Brain Development: Normal Processes and the Effects of Alcohol ...

may no t b e observe d under nonstresse d conditions ,
and become apparent only when FEE animal s are exposed
to stressors. In addition , sexually dimorphic effects
of prenatal ethanol exposure may be observed,
In FE E males , exposur e t o chroni c intermitten t
stressors selectivel y down-regulates th e number s o f
thymic and periphera l blood CD43 + cells as well as
peripheral bloo d CD4 + T cells , an d marginall y decreases
the numbe r o f peripheral bloo d MH C Clas s
II Ia + (antige n presenting ) cells . I n contrast , CD4 3
antigen expressio n o n periphera l bloo d T cell s i s
selectively up-regulate d (Giberso n an d Weinberg ,
1995). Stres s doe s no t differentiall y alte r thes e im -
mune measure s i n FE E females . The findin g tha t
FEE males exhibit greater stress-induced immune abnormalities
tha n FE E females , despit e showin g less
adrenal hypertrophy , suggest s tha t male s ar e mor e
sensitive t o smal l change s i n glucocorticoi d con -
centrations tha n females . Role s fo r estroge n a s a n
immunoprotective hormon e an d testosteron e a s a n
immunosuppresive hormone i n these sexually dimorphic
immune responses remain to be determined.
One o f the first demonstrations tha t stress differentially
alters immune functio n in FE E an d contro l females
is the finding of an interaction between prenata l
ethanol an d chroni c col d stres s i n femal e offsprin g
(Giberson et al., 1997) . After 1 day of cold stress, FEE
females exhibi t increase d lymphocyt e proliferatio n in
response t o pokewee d mitoge n (PWM ; a T cell -
dependent B cell mitogen) an d Con A challenge. No
ethanol-induced difference s i n immun e responsive -
ness ar e detecte d amon g males . I n contrast , FE E
males expose d t o 1 or 3 days of col d stres s have in -
creased basa l COR T concentration s compare d t o
those o f FEE male s not expose d t o cold. These findings
ar e consisten t wit h dat a fro m Halas z an d col -
leagues (1993) , wh o foun d tha t th e challeng e o f
chronic ethano l exposur e i n adulthood selectivel y increased
Co n A-induce d lymphocyt e proliferatio n in
FEE females but not in males. These data have important
implication s for understandin g th e mechanism s
underlying immune deficits induced by prenatal exposure
to ethanol, because defective interactions between
T an d B cells would significantly hinder th e develop -
ment of a normal immune response .
Cytokines and the HPA Axis
Prenatal ethano l exposur e blunt s th e LPS-induce d
febrile respons e i n mal e rat s (Taylo r e t al. , 1999b ,
ETHANOL EFFECTS ON ENDOCRINE AND IMMUNE FUNCTION 16 9
2002a). Thi s effec t o f ethano l ma y b e mediate d b y
a decrease d respons e o f centra l thermoregulator y
systems to IL-1(3 , which coul d b e mediate d b y a decreased
hypothalami c IL-1( 3 respons e t o LP S ad -
ministration, possibl y throug h a n impaire d releas e
of endogenous pyrogens (Ylikorkala e t al. , 1988 ; Yirmiya
et al, 1993 , 1996) . Interestingly , both ADX and
sham surger y i n th e pregnan t femal e abrogat e th e
effect o f ethanol o n th e febril e respons e o f female
offspring t o IL-1(3 , bu t onl y AD X ha s a n effec t o n
male offspring . Thi s observatio n implies tha t mater -
nal adrena l mediator s play an importan t rol e i n th e
blunted febrile response of FEE male s and that nonadrenal
mediator s participat e in modulatio n of ther -
moregulatory system s in FE E female s (Taylo r et al. ,
2002a, 2002b).
Parallel to blunted hormonal responses to stressors
observed i n FEE animal s during th e preweaning period,
FE E preweanling s exhibi t reduce d ACTH , (3-
EP, an d TNF-o c response s t o immun e challenge s
(IL-1(3, LPS) , Thi s reductio n persist s int o adoles -
cence i n FEE male s but not in females (Lee and Rivier,
1993 , 1996 ; Chiappell i e t al., 1997 ; Ki m et al,
1999b). A n altered abilit y of IL-1 to stimulat e secre -
tion o f POMC-relate d peptide s ma y underli e thi s
reduced responsiveness (Lee and Rivier, 1993). Interestingly,
ovariectom y prior to puberty eliminates th e
difference i n ACTH response between FE E an d con -
trol females (Lee and Rivier, 1996), a finding suggesting
tha t ethano l an d femal e se x hormones regulat e
HPA activity through a common pathway.
In contras t to the preweaning period, ACTH an d
CORT responses t o immune signal s such a s LPS or
IL-1 (3 increase i n FE E animal s b y adulthoo d (Ki m
et al. , 1999b) . Thi s respons e parallel s thei r HP A
hyperresponsiveness to stressors. The finding that prenatal
ethano l exposur e doe s no t alte r cytokin e re -
sponses to immune challenge s suggest s that cytokine s
probably d o no t mediat e th e ethanol-induce d in -
crease in HPA responsiveness to immune signals . O n
the other hand, FE E male s exhibit increased plasma
concentrations o f pro-inflammatory cytokine s to LP S
challenge followin g repeate d restrain t stres s (Eske s
and Weinberg , 2003 ; Eske s e t al , 2004) . Wherea s
CORT response s t o LP S ar e comparabl e amon g
groups, FE E animal s hav e greate r an d mor e sus -
tained elevation s o f IL-1(3 , TNF-ot , an d IL- 6 tha n
those i n controls. These data support and extend pre -
vious studie s suggestin g tha t although FEE animal s
may no t diffe r i n cytokin e response s unde r basa l o r