ROS, and antioxidant as keywords
IURPVFLHQWL¿FGDWDEDVHVEHWZHHQDQG
After a review of all abstracts, we included strong,
reliable research in this report.
3URGXFWLRQ RI UHDFWLYH R[\JHQ VSHFLHV DQG
JHQHUDWLRQRIR[LGDWLYHVWUHVV
OS is caused by an imbalance between pro-oxi-
dants and antioxidants (17). This ratio could change
with increased levels of pro-oxidants, such as ROS,
or a decrease in antioxidant defense mechanisms
WKHUHE\DIIHFWUHSURGXFWLYHRXWFRPHV$EHW-
ter understanding of the OS status and its regula-
tion during IVM is needed. However, one must
DOVRFRQVLGHUZKHWKHUDQGKRZ26PD\LQÀXHQFH
the process of IVM. This section focuses on re-
ports that refer to mechanistic roles for OS in oo-
cyte maturation, especially with respect to key
features of nuclear and cytoplasmic events within
the oocyte.
5HDFWLYH R[\JHQ VSHFLHV DQG QXFOHDU DQG
F\WRSODVPLFPDWXUDWLRQ
Increased levels of ROS associated with induce
cell cycle arrest in human oocytes as well as in
mouse embryos (31). A multitude of key factors
regulate the generation of ROS in the media and in-
clude various cellular metabolic reactions, oxygen
concentration, light, oocyte handling, and general
physicochemical parameters that may have a nega-
tive impact on oocyte physiology by inducing apop-
tosis (Fig.1). One of the major constituent that may
526UHSUHVHQWVDZLGHFODVVRIPROHFXOHV
that indicate the collection of free radicals (hy-
droxyl ion, superoxide, etc.), non-radicals (ozone,
single oxygen, lipid peroxides, hydrogen perox-
ide) and oxygen derivatives (21). They are highly
reactive and unstable. Hence, ROS can react with
nucleic acids, lipids, proteins, and carbohydrates to
acquire an electron and become stable. These reac-
tions induce a cascade of subsequent chain reac-
tions that eventually result in cell damage (22-24).
ROS can diffuse and pass through cell membranes
and alter most types of cellular molecules (nucleic
acids, proteins, and lipids), leading to mitochondrial
alterations (25), meiotic arrest in the oocytes (26),
embryonic block, and cell death (27). On the other
alter developmental responses in the oocyte is rele-
vant to OS since light is known to result in an imbal-
ance of pro- and antioxidants in somatic cells and
embryos. Similarly, a relationship has been shown
in a mouse model between a type of light com-
monly used in the laboratory with increased ROS
concentrations and compromised embryonic and
fetal development (32). Oxygen tension is another
important difference between the in vivo and in vitro
environments for the oocyte culture. Toxic effects
of atmospheric oxygen concentration under stand-
DUGFXOWXUHFRQGLWLRQVDQGWKHEHQH¿FLDOHIIHFWVRI
lower O2 concentrations (5-7%) on developmental
competence of oocytes in vitro have been reported
in mice (33, 34), hamsters (35, 36), rats (37), sheep
hand, OS occurs when increased ROS levels which DQGFDWWOHDQGKXPDQV
disrupt cellular redox circuits, result in disturbances The conditions of an IVC generate ROS, which
of redox-regulated cellular processes and/or oxida- FRXOGH[HUWVRPHEHQH¿FLDOHIIHFWVLIWKH526OHY-
tively damage cellular macromolecules (28). els remain under physiological levels (44). The

Int J Fertil Steril, Vol 11, No 2, Jul- Sep 2017 64

526(IIHFWRQ2RF\WH,90
tonic generation of ROS triggers meiotic resump-
tion from diplotene as well as the MII arrest stage
in several mammalian species (44, 45). It has been
reported that levels of ROS beyond the physiologi-
cal range could induce destabilization of matura-
tion MPF, reduce survival factors, and trigger
mitochondria-mediated apoptosis of oocytes (15,
converts H2O2 to O2 and H2O. The enzyme SOD
exists as three isoenzymes (49): SOD1, SOD2, and
SOD3. SOD1 contains Cu and zinc (Zn) as metal
co-factors in the cytosol. SOD2 is a mitochondrial
isoform that contains manganese (Mn), whereas
SOD3 encodes the extracellular form. Nutrients
such as Se, Cu, and Zn are required for the activi-
7KHELSKDVLFUROHRI526PXVWEHVXI¿FLHQWO\ ties of some antioxidant enzymes, although they
discussed in order to update OS and its impact on have no antioxidant actions. Non-enzymatic anti-
RRF\WH TXDOLW\  7KH EHQH¿FLDO UROH RI 526
comes from the observations that non-enzymatic
antioxidants, such as ascorbic acid and 3-tert-bu-
tyl-4-hydroxyanisole (BHA), inhibit spontaneous
meiotic resumption from diplotene arrest (47).
7KHVH UHVXOWV VXJJHVW D EHQH¿FLDO WKUHVKROG OHYHO
for ROS.
$QWLR[LGDQWV
Antioxidants scavenge ROS, which helps main-
tain the cell oxidant/antioxidant balance. On the
other hand, antioxidants are the compounds which
either suppress the formation of ROS or oppose
oxidants are composed of glutathione (GSH), vita-
min C, taurine, hypotaurine, vitamin E, Zn, seleni-
um (Se), beta carotene, and carotene (47). GSH is
a tripeptide thiol compound with many important
functions in intracellular physiology and metabo-
lism. One of the most important roles of GSH is
to maintain the redox state in cells which protects
them against harmful effects effects caused by
oxidative injuries. The protective action of GSH
against ROS is facilitated by the interactions with
its associated enzymes, such as GPx and GSH re-
ductase (Fig.2).
Vitamin C (ascorbic acid) is a known redox
their actions. There are two types of antioxidants: FDWDO\VWWKDWFDQUHGXFHDQGQHXWUDOL]H526
enzymatic and non-enzymatic (Table 1). Based on its chemical structure, ascorbic acid is
an electron donor and therefore a reducing agent.
Table 1: >ŝƐƚ ŽĨ ƐƚƵĚŝĞƐ ƚŚĂƚ ƐŚŽǁ ƚŚĞ ĞīĞĐƚƐ ŽĨ ĂŶƟŽdžŝĚĂŶƚ
ƐƵƉƉůĞŵĞŶƚƐƚŚĂƚŝŵƉƌŽǀĞin vitroŵĂƚƵƌĂƟŽŶ It has two different biochemical roles-antioxidant
and enzymatic cofactor. Ascorbic acid is main-
$QWLR[LGDQW ([SHULPHQWDOPRGHO
tained through reactions with GSH and can be
Enzymatic antioxidants FDWDO\]HGE\SURWHLQGLVXO¿GHLVRPHUDVHDQGJOX-
Superoxide dismutase (SOD) Mouse taredoxins. Cysteamine is a low-molecular weight
Thioredoxin Porcine amino acid that contains thiol (51). The addition
Catalase (CAT) Bovine of cysteamine not only enhances the GSH content
Sericin Bovine
in MII oocytes but also protects the membrane li-
pids and proteins due to indirect radical scaveng-
Non-enzymatic antioxidants
ing properties (52). The concentrations of many
Glutathione (GSH) Hamster, pig, ovine, amino acids, including taurine and hypotaurine are
Bovine and equine non-enzymatic antioxidants that help maintain the
Cysteamine Canine, mice, goats, porcine redox status in oocytes (53).
Vitamin C (Ascorbic acid) Mouse
Vitamin E and trolox - vitamin with antioxidant activity. It consists of
Enzymatic antioxidants neutralize excess ROS
and prevent it from damaging the cellular struc-
ture. Enzymatic antioxidants are composed of
superoxide dismutase (SOD), catalase (CAT),
various peroxidases and peroxiredoxins (PRDXs),
including glutathione peroxidases (GPXs), which
can convert peroxides to water and alcohol (48).
SOD enzymes catalyze the dismutation of super-
oxide anion (O2í) into O2 and H2O2 while CAT
Int J Fertil Steril, Vol 11, No 2, Jul- Sep 2017
9LWDPLQ ( ĮWRFRSKHURO LV D OLSLG VROXEOH
eight tocopherols and tocotrienols. Vitamin E
may directly destroy free radicals such as perox-
yl and alkoxyl (ROO•) generated during ferrous
ascorbate-induced lipid peroxidation (LPO),
thus it is suggested as a major chain breaking
antioxidant (54). Hyaluronan, melatonin, tea
and sericin are known to act as indispensable
antioxidants in IVEP. They can block the release
of pro-oxidant factors released as a result of OS
(12, 55, 56).
65
 Khazaei and Aghaz

Hyaluronan, an essential component of the ex- (77). Although, other studies in goats (78), pigs
tracellular matrix and non-sulfated glycosami-
noglycan may play an important role in meiotic
resumption of oocytes (57). The hormone mela-
tonin (N-acetyl-5-metoxy tryptamine) is an anti-
oxidant that, unlike GSH and vitamins C and E, is
produced by mammals. In contrast to other anti-
oxidants, however, melatonin cannot undergo re-
dox cycling. Once oxidized, it is unable to return
 KRUVHV  EXIIDORV  DQG FDWWOH 
did not show any increase in nuclear maturation
rates. Addition of cysteamine to the IVM medium
improved embryo development to the blastocyst
stage in mammalian oocytes (82).
Ascorbate is concentrated in granulosa cells,
theca cells, luteal cells, and oocytes (28). Choi
HW DO  UHSRUWHG D EHQH¿FLDO UROH IRU YLWDPLQ
to its reduced state because of the formation of
C in protecting spindle structures of MII mouse
stable end-products after the reaction (14). As an
oocytes and chromosomal alignment against an
antioxidant, green tea has been shown to improve
oxidant (hydrogen peroxide)-induced damage. It
IVM and embryo development of sheep COCs to
is suggested that the effect of vitamin C is as-
the blastocyst stage in IVM medium (58). Sericin
sociated mainly with its capability to promote
a water-soluble globular protein (protein hydro-
RRSODVPLF PDWXUDWLRQ GXULQJ ,90 7KH EHQH¿-
lysate) is derived from the silkworm Bombyx
cial role of ROS comes from the observations
mori. This protein represents a family of proteins
that non-enzymatic antioxidants, such as ascor-
ZKRVHPROHFXODUPDVVUDQJHVIURPWRN'D
bic acid, inhibit spontaneous meiotic resumption
 'DVK HW DO  KDYH UHSRUWHG WKDW VHULFLQ
from diplotene arrest. We have presented a num-
PLJKW SURYLGH D SURWHFWLYH HIIHFW RQ ¿EUREODVWV
ber of these observations. Tatemoto et al. (84),
by promoting endogenous antioxidant enzymes
Kere et al. (85), and Córdova el al. (86) found
in vitro.
that the addition of vitamin C to the oocyte matu-
$QWLR[LGDQW VXSSOHPHQWV DQG LPSURYLQJ in ration medium exerted no effect on the matura-
vitroPDWXUDWLRQ tion rates of oocytes. Similarly, antioxidants such
as vitamin E and trolox had no effect on oocyte
The addition of enzymatic antioxidants such
maturation, but other antioxidants such as propyl
as SOD, CAT, and thioredoxin are effective for
gallate and 2,4,5-trihydroxybutrophenone inhib-
pre-embryo development as scavengers of ROS
ited the spontaneous resumption of meiosis (87).
and serving embryos a low OS condition in mice
7RJHWKHUWKHVHVWXGLHVHPSKDVL]HGWKHEHQH¿FLDO
(61, 62), porcine (63), and bovines (64). Sericin,
roles of ROS during IVM at certain concentra-
an antioxidant protein, improves embryo devel-
tions (low level).
RSPHQWDQGLVDFULWLFDOVXSSOHPHQWIRU
oocyte maturation (12, 56).
A series of non-enzymatic antioxidants protect
oocytes against ROS damage during oocyte mat-
uration. GSH is one of the naturally synthesized
antioxidants that protect cells from ROS toxic-
ity and regulate the intracellular redox balance
(66). The intracellular level of GSH increases
during oocyte maturation in hamsters (67), pigs
RYLQHERYLQHVDQGHTXLQHV
Recent reports have shown that addition of low
molecular weight thiol compounds, such as cy-
steamine and b-mercaptoethanol to IVM media
improved the cytoplasmic maturation of oocytes
and embryo development by increasing GSH
synthesis (66, 72, 73).
Cysteamine supplementation during IVM re- Fig.1: dŚĞƉŽƐƐŝďůĞĨĂĐƚŽƌƐƚŚĂƚŝŶĚƵĐĞŐĞŶĞƌĂƟŽŶŽĨƌĞĂĐƟǀĞŽdžLJŐĞŶ
ƐƉĞĐŝĞƐ;ZK^ͿŝŶƚŚĞŽŽĐLJƚĞ͘dŚĞŝŵďĂůĂŶĐĞďĞƚǁĞĞŶZK^ĂŶĚĂŶƟ-
portedly improved nuclear maturation rates in ŽdžŝĚĂŶƚƐ͕ƚŚĞŝŵƉĂĐƚŽĨŚŝŐŚůĞǀĞůƐŽĨZK^͕ĂŶĚƚŚĞƌĞƐƵůƟŶŐŽdžŝĚĂƟǀĞ
canines (74), mice (75), goats (76), and porcine ƐƚƌĞƐƐ;K^ͿŽŶŵĞŝŽƟĐĂƌƌĞƐƚĂŶĚĂƉŽƉƚŽƐŝƐŝŶŽŽĐLJƚĞƐ͘

Int J Fertil Steril, Vol 11, No 2, Jul- Sep 2017 66

526(IIHFWRQ2RF\WH,90

Fig.2: dŚĞƉƌĞƐĞŶĐĞŽĨĂŶƟŽdžŝĚĂŶƚĞŶnjLJŵĞƐƐƵĐŚĂƐƐƵƉĞƌŽdžŝĚĞĚŝƐŵƵƚĂƐĞ;^KͿ͕ŐůƵƚĂƚŚŝŽŶĞƉĞƌŽdžŝĚĂƐĞƐ;'WdžͿ͕ĂŶĚĐĂƚĂůĂƐĞ;dͿĂƐǁĞůůĂƐŶŽŶͲ
ĞŶnjLJŵĂƟĐĂŶƟŽdžŝĚĂŶƚƐ͕ƐƵĐŚĂƐǀŝƚĂŵŝŶĂŶĚ;ĂƐĐŽƌďŝĐĂĐŝĚͿ͕ŐůƵƚĂƚŚŝŽŶĞ;'^,Ϳ͕ƵƌŝĐĂĐŝĚ͕ĂŶĚĂůďƵŵŝŶŝŶƚŚĞŽŽĐLJƚĞƐ͘džĐĞƐƐĂŵŽƵŶƚƐŽĨƌĞĂĐƟǀĞ
ŽdžLJŐĞŶƐƉĞĐŝĞƐ;ZK^ͿŵĂLJďĞŝŶǀŽůǀĞĚŝŶŽdžŝĚĂƟǀĞƐƚƌĞƐƐ;K^ͿŽĨŽŽĐLJƚĞƐĂŶĚŐƌĂŶƵůŽƐĂĐĞůůƐ͘

Conclusion
It is well-known that high levels of ROS be-
yond the physiological range could induce MPF
destabilization, reduce survival factors, and trig-
ger apoptosis in oocytes of several mammalian
species. Antioxidants are the main defense fac-
tors against OS induced by ROS. Many reports
Acknowledgements
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Kermanshah University of Medical Sciences.
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References
1. &DQLSDUL 5 2RF\WHJUDQXORVD FHOO LQWHUDFWLRQV +XP
suggest that antioxidant supplementation of IVM 5HSURG8SGDWH
2. (SSLJ--2RF\WHFRQWURORIRYDULDQIROOLFXODUGHYHORSPHQW
media improves cytoplasmic maturation by al-
leviating OS during oocyte maturation via in-
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protect the embryo against oxidative aggressions
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829-838.
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during its early developmental stages. On the oth- 'HY
er hand, supplementation by antioxidants during 4. &RPEHOOHV &0 )LVVRUH 5$ $OEHUWLQL ') 5DFRZVN\ &
,Q YLWUR PDWXUDWLRQ RI KXPDQ RRF\WHV DQG FXPXOXV FHOOV
IVC improves oocyte quality by reducing ROS using a co-culture three-dimensional collagen gel system.
levels and apoptotic factors. However, some of +XP5HSURG
the non-antioxidants such as ascorbic acid and 2, 5. *LOFKULVW5%7KRPSVRQ-*2RF\WHPDWXUDWLRQHPHUJLQJ
FRQFHSWV DQG WHFKQRORJLHV WR LPSURYH GHYHORSPHQWDO
4, 5-trihydroxybutrophenone do not improve oo- SRWHQWLDOLQYLWUR7KHULRJHQRORJ\
cyte maturation; rather, they inhibit spontaneous 6. 6PLW] - 1RJXHLUD ' $OEDQR & &RUWYULQGW 5 'HYURH\
resumption of meiosis. Improvements to culture 3,PSURYLQJLQYLWURPDWXUDWLRQRIRRF\WHVLQWKHKXPDQ
WDNLQJ OHVVRQV IURP H[SHULHQFHV LQ DQLPDO VSHFLHV
conditions are complex challenges that depend 5HSURG'RPHVW$QLP
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on its concentration, the medium and its compo- RRF\WHV LQ YLWUR DQG WKHLU GHYHORSPHQWDO FRPSHWHQFH
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ing to its developmental stage. Future efforts 437-446.
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should be placed on understanding the involve- R[\JHQVSHFLHVSHUVXDGHVSRVWRYXODWRU\DJLQJPHGLDWHG
ment of ROS in oocyte apoptosis and for guiding VSRQWDQHRXVHJJDFWLYDWLRQLQUDWHJJVFXOWXUHGLQYLWUR,Q
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Int J Fertil Steril, Vol 11, No 2, Jul- Sep 2017 67

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