functional effects of glucocorticoid exposure during fetal life
TRANSCRIPT
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0278 - 6840/93 aJ24.00 8 1992Fwgamn~sUd
FUNCTIOlVAL EFFECTS OF GLUCOCORTICOID EXPOSURE DURING FJSTAL LIFE
TOMOKO FUJII, MATSUE HORINAKA AND MAMORU HATA
Department of Pharmacology, Teikyo University School of Medicine, Itabashi, Tokyo, Japan.
(Final form, April 1992)
Abstract
Fujii Tomoko, Matsue Horinaka and Mamoru Hata: Functional Effects of Glucocorticoid Exposure During Fetal Life. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1993, 17:(2) 279-293. -
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Pregnan:, rats were exposed .;o hydrocortisone in a dose of 10 mg/kg on days 9-11 or days 13-15 of gestation. The offsprings born to these mothers were observed for their behavioral development and the response to kainic acid during the infantile ;Jeriod. The response to kainic acid was assessed by the frequency of we'_-dog shakes behavior and limbic seizures. The growth rate in the infantile offspring of the 13-15dHc-F, group showed a slight but significant decrease. All the 13-15dHc-F, rats exhibited the rearing activity in an open- field at 17 days of age, earlier than in the contols. The ambulatory activity in the 9-lldHc-F, rats showed a significant decrease at 15 and 17 days of age, whereas no change was shown in the I)-lldHc-F, rats. The frequency of the wet-dog shakes during the 60 minutes observa- tion after the S.C. injection of 9 mg/kg kainic acid was signifi- cantly low in both the 9-lldHc-F I and 13-15dHc-F1 groups as compared with that in the controls when tested at 25 days of age. The decrease in the response to kainic acid was slightly greater in the 9-lldHC-F; rats. The frequency of seizures with forelimb clonus and rearing during the 60 minutes observation in the 13-15dHc-F, was less than that in the controls I whereas no significant difference in the frequency of seizures between the 9-lldHc-F1 and paired control groups was noted. The second generation rats raised from the 9-lldHc-F>rats by brother -sister mating showed a decrease in the frequency in the kainic acid-induced wet-dog shakes as shown in the F, offspring. No change in the response to kainic acid was shown in the 13-15dHc-F2 rats.
Keywords: F1 and Fn generations, fetal exposure, hydrocortisone, kainic acid, open-field behavior,
Abbreviations: exposure to He exposure to Hc on days 13-15 of (Gel, hydrocortisone (Hc).
wet-dog shakes.
on days 9-11 of gestation fQ-LldHcf, gestation (13-15dHcf, glucocorticoid
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280 T. Fu]U etaL
Introduction
Evidence showing the functional effects of maternal or even paternal
exposure to drugs on the offspring has been accumulated. The authors
have already reported that various central nervous system acting drugs,
such as haloperidol, chlorpromazine, imipramine, phenobarbital,
ethosuximide, valproate or phenytoin given to pregnant rats induce
functional alterations in the adult offsprings. Moreover, changes in the
vaginal opening (Fujii et al., 1987), basal body temperature (Fujii et
al., 19871, open-field behavior (Fujii et al., 1987: Nakanishi and
Fujii, 1990), or the response to haloperidol (Fujii et al., 1982) or to
chlorpromazine (Fujii and Ohtaki, 1986; Fujii, 1988) were exhibited in
the second generation offspring raised from the rats those exposed
prenatally to these drugs. Therapeutic uses of Gcs have been well known
to be aimed at relieving various symptoms with no limitation of the age
of patients. Recent progress in understanding of the direct action of
Gcs on the brain has been facilitated by the studies on the distribution
and function of Gc receptors and Gc receptor expression in the brain
(Funder and Sheppard, 1987; Evans and Arrizal 1989; McEwen and Gould,
1990). Evidence of the rapid induction of Gc receptor mRNAs in the
brain by bodily conditions in the animals (Nichols et al., 1988) is also
important. In addition, the highest distribution of Gc receptors was
observed by several investigators in the hippocampus where the
regulatory role for the behavioral performance is suggested. However,
there are few reports on the functional effect of maternal exposure to
Gcs on the offspring.
The present experiment was conducted to study the functional effects
of maternal exposure .to hydrocortisone on -the offspring in the rat. A
particular concern was paid upon the relation of the gestational stage
of exposure to the hormone. Neurogenesis in the cerebral cortex and
hippocampal regions has been reported to begin on days 11-12, reaching
the plateau on days 13-14 in mice (Rodier, 1980). The fetal life in
mice is average 19-20 days instead of 21-22 days as for rats.
Therefore, in the present study Gc exposure was performed on the two
different stages during gestation, i.e., days 9-11 of gestation as the
stage of neural element migration and days 13-15 of gestation as the
stage of neurogenesis.
Methods
Animals
Pregnant Wistar-Imamichi rats were purchased from Animal Research
Foundation (Saitama) and the animals were injected subcutaneously (s-c.1
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Glucocorticoideqosure duringfetalhfe 281
with 10 mg/kg hydrocortisone sodium succinate on days 13-15 or days 9-11
of gestation. Control rats received vehicle alone. The day on which
sperm was present in the vaginal smear was desiqnated as day 0 of
pregnancy. Litter size was adjusted to 14 pups at 3 days of age. All
rats were kept in a temperature controlled room (22+3'JC) with a lighting - schedule of 14 hr light (06:00-2O:OO) and 10 hr darkness. They were
supplied with a stock diet and water g libitum. The pups were weaned
at 21 days of age. In the presnt experiment, we did not use cortico-
sterone which is the species-typical Gc of rats because of its solubi-
lity. The effect of exposure of fetuses to propylene glycol or ethanol
as vehicle of Gc was avoided. Furthermore, as a preliminary experiment
to assess the transmission of some altered functions developed by Hc
exposure in the first generation offspring, the second generation was
raised from the 9-lldHc-F,, 13-15dHc-FI and vehicle-F1 rats by brother-
sister mating and their response to kainic acid was tested.
Drugs
Hydrocortisone sodium succinate (Solu-Cortefe , Upjohn Japan) was
purchased from a standing supplier and dissolved with distilled water.
Kainic acid (Sigma) was purchased from Iwai Chemical Co., Ltd. Kainic
acid solution was prepared before its use by dissolving in distilled
water, and the pH was ajusted to 7.0 with l/lON NaOH solution.
Open-Field Behavior
Open-field behavior was observed during the infantile period every
other day beginning at 15 days of age till 21 days of age. The open-
field apparatus with a diameter of 27.5 cm at the bottom and 30 cm at
the top with a hight of 11 cm was divided into 7 regions with a center
circle. Parameters observed were ambulation (number of square crossed),
rearing (number of times each rat raised its forepaws off the floor of
the apparatus), grooming, head shakes, urination and defecation. The
latency to the first line crossing was recorded at each test. In order
to avoid hypothermia of pups due to the isolation from mothers, open-
field behavior was limited to 2-minutes observation.
The Resoonse to Kainic Acid
Hc-F, rats and paired controls were injected S.C. with 9 mg/kg kainic
acid at 25 days of age and the time course changes in the frequency of
wet-dog shakes and limbic seizures were counted 10 minutes apart for 60
minutes. Only one test was applied to each rat.
Data Analysis -
Two-way analysis of variance (ANOVA) was used to assess the effect of
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282 T. Fujiietd.
Hc treatment. Average values of data are
test. A probability level of 0.05 or greater
Results
Growth Rate
compared by the Student t-
was considered significant.
As shown in the body weight curves in Fig.1, growth retardation was
manifested from 15 days of age afterward in the 13-15dHc-F, rats (ANOVA,
P< o:osj. Growth rate in the 9-lldHc-F , rats was slightly smaller at 15
days of age but it was accelerated at 17-21 days of age, though it was
not statistically significant.
DY nc *.,e 0 .
FW.1. 0 .
SC T.
7 13 15 17 19 21
Age in Days
Fig 1. Body weight curves in the 13-15dHc-F, male and female rats and controls.
Open-Field Behavior
The 9-lldHc-F1 male and female rats showed a delay of the development
of ambulatory behavior in the open-field at 15 and 17 days of age
(Fig.2). However, the ambulatory activity returned to the control level
at 21 days of age. No change in the ambulatory activity was observed in
the 13-lSdHc-F, rats (Fig.2). Ninty-five -to 100% of the Wistar-Imamichi
strain rats used in the present experiment shows rearing activities in
the open-field at 19 days of age as presented in Fig 3. All the 13-
15dHc-F, male and female rats exhibited rearing activities in the 2
minutes observation already at 17 days of age (Fig.3), while no
significant change in the rate of rearing was demonstrated between the
9-lldHc-F, and control rats at 17 days of age.
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Glucocorticoidexposureduring fetalbfe 283
g-116 MC-F1 11-156 K-F,
ts-
20 .
d E ‘*
‘$ lo-
N 5’
2 OL
2 25’
1 20-
Q 8,s. 10.
s-
o-
“.* P I5 I7 2,
15 I7 21
Age in Days
Fig 2. Ambulatory activity in the 9-lldHc-F1 and 13-15dHc-Fl rats in the open-field. Each value represents the mean+S.E.M. of 12-14 rats.
*I PiO.05 vs. age-matched controls.
9-lid HZ-F1
0 Vehicle = RC
Age in Days
Fig 3. Incidence of rearing in the same rats as in Fig 1 of the 9- IldHc-Fl and 13-lSdHc-F1 aroubs in the open-field. **, PC 0.01 vs. age-matched controls (vehicle):
Response To Kainic Acid
The frequency of the wet-dog shakes induced by kainic acid decreased
in both the 9-lldHc-F, and 13-15dHc-F, rats. The decrease in the
response to kainic acid in the 9-lldHc-F, rats, both male and female,
was greater than in the 13-15dHc-F, rats (Figs. 4, 5).
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284 T.FuJii etaI.
P $ ,,:
0 0” l HC 40 l %&df!c ,;’
,/
10 20 30 ,o 50 60
Fig 4. Time course of the frequency of wet-dog shakes following S.C. administration of kainic acid in the 9-lldHc-FI and 13-15dHc-F, male rats. The rats were tested at 25 days of age. Each point represents the mean+S.E.M. of 12-14 rats. *,p< 0.05 vs. DW-FI controls. ANOVA for - the 9-lldHc-F1, PC 0.05.
9-lid "C-F, 'or 13-15d "C-F, I
Time after K4lnic Acid (Mln)
Fig 5. Time course of the frequency of wet-dog shakes following S.C. administration of kainic acid in the littermate female rats in Fig 4. Each point represents the mean+S.E.M. of 9-12 rats. ANOVA for the 9- IldHc-FL , P< 0.05. *,P< 0.05-v~. DW-FI rats.
The response to kainic acid was tested in the second generation rats of
the 9-lldHc-F, and 13-15dHc-F, parents. _!:e 9-lldHc-F, rats in both
male and female showed a decrease in the frequency of the wet-dog shakes
after adminsitration of 9 mg/kg kainic acid (Figs. 6, 71, though the
significant decrease was observed only at 50 and 60 minutes after the
treatment with kainic acid.
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Glucocorticoid exposun during fetal life 285
9?Idl-lC-Fz 13-l?% HC-F,
Tii afw Kaid &id (Mm)
Fig 6. Time course of the frequency of wet-dog shakes following S.C. administration of kainic acid in the 9-lldHc-FI and 13-15dHc-Fa male rats. The rats were tested at 25 days of age. Each point represents the mean+S.E.M. of the number of rats in parenthesis. *,p< 0.05; **,p< 0.01 vs. BW-FI.
Q-l ld HC-Fz Female
13-156 HC-h
iii alter Kainiic A& (Min)
Fig 7, Time course of the frequency of wet-dog shakes following S.C. administration of kainic acid in the littermate females of the rats in Fig 5. Each point represents the mean+S.E.M. of the number of rats in parenthesis. *,P< 0.05; ***rP< 0,001 vE. DW-Fr.
Discussion
The present experiment was focused on the functional effects of Gc
exposure on the fetal hippocampal region and cerebral cortex.
Therefore, the endpoint for the assessment used was the locomotor
activity in an open-field and the response to kainic acid which posses-
ses a high density of its receptors on the cells of the hippocampus.
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286 -r.Fuytefc4L
The results obtained in this experiment demonstrated that maternal
exposure to hydrocortisone in the rat for 3 days at either stage of the
migration of neuronal elements or of neurogenesis mainly in the cerebral
cortex, amygdala and hippocampal pyramidal cells affected the
behavioral development and the response to kainic acid in the offspring.
Glucocorticoid Receptors in the Brain
Glucocorticoid (Gc) receptors are widely distributed in the brain and
the hippocampus is a principal neural target tissue for Gcs with high
concentraions of the receptors. However, physiological role of the Gc
receptors in the brain is still obscure. Reul et al. (1989) studied on
the gene expression of Type I Imineralocorticoid, high affinity gluco-
corticoid) and Type II (classical glucocorticoid) receptor mRNA in
various tissues and clarified that Type I mRNA is high in the hippo-
campus, colon, and heart, and Type II mRNA was high in the liver,
thymus, and brain. Adrenalectomy induces a transient increase in both
hippocampal Type I and Type II mRNA.
There are few reports on the ontogenetic appearance of Gc receptors in
the hippocampus or other regions of fetal brain. Kalinyak et al. (1989)
found that Gc receptor mRNA is detected in rat brain at 20 days in fetal
life. On the other hand, adrenal cells have been indicated to appear at
days 13.5-15 of fetal life in the rat (Roes, 1967; Sugihara, 1977).
With these findings, it can be assumed that fetal Gc may play some role
not only in adaptation to stress during parturition but also in the
brain development. Cells in the process of migration and/or proli-
feration in fetal body, in a highly active state, could be affected by
exogenous Gc to a greater extent as compared with those in resting or
mature condition.
Numerous neurochemical and electrophysiological studies demonstrate
that the hippocampus is extremely sensitive to the presence of Gcs (Reul
and De Kloet, 1985). Sapolsky and his colleague have suggested that Gcs
appear to induce a general metabolic vulnerability in hippocampal
neurons, impairing their capacity to survive varied insults (Sapolsky,
1986; Sapolsky and Pulsinelli, 1985). Armanini et al. (1990) suggested
that Gcs endanger hippocampal neurons by enhancing glutamatergic signals
and/or enhancing vulnerability to such signals. Therefore prolonged Gc
exposure can ultimately be deleterious. Indeed, when exposure to Gcs is
prolonged in therapeutic uses consequently steroid diabetes, fatigue,
myopathy, hypertension, and immunosuppression develop. The findings
that chemical adrenalectomy reduces hippocampal damage induced by kainic
acid (Stein and Sapolsky, 1988) may support the ability of Gcs to
compromise neuronal viability in the hippocampus.
Rat hippocampal cells prepared from embryos at days 17 and 21 of
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Glucocorticoidexposureduringfetallife 287
gestation are capable of responding with depolarization to nanomolar
concentrations of muscimol, a GABA agonist, suggesting that a receptor
mediated response exists (Fiszman et al., 1990). The time of neuron
origin in all areas of rat hippocampal region was examined by Bayer
(1980) with "H-thymidine autoradiography. The progress of neurogenesis
in the hippocampal region begins from embryonic days 15-16 through days
17-19. In his experiment, the presence of sperms in the vaginal smear
was designated as embryonic day 1 instead of day 0 in our experiment.
In the present experiment, exposure to hydrocortisone on days 9-11 of
gestation before the peak of neurogenesis in the hippocampus and
cerebral cortex (Rodier, 1980) resulted in more marked changes in
behavioral development and the response to kainic acid.
Response to Kainic Acid
Kainic acid is a rigid glutamate analogue and it binds with cells in
the hippocampus which possesses glutamate receptors. Behavioral mani-
festations after kainic acid treatment are characterized by scratching,
wet-dog shakes, rearing, forelimb clonus and generalized clonic and
tonic limbic seizures. Appearance of the wet-dog shakes behavior
following administration of kainic acid has been considered as the
result of the binding of kainic acid to high affinity components in the
limbic system (Berger et al., 1984). Kainic acid binding sites are
associated with the mossy fiber terminals which project upon the
pyramidal neurons of the CA3 region in the hippocampus (Represa et al.,
1987). Albala et al. (1984) observed that rat pups at 15-18 days of age
do show early generation of convulsions with few wet-dog shakes after
kainic acid administration, and that selective lesions consisting of
neuronal cell loss in the hippocampus, amygdala and pyriform cortex were
only shown in puberscent and adult rats. The necrotic lesion was well
associated with the limbic seizures. Hata and Fujii (1991) also have
examined the age difference in the response to kainic acid in Wistar-
Imamichi rats and found that the wet-dog shakes behavior and limbic
seizures can be developed following the systemic administration of
kainic acid after 3 weeks of age. Therefore, in the present experiment,
the response to kainic acid was assessed at 25 days of age.
The wet-dog shakes behavior can also be induced by administration of
various drugs. Systemic administration of a precursor of serotonin, 5-
hydroxytryptophan (5-HTP) is well known to induce wet-dog shakes
behavior (Bedard and Pycock, 1977) and it induces an increase in
cerebral serotonin concentration. Yoshida et al. (1986) observed that
intraventricular administration of [D-Ala2,Met']enkephalinamide is capable
of inducing wet-dog shakes and epileptic discharges in the hippocampus.
Wet-dog shakes elicited by kainic acid, however, differ from that
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288 T. Fujii et al
produced by 5-HTP in the features with the onset of frequent scratching
and with limbic seizures. The frequency of 5-HTP induced wet-dog shakes
was lesser than that induced by kainate (Taguchi and Fujii, 1987).
Behavioral Development
In the present experiment, the offspring exposed prenatally to Hc on
days 13-15 of gestation showed accelerated development of rearing
behavior without reduction in the scores of ambulation at 17 days of
age. This was earlier than the time of its appearance in normal rats.
Rearing behavior has been considered to reflect increases in
dopaminergic activity primarily in the nucleur accumbens (Costa11 et
al., 1977). In the 13-15dHc-F, rats, ambulatory score did not show any
change in spite of the increased number of rearing, suggesting that
locomotor activity in these rats increased. Behavioral performance has
been considered by many researchers as to be well related to the
functional activity of the frontal cortex, hippocampus and amygdala.
Moreover, spontaneously generated behavior can be very sensitive to drug
treatment and can even indicate the severity of the effects as reported
previously on the several CNS acting drugs (Fujii et al., 1987, Fujii
and Kusama, 1991; Nakanishi and Fujii, 1990).
Catecholaminergic systems, particularly dopaminergic systems play an
important role in the mediation of general activities in young animals
in controlling the spontaneous activity in rodents (Barrett et al,,
1982; Beninger, 1983; Camp and Rudy, 1987; Pichler and Pifl, 1989).
Cholinergic neurons in the hippocampus and cortex also correlated with
the level of locomotor activity (Day et al., 1991). It is of interest
that the exposure to Hc in the rat on days 9-11 of gestation before the
stage of the neurogenesis in the cerebral cortex and hippocampus
suppressed the development of spontaneous behavior in an open-field to a
greater extent as compared with that seen in the rats exposed to Hc on
days 13-15 of gestation. The rats exposed to Hc on days 13-15 of fetal
life showed a slight but significant delay of the body growth. There
are several reports on the growth retardation after Gc treatment in man
and animals. This inhibition is probably due to its catabolic action.
However, it is difficult to propose the long-term metabolic effect of
the short-term exposure to Gc during fetal life. Gc appears to reduce
the growth hormone secretion (Wehrenberg et al., 1990).
Maternal Exposure to Glucocorticoid
There are several reports on the effect of maternal exposure to Gc
during pregnancy on the fetal brain. Velazquez and Roman0 (1987)
treated pregnant mother rat at 17, 18 and 19 days of gestation. They
observed the pups at birth or at 6 or 12 days of postnatal age and found
the decreased DNA content and accelerated decrement of the external
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granular layer in the cerebellum. Recent observations by Slotkin and
his colleagues (1991) have demonstrated that dexamethasone given to
pregnant rats on gestational days 17, 18 and 19 resulted in an enhance-
ment of the binding of ($B]desmethylimipramine (DMI) in the midbrain,
brainstem and in cerebellum when 0.05 mgJkg was given but without change
in the growth. At a higher dose, 0.2 mq/kg that elicited moderated
growth impairment induced an initial enhancement and subsequent deficits
in binding of /IQ]DMI in the midbrain and brain stem. Cc-induced
behavioral changes have been observed in rats by Wolkowitz and his
coleagues (1986). Seven daily injections of 10 mg/'kg of corticosterone
induced a significant increase in the vertical and ambulatory locomotion
with an increase in the caudate homovanillic acid, suggesting the
increased central dopaminergic activity. Lee and his coleagues (1989)
reported that administration of dexamethasone 1 hr before kainic acid
administration in adult rats potentiated the wet-dog shakes and severity
of seizure activity. In the present results, however, the response to
kainic acid decreased significantly in all the rats born to &z-exposed
mother rats when the frequencies of wet-dog shakes were assessed. The
suppression was slightly larger in the 9-lldHc-FI rats and this altered
feature was transmitted to their second generation. It might be
possible that acute effect of Gc priming in modulating the effect of
kainic acid differs from the long-lasting effect of prenatal exposure to
Cc. The present results suggest a possibility that the development of
receptors for kainic acid might be altered in the Hc-FI and Fr rats,
Transgenerational Effect
This is the first report showing the transgeneration of the altered
response to kainic acid developed in the FI rats after a short-term
exposure to hydrocortisone during gestation. The decreased incidence in
kainic acid-induced wet-dog shakes behavior shown in the 9-lldHc-Flrats,
male and female, was transmitted to the second generation. Although its
mechanism is unknown at present, evidence showing the transgeneration of
altered function developed in the F1 animals after maternal exposure to
drugs or chemicals has been accumulated (Reimers and Sluss, 1978; Beach
et a1.,1982; Fujii et a1.,1982, 1987; Fujii,1988). Even maternal
endocrine disorders such as calcium regulatory system (Fujii, 1978;
Fujii et al., 1980, 1988) or glucose metabolism (Baranov et al., 1988)
can induce alterations of the regulatory function of blood calcium or
glucose in the F, rats and the altered features have been found to be
heritable to subsequent generations. Though the mechanism of these
findings have not been defined at present, there are some hypothetical
interpretaitons made on the trangenerational effects (Campbell, 1991;
Gruenert and Cozens, 1991).
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290 T.Fujfl etaL
Conclusion
Maternal exposure to hydrocortisone only for 3 days during the
migration of neural elements (days 9-11 of gestation) or during the
neurogenesis (days 13-15 of gestation) in the fetal brain clearly showed
to affect the growth, behavioral development, and functional development
of hippocampal regions in the rat when assessed using 3 measures, body
weight, open-field behavior and frequencies of kainic acid-induced wet-
dog shakes and seizures. The decreased wet-dog shakes response to
kainic acid in the 9-lldHc-F, rats was transmitted to the Fz generation,
while no change in the response to kainic acid was observed in the 13-
15dHc-Fn rats.
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Inquiries and reprint requests should be addressed to:
Dr. Tomoko Fujii Department of Pharmacology Teikyo University School of Medicine 2-11-1, Kaga, Itabashi-ku, Tokyo 173 Japan.