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

complement, an d phagocyte s usuall y lead t o infec -
tion by encapsulated and pyrogeni c bacteria, such as
Haemophilus influenzae, Streptococcus pneumoniae,
and Staphylococcus aureus. I n childre n wit h FAS D
both types of recurrent infections have been reported,
suggesting tha t bot h T an d B cell-mediated immu -
nity are compromised (Johnso n et al., 1981) .
Work with animal models confirms the findings in
human subjects . For example, th e immun e respons e
of FEE neonate s t o the intestina l parasit e Trichinella
spiralis indicate s a diminished capacit y to respond t o
the pathogen , demonstrate d b y a n increase d intes -
tinal wor m coun t (Steve n e t al. , 1992 ; Seeli g e t al. ,
1996). The abnormalitie s involve depressed T an d B
cell-mediated response s suc h a s lowe r seru m IL- 2
and tumor necrosis factor (TNF ) contents , an d lower
IgM an d Ig G antibod y titers. Interestingly, the detri -
mental effect s o f ethano l appea r t o increas e acros s
generations. Tha t is , FEE pup s (secon d generation)
mothered b y FE E adul t offsprin g (firs t generation)
who themselves consumed ethanol during pregnancy
show reduce d proliferativ e response s t o T . spiralis
antigen and stimulation with concanavalin A (Con A),
lower titer s o f serum Ig M an d Ig G anti-T . spiralis,
and lower percentages of T cells and cytotoxic T cells,
compared t o th e first-generatio n FE E an d pair-fe d
groups (Seelig et al., 1999) . The nex t two sections review
r studie s tha t describ e specifi c deficit s i n eithe r
cell-mediated o r humoral immunity.
Deficits in Cell-Mediated Immunity
Prenatal ethano l exposur e alters development o f the
thymus i n rat s an d mice . Delaye d thymi c ontogen y
(Ewald and Walden, 1988) , decreased tota l number s
of thymocytes, and diminishe d mitogen-induce d cel l
proliferation hav e been reported i n near-term fetuses
(Ewald an d Frost , 1987) . Decrease d thymu s weight,
size, and cell counts have also been observe d at birth
(Redei et al., 1989) . These changes persisted through
the preweanin g perio d an d eve n int o adolescenc e
(Ewald an d Frost , 1987 ; Ewald , 1989 ; Giberso n an d
Blakley, 1994 ; Taylo r e t al , 1999a) , althoug h on e
study o f mic e foun d tha t tota l thymocyt e number s
could retur n t o contro l level s as early as P6 (Ewald,
1989). Similarly , mitogen-induce d proliferativ e re -
sponses of thymic cells was suppressed in FEE male s
at weaning (Redei et al, 1989) , but may be increased
in adolescen t (44-day-old ) rat s (Chiappell i e t al ,
1992; Wong et al., 1992) . This increase i n thymocyte
ETHANOL EFFECTS ON ENDOCRINE AND IMMUNE FUNCTION 16 7
proliferation durin g adolescence doe s no t appea r to
be mediate d b y change s i n numbe r o f GR s o n th e
thymocytes; furthe r studie s ar e neede d t o elucidat e
the mechanism s underlyin g these varyin g effect s o f
ethanol.
The advers e effects o f ethanol on thymic develop -
ment have been confirme d by in vitr o studies usin g
organotypic cultures . Tota l cel l number s an d per -
centages of immature fetal thymocytes (CD4+/CD8+)
decrease i n a concentration-responsiv e manne r i n
ethanol-treated orga n culture s (Bra y e t al , 1993) .
This decrease is a consequence o f accelerated apopto -
sis, which then result s in a n increase d percentag e of
more mature thymocytes expressing CD4 + /CD8~ and
Y/8 TC R (Ewal d an d Walden , 1988 ; Ewal d e t al ,
1991; Bray et al., 1993 ; Ewald and Shao , 1993) . Similar
outcome s ar e observe d i n 20 - to- 40-day-old FE E
animals. That is , thymic cel l count s an d tota l num -
bers of CD4 + and CD8 + cells are decreased throughout
thi s period , an d immatur e CD8 + /TCR + an d
CD8+/CD4SRC+ thymocyte s ar e reduce d b y P3 5
(Taylor e t al. , 1999a) , finding s suggestin g tha t pre -
natal ethano l treatment alters the late r stage s of thymocyte
maturation , suc h a s afte r double-positiv e
(CD4 + /CD8 + ) thymocytes acquire TCR expression.
Prenatal ethano l exposur e ha s long-ter m advers e
effects o n the immune system that last well into adulthood.
FE E animal s hav e decrease d number s o f
Thyl.2 + , CD4 + , CD8 + , and IgG + splenocytes (Ewald
and Huang, 1990 ; Giberson and Blakley, 1994; Giber -
son e t al. , 1997) . Decrease d percentage s o f Thyl.2 +
splenocytes ar e also evident i n pups born t o mother s
consuming ethano l durin g pregnanc y an d lactatio n
or during lactation alone , indicatin g direct effect s of
ethanol o n postnatal development o f the immune system
(Giberso n an d Blakley , 1994) . Similarly , roden t
and primat e studie s indicat e tha t spleni c lympho -
cytes from FEE male s have decreased proliferative responses
to mitogens from adolescenc e throug h youn g
adulthood (Norma n et al, 1989 ; Rede i e t al, 1989 ;
Gottesfeld e t al, 1990 ; Weinber g and Jerrells , 1991 ;
Grossmann et al, 1993 ; Jerrells and Weinberg, 1998 )
and that the response normalizes by 8 months of age
(Gottesfeld an d Ullrich, 1995 ; Norman et al, 1991) .
Furthermore, deficit s no t onl y i n th e respons e o f
freshly isolated splenic T cells but also in the response
of T blas t cell s (obtaine d followin g treatment wit h
Con A ) to IL- 2 or furthe r Co n A stimulation (Got -
tesfeld e t al, 1990 ; Norma n e t al, 1991 ; Weinber g
and Jerrells , 1991; Jerrell s and Weinberg , 1998 ) hav e