Gestational exposure to loud noise alters the development and postnatal responsiveness of humoral and cellular components of the immune system in offspring.

Gestational exposure of the female to environmental toxins can alter immune function in the offspring. We have recently shown that prenatal maternal stress, that is, stress applied to or induced in the female during pregnancy, can also alter the development of humoral immunocompetence in the offspring and their hormonal and immunologic responses to postnatal stress. This report presents data from two experiments on the effects of prenatal exposure to loud noise-prenatal sound stress (PSS)-on the development and responsiveness of in vitro and in vivo humoral and cellular immune function in the offspring. Pregnant rats were exposed daily from Day 15 to Day 21 of gestation to an inescapable loud noise (an 85- to 90-decibel fire alarm bell) delivered randomly for 1 hr. In developing offspring, PSS produced age-dependent and mitogen-specific alterations in lymphoproliferative activity and reduced immunoglobulin G levels at Postnatal Day 21. Antibody titers to herpes simplex virus type 1 were also reduced. Exposure to loud noise before or after infection produced an additional reduction in titers in these offspring. Arthus skin reaction (AR) to old tuberculin was reduced by PSS. Combined prenatal/postnatal sound stress further reduced this response and the AR to bovine serum albumin (BSA). Delayed hypersensitivity reaction to BSA was reduced in PSS offspring; postnatal sound stress enhanced the reaction to both antigens, but only in males. Antibody titers to BSA were increased by PSS; adjuvant-induced inflammation was attenuated by postnatal sound stress. These data suggest that in utero exposure to loud noise, which can occur in the workplace, is toxic to the developing immune system.

Interactive effects of prenatal cocaine and nicotine exposure on maternal toxicity, postnatal development and behavior in the rat.

Two experiments were performed to investigate the interactive effects of prenatal coadministration of cocaine hydrochloride (C) and nicotine tartrate (N). Experiment I was designed to determine doses of C and N that could be coadministered without altering maternal gestational parameters and/or fetal viability. Exposure of Sprague-Dawley rats to combined high-dose C (20 mg/kg) and high-dose N (5.0 mg/kg) on gestation days 8-21 was not more toxic to dam or fetus that that of exposure to C alone. Experiment II investigated pregnancy outcome, postnatal development, and behavior of the offspring following drug exposure to either high-dose cocaine (20 mg/kg: CS), high-dose nicotine (5.0 mg/kg: NS), or both (NC) on gestation days 8-21. N was administered by osmotic minipump and C by sc injection. Saline-injected dams, fitted with saline-fitted pumps (SS), and untreated dams, pair-fed (PF) to NC females, served as controls. Alterations in maternal variables were limited to a 10-15% decrease in food consumption in NC and CS groups. Pregnancy outcome and birth statistics were unaffected by prenatal treatment, as was offspring body weight during the first four postnatal weeks. However, the development of surface righting was delayed inC CS pups, and only CS offspring were underresponsive to the stimulatory effects of dopamine agonists on activity and stereotypy. Behavioral responses to N challenge were similar in all groups. In addition, only CS offspring showed altered behavioral responses in a spontaneous alternation task. Treatment effects on dopamine D1 and D2 binding in the caudate nucleus were not observed. The combination of N and C did not exacerbate any of the behavioral changes seen in CS offspring. These results support the hypothesis that C is a behavioral teratogen in rodents, and suggest that in the present model, nicotine can mitigate some of the consequences of in utero exposure to cocaine.

Influence of prenatal maternal stress on the immunocompetence of the offspring.

To evaluate the effects of prenatal maternal stress on the development of humoral immunocompetence in the offspring and on their hormonal and immunologic responses to postnatal stress, gravid Sprague-Dawley rats were exposed daily on gestational days 15-21 to prenatal environmental stress [(PES) 15 unsignaled, inescapable electric foot-shocks (0.05 mA for 0.5 s)] or prenatal psychological stress [(PPS) pregnant rats were placed in the nonelectrified section of the apparatus and allowed to see, hear, and smell a nonpregnant partner being environmentally stressed]. Pregnant controls (PC) were placed in the apparatus for 30 min. Serum corticosterone (CCS) and immunoglobulin G (IgG) levels were measured in the offspring every 7 days from birth to postnatal day (PND) 28. On PND 29-33, offspring were environmentally stressed; hormonal and immune status were determined on PND 34. Levels of IgG were reduced in PES and PPS offspring on PND 0 and in PES offspring on PND 7 and 28. These changes were unrelated to differences in CCS and did not reflect altered maternal-pup interactions or nutritional factors. Postnatal stress was immunosuppressive in PC pups but did not alter immune parameters in PPS offspring. In PES females, postnatal stress was also immunosuppressive. However, in PES males with already reduced IgG levels postnatal stress enhanced immune function. These data provide the first experimental evidence that prenatal maternal stress can alter immune parameters in the rat offspring.

Neurobehavioral and immunological effects of prenatal cocaine exposure in rat.

Time-pregnant Sprague-Dawley rats were injected subcutaneously with 20 mg/kg of cocaine HCl or 0.9% saline daily from gestation days 15 through 21. Maternal plasma levels of approximately 720 ng/ml of cocaine did not alter maternal weight gain during treatment, duration of pregnancy, any of the litter variables or several indices of maternal behavior. Offsprings' body weight from birth to 30 days of age and physical maturation were not generally affected by prenatal cocaine exposure. While the development of surface righting, cliff avoidance, and the startle response was accelerated in cocaine-exposed offspring, acquisition of a preference for a social odor was unaltered. Prenatal cocaine also attenuated the locomotor response of the offspring to d-amphetamine and cocaine at PND 15; at PND 30 both of these catecholaminergic agonists increased activity in prenatal saline and prenatal cocaine offspring. However, the difference in plasma levels of cocaine at PND 30 suggests a possible down-regulation of adrenergic receptors following prenatal cocaine exposure. Decreased thymus/body weight ratios and splenomegaly were observed in prenatal cocaine animals at 55 days of age. Although complete neutralization of herpes simplex virus-type 1 was not observed, sera from prenatal cocaine offspring showed an increased rate of appearance of cytopathic effect, while sera from animals given cocaine postnatally showed a reduction in the rate at which viral infectivity was expressed in culture. These results indicate that prenatal cocaine exposure can alter neurobehavioral ontogeny and humoral immune responsitivity in the offspring.

Prenatal antiepileptic drug exposure alters seizure susceptibility in rats.

An animal model is used to address the issue of prenatal exposure to certain antiepileptic drugs and seizure susceptibility in the offspring. Administration of doses established as median therapeutic doses in humans of phenobarbital, valproate and clonazepam to pregnant rats during the last third of gestation produced sexually dimorphic alterations in pentylenetetrazol (PTZ)-induced seizures as well as in non-convulsive (spontaneous alternation and cliff avoidance) behaviors in the offspring. Altered seizure susceptibility occurred in the absence of overtly recognizable morphological abnormalities and did not appear to reflect differences in the status of circulating drug-binding plasma proteins. Possible neural and/or metabolic mechanisms responsible for these behavioral changes are discussed.

6-Hydroxydopamine reduces preference for conspecific but not other familiar odors in rat pups.

Rat pups injected subcutaneously with 6-hydroxydopamine (6-OHDA) showed reduced preference for a familiar combination of conspecific and botanical odors when subsequently tested in a two-choice situation. However, drug treatment did not influence preference for the simple botanical odor. 6-OHDA also reduced norepinephrine (NE) concentrations in the forebrain and the olfactory bulbs. The data implicate NE in the ontogeny of the acquired responses to conspecific odors.

Potentiation of apomorphine action in rats by l-prolyl-l-leucyl-glycine amide.

Although the antiparkinsonian activity of 1-prolyl-l-leucyl-glycine amide (PLG=MIF-I) has been previously observed in several clinical trials, little is known of the mechanism of action of this tripeptide on the brain. Our study demonstrated potentiation of the action of apomorphine by PLG on the rotational behavior of mature rats which received unilateral 6-OHDA (16 microgram) lesions of the striatum as neonates. No change in tyrosine hydroxylase or dopa decarboxylase activities in rat striatal homogenates was found after addition of PLG (10(-8-10(-3) M). The results suggest that PLG modifies the dopamine receptor, making it more responsive to stimulation by the agonistic agent apomorphine and perhaps by the natural neurotransmitter dopamine.

Development of odor-guided behavior in Wistar and Sprague-Dawley rat pups.

The odor of home-cage shavings attracts Sprague-Dawley and Wistar pups 3-4 days old. Attraction increases during postnatal week one in both strains. Lemon odor repels Sprague-Dawley pups 3 and 8 days old equally, while Wistar aversion to lemon increases during the first postnatal week. Shavings from the nests of strange litters 4 or 8 days old attract Sprague-Dawley pups 4 but not 8 days old equally. Sensory changes appear to underlie Sprague-Dawley response development, while locomotor and sensory changes may mediate Wistar response ontogeny.

Prenatal morphine administration alters behavioral development in the rat.

Female rats were administered increasing doses of morphine sulfate 5 days prior to mating and during gestation until 4-6 days before the birth of their litters. Prenatal morphine exposure altered the normal during the 3rd and 4th postnatal weeks. This disruption in behavioral ontogeny did not coincide with changes in physical parameters. Decreased body weight ant postnatal week. The appearance of behavioral disturbances in the absence of physical abnormalities stresses the need for follow-up studies of infants born to narcotic-dependent mothers after signs of physical withdrawal or retarded growth have disappeared.

Aversive prenatal stimulation: effects on behavioral, biochemical, and somatic ontogeny in the rat.

Electric foot shock administered to pregnant rats altered the ontogeny of spontaneous motor activity in their pups. Prenatally stimulated (PMS) offspring were more active than controls on Days 1-10 but less active during the 3rd postpartum week. The age of peak activity, a major developmental landmark, occurred in PMS pups around 10 days of age; in controls maximum activity was not seen until the 3rd week. This effect was independent of the gender of the offspring and the timing of the gestational stimulation. Its appearance in both cross-fostered and fostered pups indicated the prenatal origin of the effect. The maturation of spontaneous alternation behavior and several reflexes and the appearance of physical features were not affected by prenatal stimulation. Moreover, both PMS and control groups exhibited an age-related increase in brain concentrations of norepinephrine, serotonin, and 5-hydroxyindoleacetic acid. These findings indicate that spontaneous motor activity is uniquely sensitive to PMS, and as far as can be determined here, PMS produces no generalized alteration in behavioral and physical ontogeny.

Neonatal locomotor and long-term behavioral effects of d-amphetamine in the rat.

Locomotor activity in the neonatal rat was found to increase from birth until the beginning of the 3rd week of life, at which time it peaked and then subsequently declined. Subcutaneous injections of both .25 and 2.0 mg/kg of d-amphetamine increased activity in rats 1-21 days of age, with the maximum effect observed at 4 days of age. No tolerance to d-amphetamine was observed after 6 daily injections beginning at 1, 7, or 14 days of age. The decline in the excitatory effects of the drug thus reflected maturational changes in response to it. Consistent with other observations from this laboratory, no persisting effects of the neonatal drug treatment was observed on adult 2-way avoidance learning.