Biomedical Engineering Reference
In-Depth Information
(LH) and FSH (LH-R and FSH-R, respectively)
on granulosa cells (Hsueh et al.
1994
; Bodensteiner
et al.
1995
). Heat stress suppresses aromatase
activity in granulosa cells and decreases the
oestradiol concentrations in the follicular fluid
and plasma of dairy cows (Badinga et al.
1993
) .
In addition, in both lactating cows and heifers,
heat stress decreased serum oestradiol concentra-
tion between days 11 and 21 of the oestrus cycle
(Wilson et al.
1998a,
b
). Seasonal and acute heat
stresses were observed to affect steroid produc-
tion in the dominant follicles of cows (Wolfenson
et al.
1997
). Thus, heat stress affects the viability
of granulosa cells and the follicular oestrogenic
activity. Follicular cells in atretic follicles are
normally eliminated by apoptosis (Tilly
1993
;
Palumbo and Yeh
1994
), as can be observed in
granulosa cells during follicular development
(Tilly
1996
) .
Apoptosis of granulosa cells due to heat stress
Apoptosis of granulosa cells is provoked by
the lack of survival factors such as FSH and
oestradiol (Billing et al.
1993
; Chun et al.
1996
). Expression of genes encoding apoptosis-
regulating proteins in the follicle has been
reported. Two members of the
bcl-2
family,
bcl-2
and
bax
, have been shown to regulate apoptosis in
the ovary (Tilly et al.
1995
). In the rat ovary, Bax
appears to antagonise the apoptosis-suppressive
effects of Bcl-2, and the fate of the cell appears to
be decided by the balance between these two
regulatory proteins (Tilly et al.
1995
) . The ability
of gonadotrophins to prevent apoptosis and atre-
sia in ovarian follicles may be linked to a shift in
the ratio of bcl-2 to bax gene expression (Tilly
et al.
1995
). FSH receptors are confined to the
granulosa cells of healthy, developing follicles
(Camp et al.
1991
). Oestradiol contributes to the
maintenance and expression of both LH-R and
FSH-R in granulosa cells (Hsueh et al.
1994
;
Bodensteiner et al.
1995
) . FSH-R expression in
the granulosa cells is also regulated by oestradiol-
independent mechanisms (Shimizu et al.
2005
) .
The PMSG administration causes a marked
increase of FSH-R mRNA expression and FSH-
binding sites (Nakamura et al.
1991
; LaPolt et al.
1992
). Locally produced intraovarian growth
factors, like transforming growth factor-beta
(TGF-ß) and insulin-like growth factor-1 (IGF-1),
induce FSH-R expression in granulosa cells
(Dunkel et al.
1994
; Zhou et al.
1997
) . Heat stress
suppresses FSH-R expression in granulosa cells
of follicles at the early antral, antral and preovu-
latory stages after PMSG treatment. The increase
in atresia caused by heat stress (Shimizu et al.
2000
) may be induced by the inhibition of FSH-R
expression in granulosa cells.
One key group of intracellular factors regula-
ting apoptosis is the Bcl-2 family of proteins
(Adams and Cory
1998
) . The members of this
family can be subdivided into antiapoptotic pro-
teins (such as Bcl-2 and Bcl-xL) and proapop-
totic proteins (such as Bax and BAD). Anti- and
proapoptotic proteins regulate cell death by
binding to each other and forming heterodimers
(Oltvai et al.
1993
; Yang et al.
1995
) . Therefore,
a delicate balance between anti- and proapoptotic
Bcl-2 family members exists in each cell, and the
relative concentrations of these two groups of
proteins determine cell death or survival. The levels
of
bcl-2
and
bax
mRNA and the ratio of
bax
to
bcl-2
mRNA are the deciding factor for apoptotic
signal. However, the expression of
bax
mRNA in
granulosa cells of follicles from heat-stressed
animals has been found to increase significantly
after the 12-h culture period suggesting that the
amount of
bax
present in granulosa cells that
maintain a constitutive level of
bcl-2
expression
may be linked to the induction of granulosa cell
apoptosis and follicular atresia caused by heat
stress. Another apoptotic signalling cascade, the
Fas/Fas ligand (FasL) system, can also lead to
granulosa cell apoptosis (Kim et al.
1998
) . Thus,
it is likely that heat stress stimulates the Fas/FasL
cascade in the granulosa cells of growing follicles.
Heat stress inhibits the FSH-R signalling pathway
in the granulosa cells of growing follicles that
decrease oestrogen levels and induce follicular
atresia. Thus, the regulators of FSH-R expression
may be potential targets for therapeutic interven-
tion for improving summer fertility (Shimizu
et al.
2005
) .
The mechanisms by which heat stress alters
the reproduction in susceptible mammals are
through concentrations of circulating reproduc-
tive hormones through adrenal-gonadal axis and
