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Sains Malaysiana 47(10)(2018):
2509–2517 http://dx.doi.org/10.17576/jsm-2018-4710-28 Testosterone Down-Regulates Expression of αvβ3-Integrin, E-Cadherin and Mucin-1 during
Uterine Receptivity Period in Rats (Testosteron Menindas
Ekspresi αvβ3-Integrin, E-Cadherin
dan Mucin-1 semasa Tempoh
Reseptif Rahim dalam
Tikus) HELMY MOHD MOKHTAR1*,
NELLI
GIRIBABU2
& NAGUIB SALLEH2* 1Department of Physiology, Faculty
of Medicine, Universiti Kebangsaan
Malaysia Medical Center, Jalan Yaacob
Latiff, Bandar Tun
Razak, 56000 Cheras, Kuala Lumpur,
Federal Territory, Malaysia 2Department of Physiology, Faculty
of Medicine, University of Malaya, 50603 Kuala Lumpur, Federal
Territory, Malaysia Received: 27 March 2018/Accepted: 20 June 2018 ABSTRACT Adequate
development of uterine receptivity is crucial for establishment
of pregnancy. Expression of uterine receptivity molecules i.e.
αvβ3 integrin, E-cadherin and mucin-1 could be affected
by testosterone. The objective of this study was to investigate
effect of testosterone on expression of these molecules during
early pregnancy. 30 ovariectomised
female Sprague-Dawley rats were divided into 5 groups that consisted
of vehicle control, rats received eight days sex-steroid replacement
regime (intended to mimic the hormonal changes in early pregnancy)
and three groups of rats given testosterone (1 mg/kg/day) subcutaneously
with or without flutamide or finasteride
between day 6 and 8 representing the period of uterine receptivity.
At the end of the treatment, rats were sacrificed and uteri
were removed. Expression and distribution of αvβ3
integrin, E-cadherin and mucin-1 were examined by immunoflourescence
and levels of messenger RNA (mRNAs) were evaluated by real-time
PCR. Expression of αvβ3 integrin, E-cadherin and mucin-1
in the uteri of rats receiving sex-steroid replacement regime
increased significantly as compared to control (p<0.05). In these rats, concomitant administration of testosterone between
day 6 and 8 resulted in expression of αvβ3 integrin,
E-cadherin and mucin-1 to decrease significantly (p<0.05)
as compared to rats receiving sex-steroid replacement regime
without testosterone treatment. Moreover, the testosterone effects
were not antagonized by either flutamide
or finasteride. As a result, reduced expression of uterine receptivity
molecules by testosterone might interfere with early pregnancy
establishment, therefore could adversely affect the female fertility. Keywords: αvβ3 integrin;
E-cadherin; mucin-1; testosterone; uterine receptivity ABSTRAK Perkembangan yang mencukupi
bagi reseptif
rahim adalah penting
untuk membolehkan
kehamilan berlaku.
Pengekspresan molekul reseptif
rahim seperti
αvβ3 integrin, E-cadherin dan
mucin-1 boleh dipengaruhi oleh testosteron. Objektif kajian ini adalah
untuk mengkaji
kesan testosteron terhadap pengekspresan molekul ini semasa
peringkat awal
kehamilan. 30 ekor tikus Sprague-Dawley yang telah
diovariektomi dibahagikan kepada 5 kumpulan terdiri daripada kumpulan kawalan, kumpulan tikus yang menerima regim penggantian steroid seks selama lapan hari
(bertujuan untuk
meniru perubahan hormon semasa peringkat
awal kehamilan)
dan tiga kumpulan
tikus yang diberikan
rawatan testosteron (1 mg/kg/hari) secara subkulitan
dengan atau
tanpa kehadiran flutamide atau finasteride antara hari ke-6 hingga ke-8 rawatan yang mewakili tempoh reseptif rahim. Di akhir rawatan,
tikus telah
dikorbankan dan uteri dikeluarkan. Pengekspresan dan taburan αvβ3
integrin, E-cadherin dan mucin-1 ditentukan dengan menggunakan immunoflourescence dan paras mRNA ditentukan dengan menggunakan Real-time PCR.
Pengekspresan αvβ3 integrin, E-cadherin dan
mucin-1 dalam uteri tikus
yang menerima regim
penggantian steroid seks didapati meningkat secara signifikan berbanding kawalan (p<0.05). Pada tikus
ini, pemberian
bersama testosteron antara hari ke-6 hingga hari ke-8 telah menyebabkan pengekspresan αvβ3 integrin, E-cadherin dan mucin-1 menurun dengan signifikan (p<0.05) berbanding
kumpulan yang menerima
regim penggantian steroid seks tanpa rawatan
testosteron. Selain itu,
kesan testosteron
ini tidak ditentang
oleh flutamide
atau finasteride. Kesimpulannya, penurunan
pengekspresan molekul
reseptif rahim oleh testosteron mungkin mengganggu perkembangan awal kehamilan dan seterusnya
boleh menjejaskan
kesuburan wanita. Kata kunci:
αvβ3 integrin; E-cadherin; mucin-1; reseptif
rahim; testosteron REFERENCES Achache, H. & Revel, A. 2006. Endometrial
receptivity markers, the journey to successful embryo implantation.
Hum. Reprod. Update 12(6):
731-46. Aplin, J.D. 2000. The cell biological
basis of human implantation. Baillieres Best Pract. Res. Clin.
Obstet. Gynaecol. 14(5): 757-764.
Aplin, J.D., Hey, N.A. & Graham, R.A. 1998. Human endometrial MUC1 carries
keratan sulfate: Characteristic glycoforms
in the luminal epithelium at receptivity. Glycobiology
8(3): 269-276. Apparao, K., Lovely, L.P., Gui, Y., Lininger, R.A. & Lessey, B.A. 2002. Elevated endometrial
androgen receptor expression in women with polycystic ovarian
syndrome. Biology of Reproduction 66(2): 297-304.
Apparao, K.B., Murray, M.J., Fritz, M.A., Meyer,
W.R., Chambers, A.F., Truong, P.R. & Lessey,
B.A. 2001.
Osteopontin and its receptor alphavbeta(3) integrin are
coexpressed in the human endometrium during the menstrual
cycle but regulated differentially. J. Clin.
Endocrinol.
Metab.
86(10): 4991-5000. Brayman, M., Thathiah,
A. & Carson, D.D. 2004. MUC1: A multifunctional cell surface component of reproductive
tissue epithelia. Reprod.
Biol. Endocrinol. 2:
4. Carson, D.D.,
Bagchi, I., Dey,
S.K., Enders, A.C., Fazleabas, A.T.,
Lessey, B.A. & Yoshinaga,
K. 2000. Embryo implantation.
Dev. Biol. 223(2): 217-237. Davison, S., Bell, R., Donath,
S., Montalto, J. & Davis, S. 2005.
Androgen levels in adult females: Changes with age, menopause,
and oophorectomy. The Journal of Clinical Endocrinology &
Metabolism 90(7): 3847-3853. Dehghan, F.M.S., Yusof,
A. & Salleh, N. 2014. Sex-Steroid
regulation of relaxin receptor isoforms
(rxfp1 & rxfp2) expression in the patellar tendon and
lateral collateral ligament of female wky
rats. Int. J. Med. Sci. 11(2): 180-191. DeSouza, M.M., Mani, S.K., Julian, J. & Carson,
D.D. 1998. Reduction of mucin-1 expression during the receptive
phase in the rat uterus. Biol. Reprod. 58(6): 1503-1507. Giudice, L.C. 1999. Potential
biochemical markers of uterine receptivity. Human
Reproduction 14(2): 3-16. Gonzalez, D.,
Thackeray, H., Lewis, P., Mantani,
A., Brook, N., Ahuja, K., Margara,
R., Joels, L., White, J. & Conlan,
R. 2012. Loss of WT1 expression in the
endometrium of infertile 2408 PCOS patients: A hyperandrogenic effect? The Journal of Clinical Endocrinology
& Metabolism 97(3): 957-966. Horne, A.W.,
White, J.O., Lalani el., N., Mobberley,
M.A., Margara, R.A., Trew,
G.H. & Ryder, T.A. 2002. Analysis of epitopes on endometrial epithelium
by scanning immunoelectron microscopy.
Biochem. Biophys. Res. Commun. 292(1): 102-108.
Jha, R.K., Titus, S., Saxena, D., Kumar, P.G. & Laloraya,
M. 2006. Profiling of E-cadherin, beta-catenin and Ca(2+)
in embryo-uterine interactions at implantation. FEBS.
Lett. 580(24): 5653-5660. Johansson, J.
& Stener-Victorin, E. 2013. Polycystic ovary syndrome: Effect
and mechanisms of acupuncture for ovulation induction. Evidence-Based
Complementary and Alternative Medicine 2013: Article ID.
762615. Kennedy, T.G. 1986. Intrauterine
infusion of prostaglandins and decidualization
in rats with uteri differentially sensitized for the decidual
cell reaction. Biology of Reproduction 34(2): 327-335.
Kowalski, P.J.,
Rubin, M.A. & Kleer, C.G. 2003. E-cadherin
expression in primary carcinomas of the breast and its distant
metastases. Breast Cancer Res. 5(6): R217-R222.
Lessey, B.A. 2003. Two pathways of progesterone
action in the human endometrium: Implications for implantation
and contraception. Steroids 68(10-13): 809-815. Lessey, B.A. 1998. Endometrial
integrins and the establishment of uterine receptivity.
Hum. Reprod. 13(Suppl
3): 247-258; discussion 259-261. Lessey, B.A., Castelbaum,
A.J., Buck, C.A., Lei, Y., Yowell,
C.W. & Sun, J. 1994.
Further characterization of endometrial integrins
during the menstrual cycle and in pregnancy. Fertil. Steril.
62(3): 497-506. Li, Q., Wang,
J., Armant, D.R., Bagchi,
M.K. & Bagchi, I.C. 2002. Calcitonin down-regulates E-cadherin
expression in rodent uterine epithelium during implantation.
J. Biol. Chem. 277(48): 46447-46455. Liu, G., Zhang, X., Lin, H., Wang,
H., Li, Q., Ni, J. & Zhu, C. 2006. Effects
of E-cadherin on mouse embryo implantation and expression of
matrix metalloproteinase-2 and-9. Biochemical And
Biophysical Research Communications 343(3): 832-838. Mohamad, N.V.,
Soelaiman, I.N. & Chin, K.Y. 2016. A concise review
of testosterone and bone health. Clin. Interv.
Aging 11: 1317-1324. Mohamed-Hussein, Z.A. & Harun,
S. 2009. Construction of a polycystic ovarian syndrome (PCOS)
pathway based on the interactions of PCOS-related proteins retrieved
from bibliomic data. Theor. Biol. Med. Model. 6: 18. Mohd Mokhtar,
H., Giribabu, N., Kassim,
N., Muniandy, S. & Salleh,
N. 2014.
Testosterone decreases fluid and chloride secretions in the
uterus of adult female rats via down-regulating cystic fibrosis
transmembrane regulator (CFTR) expression and functional activity.
J. Steroid Biochem. Mol. Biol.
144 Pt B: 361-372. Mokhtar, H.M.,
Giribabu, N., Muniandy,
S. & Salleh, N. 2014. Testosterone decreases the expression
of endometrial pinopode and L-selectin
ligand (MECA-79) in adult female rats during uterine receptivity
period. Int. J. Clin. Exp. Pathol.
7(5): 1967-1976. Nur Vaizura, M., Soelaiman, I.N. & Kok-Yong,
C. 2018.
A review on the effects of testosterone supplementation in hypogonadal men with cognitive impairment. Current
Drug Targets 19(8): 898-906. Nurismah, M.I., Noriah,
O., Suryati, M.Y. & Sharifah,
N.A. 2008. E-cadherin expression correlates
with histologic type but not tumour
grade in invasive breast cancer. Asian Pac. J. Cancer Prev.
9(4): 699-702. Paulson, R.J.
2011.
Hormonal induction of endometrial receptivity. Fertil.
Steril.
96(3): 530-535. Perusquía, M., García-Yañez,
E., Ibáñez, R. & Kubli-Garfias,
C. 1990. Non-genomic
mechanism of action of Δ-4 and 5-reduced androgens and
progestins on the contractility of
the isolated rat myometrium. Life Sciences 47(17):
1547-1553. Reddy, V.R.,
Gupta, S.M. & Meherji, P.K. 2001. Expression of integrin receptors
on peripheral lymphocytes: Correlation with endometrial receptivity.
Am. J. Reprod. Immunol. 46(3): 188-195. Salleh, N., Baines, D.L., Naftalin,
R.J. & Milligan, S.R. 2005. The hormonal control of uterine luminal
fluid secretion and absorption. J. Membr.
Biol. 206(1): 17-28. Shafiee, M.N., Chapman, C., Barrett, D., Abu, J.
& Atiomo, W. 2013. Reviewing the molecular mechanisms which
increase endometrial cancer (EC) risk in women with polycystic
ovarian syndrome (PCOS): Time for paradigm shift? Gynecologic
Oncology 131(2): 489-492. Simon, C., Martin,
J.C. & Pellicer, A. 2000. Paracrine regulators
of implantation. Baillieres Best Pract. Res. Clin. Obstet. Gynaecol. 14(5):
815-826. Slater, M.,
Murphy, C.R. & Barden, J.A. 2002. Tenascin, E-cadherin and P2X calcium channel
receptor expression is increased during rat blastocyst implantation.
Histochem.
J. 34(1-2): 13-19. Srinivasan, K.R., Blesson, C.S., Fatima, I., Kitchlu,
S., Jain, S.K., Mehrotra, P.K. &
Dwivedi, A. 2009. Expression of alphaVbeta3
integrin in rat endometrial epithelial cells and its functional
role during implantation. Gen. Comp. Endocrinol.
160(2): 124-133. Thomas, K., Thomson, A.J., Sephton, V., Cowan, C., Wood, S., Vince, G., Kingsland, C.R.
& Lewis-Jones, D.I. 2002. The effect of
gonadotrophic stimulation on integrin expression in the endometrium.
Hum. Reprod. 17(1): 63-68. Tsai, Y.L.,
Wang, H.T.T., Chang, H.F.G., Tsai, C.F., Lin, C.K., Teng,
P.H., Su, C., Jeng, C.C. & Lee,
P.Y. 2012. Development of TaqMan probe-based insulated isothermal PCR (iiPCR) for sensitive and specific on-site pathogen detection.
PloS One 7(9):
e45278. Wang, H. &
Dey, S.K. 2006. Roadmap to embryo implantation: Clues from
mouse models. Nature Reviews. Genetics 7(3): 185-199.
Yan, L., Wang, A., Chen, L., Shang,
W., Li, M. & Zhao, Y. 2012. Expression
of apoptosis-related genes in the endometrium of polycystic
ovary syndrome patients during the window of implantation.
Gene 506(2): 350-354. Yoshida-Noro,
C., Suzuki, N. & Takeichi, M.
1984. Molecular nature of the calcium-dependent
cell-cell adhesion system in mouse teratocarcinoma
and embryonic cells studied with a monoclonal antibody. Dev.
Biol. 101(1): 19-27. *Corresponding authors; email: naguib.salleh@gmail.com
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