Fetal hydantoin syndrome in rats: dose-effect relationships of prenatal phenytoin on postnatal development and behavior

Sprague-Dawley rats were gavaged once daily on days 7-18 of gestation with, 100, 150, or 200 mg/kg of phenytoin. Only the highest dose of phenytoin decreased maternal weight during gestation or increased offspring mortality up to weaning. Offspring were evaluated for activity prior to weaning (pivoting and photocell) and afterwards (figure 8, open-field, and hole-board), dynamic righting development, maze learning (Biel maze), and visual discrimination (Y maze), and for startle reaction to both auditory and tactile stimuli. The highest dose of phenytoin produced increased activity on all tests of activity, delayed dynamic righting development, impaired Biel maze and Y-maze learning, and inhibited tactile startle responses. The two lower doses of phenytoin generally showed a dose-effect relationship with values on most measures intermediate between values for controls and for the highest-dose group. Dose-effect relationships were most evident on measures of early activity (both tests), dynamic righting, and Biel maze learning, whereas only trends were evident on measures of later activity, Y maze, and startle. A dose-related rotational defect was found in a minority of phenytoin offspring, and although these individuals contributed to the behavioral abnormalities observed, they in no instance accounted for the overall pattern of effects seen in the phenytoin offspring. Maternal plasma phenytoin levels at the end of treatment were dose-related. Offspring showed no effects on postnatal growth, total brain weight, or brain protein content as adults. The data support the view that phenytoin is a potent behavioral teratogen at doses well below those causing any evidence of gross teratogenicity or embryotoxicity.     

Action of the phenothiazine derivative methophenazine on prenatal development in rats.

Single doses of 100-400 mg/kg or multiple doses of 10 or 50 mg/kg of the phenothiazine derivative methophenzaine were given per osto Wistar rats at various times on the 7th-14th days fo gestation and the fetuses examined near term. Results indicated that methophenazine was mainly embryolethal when administered on the 8th-11th days, and was teratogenic at later times, producing types of malformations that depended on the day of treatment, the most susceptible period being the 13th and 14th days of gestation. Teratogenicity occurred only when the dosages were highly toxic to the pregnant rats. Ribovlavin given ip on the 14th day significantly reduced the embryolethal but not the teratogenic action of methophenazine.     

The postnatal development of the genital system in male rats following the prenatal administration of corticosterone

Corticosterone administration to pregnant Wistar rats on days 16 and 18 of pregnancy leads to changes in genital system of male offspring during postnatal ontogenesis: reduction of ano-genital distance in two days old rats, increase of preputial glands' weight in 35 and 70 day old embryos, changes in nature of puberal increase in testosterone blood level from day 35 to day 70 of life. The obtained data suggest that the increase in the corticosteroid level in blood of pregnant females owing to any stress factor can affect the postnatal development of genital system of male offspring.     

Influence of modified casomorphins on yawning behavior of rats.

Apomorphine-induced yawning was completely suppressed in animals treated with 5 nmol [D-Pro4]casomorphin (CM) (ICV), 10 nmol [D-Phe3]CM (ICV) or 10 nmol [D-Pip4]CM (ICV). The apomorphine-induced yawning was also decreased, by des-Tyr analogs, but only by about 50%. Physostigmine (0.15 mg/kg, IP) induced yawning. The physostigmine-induced yawning was suppressed by 5 nmol [D-Pro4]CM and 10 nmol [D-Phe3]CM. Both [des-Tyr-D-Phe3]CM and [des-Tyr-D-Pip4]CM were without effect, whereas [des-Tyr-D-Pro4]CM increased significantly the physostigmine-induced yawning. The results suggest that dopaminergic transmission can be modulated by beta-casomorphin derivatives, thus resulting in a decrease in yawning. In the case of the des-tyrosine derivatives, we can assume a dopaminergic modulation, too. An increase in serotonergic activity might be supposed for [des-Tyr-D-Pro4]CM.     

The effects of prenatal PCBs on adult social behavior in rats

Endocrine disrupting chemical (EDC) exposures during critical periods of development may influence neuronal development and the manifestation of sexually dimorphic sociability and social novelty behaviors in adulthood. In this study, we assessed the effects of gestational exposure to PCBs on the social behavior of males and females later in adulthood. A weakly estrogenic PCB mixture, Aroclor 1221 (A1221, 0.5 or 1 mg/kg) was administered to pregnant Sprague–Dawley rat dams. Both a positive control (estradiol benzoate; EB, 50 μg/kg) and negative control (dimethylsulfoxide; DMSO in sesame oil vehicle) were similarly administered to separate sets of dams. The sexes responded differently in two tasks essential to sociality. Using a three-chamber apparatus that contained a caged, same-sex, gonadectomized stimulus animal and an empty stimulus cage, we found that both sexes showed a strong preference for affiliating with a stimulus animal (vs. an empty cage), an effect that was much more pronounced in the males. In the second task, a novel and a familiar stimulus animal were caged at opposite ends of the same apparatus. Females displayed a higher degree of novelty preference than the males. During both tests, females had significantly higher social approach behaviors while male engaged in significantly more interactive behaviors with the conspecific. Of particular interest, males born of dams that received prenatal A1221 (0.5 mg/kg) exhibited an overall decrease in nose-to-nose investigations. These behavioral data suggest that the males are more sensitive to A1221 treatment than are females. In addition to behavioral analysis, serum corticosterone was measured. Females born of dams treated with A1221 (0.5 mg/kg) had significantly higher concentrations of corticosterone than the DMSO female group; males were unaffected. Females also had significantly higher corticosterone concentrations than did males. Overall, our results suggest that the effects of gestational exposure to PCBs on adult social behavior are relatively limited within this particular paradigm.     

Influence of low-intensity ultrasonic irradiation on prenatal development of two inbred mouse strains.

Effects of low-intensity ultrasonic irradiation on prenatal development of DHS and A/HeMk mice were studied. On day 8 of gestation (VP day = 0) pregnant females were exposed to ultrasonic waves with a frequency of 2.25 MHz and power of 40 mW/cm2 for 5 h. A low frequency of severe cranial and facial anomalies occurred that was attributable to the irradiation in both strains. The difference in frequency of malformed fetuses was marked between irradiated and untreated control A/HeMk mice, but not DHS mice. Fetal growth inhibition and death were also produced in both strains, although the possible effect of binding the pregnant mice for irradiation cannot be discounted.     

Influence of androgen on the development of sexual behavior in rats : I. Time of administration and masculine copulatory responses, penile reflexes, and androgen receptors in females

The objective of the present study was to investigate the effect of the time of administration of androgen, during the neonatal period, on the development of masculine copulatory behavior in female rats. In addition, the influence of androgen, administered neonatally, on the development of penile reflexes and cytoplasmic androgen receptor levels in the hypothalamic-preoptic area (HPOA) was examined. Female rats were injected with 0.5 mg testosterone propionate (TP) at either 1, 8, or 24 hr after birth and again 24 hr after the first injection. Fifty percent of the females treated with TP at 1 and 8 hr after birth displayed the ejaculatory response when tested in adulthood. In contrast, 93 and 87.5% of oil-treated males and females, respectively, which were androgenized at 24 hr after birth exhibited this response. The results indicate that a considerable amount of masculinization occurs postnatally in the rat. However, none of the androgenized females displayed any penile reflexes even when tested following the display of an ejaculatory response. HPOA androgen receptor levels were somewhat higher in the oil-treated females than in males but were not correlated with the ability to exhibit ejaculation patterns.     

Effects of prenatal exposure to 50 Hz magnetic fields on development in mice: II. Postnatal development and behavior

To investigate the potential of magnetic fields to act as a behavioral teratogen, pregnant CD1 mice were exposed or sham-exposed for all of gestation to a 50 Hz/20 mT magnetic field. Maturation of offspring was assessed using a range of standard developmental indices (eye opening, pinna detachment, hair coat, tooth eruption, sexual maturity, and weight) and simple reflexive behaviors (air righting, surface righting, forepaw grasp, cliff avoidance, and negative geotaxis). Activity and coordination levels were explored in juvenile and adult mice using an open field arena, a head-dip board, an accelerating Rotarod, and a residential activity wheel. All assessments were carried out without knowledge of exposure condition. Results from 168 sham-exposed mice from 21 litters and from 184 exposed mice from 23 litters were compared using survival analysis techniques and multivariate regression methods. Three possible field-dependent effects were found: Exposed animals performed the air righting reflex earlier (P < 0.01); exposed males (but not females) were significantly lighter in weight (P = 0.008) at 30 days of age; and exposed animals remained on a Rota-rod for less time as juveniles (P = 0.03). Some of these results have not been reported in other studies and may reflect spurious statistical significance, although some effect of magnetic field exposure cannot be ruled out. Overall, these results suggest that prenatal exposure to a 50 Hz magnetic field does not engender any gross impairments in the postnatal development or behavior of mice. This does not preclude such exposure affecting more subtle aspects of behavior. Published 1994 by Wiley-Liss, Inc.     

Generalized lipidosis in newborn rats and guinea pigs induced during prenatal development by administration of amphiphilic drugs to pregnant animals

Pregnant rats and guinea pigs were treated throughout the second half of gestation with amphiphilic drugs (chlorphentermine, chlorcyclizine, chloroquine) known to induce generalized lipidosis. The offspring were sacrificed immediately after birth, and several tissues (lung, liver, kidney, spleen, pituitary gland, adrenal gland, spinal cord, hypothalamus) were examined by electron microscopy. Generalized lipidosis was found in the offspring of both species, albeit of lesser degree than in the mothers. The results show that fetal and adult tissues respond to lipidosis-inducing drugs in a qualitatively similar way; the quantitative differences found may be related to pharmacokinetic and cellular factors.     

Postnatal physiological development of rats after acute prenatal hypoxia

The aim of study was to investigate the physiological development of the brain and behaviour in rats subjected to prenatal hypoxia on the 13.5th day of embryogenesis. We have found that such rats manifested a delayed physiological development and a change in nervous tissue of the sensorimotor cortex, as well a disturbed formation of motor responses during the first month of postnatal ontogenesis. During maturation these modifications were in part compensated, however we observed a decrease of the rats' ability to learn new forepaw movements. The destruction of the brain tissue and the modification of neurons composition in the sensorimotor cortex correlated with changes of behaviour at different stages of ontogenesis. Thus, changes of the conditions under which an organism develops during embryogenesis, predetermine a disturbance in ontogenesis and the learning ability.     

Androgens in relation to prenatal development and postnatal inversion of the gubernacula in rats.

Exposure of male rats to the anti-androgen flutamide during fetal life, from day 10 after conception to the day of birth, allowed quantitatively unaltered development of the gubernacula. Apparently, androgens play no important role or no role at all in their growth. Castration of newborn male rats did not interfere with the inversion during further postnatal life of the gubernacula to create the muscular parts of the scrotum (cremaster muscles). Prenatal exposure to flutamide, followed by castration immediately after birth, also allowed gubernacular inversion and cremaster muscle growth. Neonatal administration of testosterone, after castration at birth, did not enhance gubernacular inversion or promote cremaster muscle growth in infancy or during adulthood. Apparently, postnatal gubernacular inversion and cremaster muscle growth are independent not only of androgens, but also of all testis hormones. Neonatal administration of the potent androgen 5 alpha-dihydrotestosterone propionate suppressed gonadotrophin secretion and, in intact males, inhibited testicular growth. Administration from the day of birth to day 33 delayed testicular descent and enhanced growth of the genital apparatus, but did not affect the size of the cremaster muscles. These experiments indicate that androgens are not involved in the processes that create the cavities into which testes descend to acquire their full reproductive potential.     

Influence of androgen on the development of sexual behavior in the rat. II. Time and dosage of androgen administration during the neonatal period and masculine and feminine copulatory behavior in females

The objective of the present study was to delineate the period of sensitivity to a single androgen exposure during the initial neonatal hours on the development of masculine and feminine copulatory behavior in female rats. Female rats were injected once with either 500, 50, or 5 micrograms testosterone propionate (TP) at either 1 or 24 hr after birth. Following castration in adulthood and TP replacement, the females were tested four times at weekly intervals in prolonged sessions for masculine copulatory behavior. One month following the masculine copulatory tests the females were tested for 3 weeks for feminine copulatory behavior with weekly increasing levels of estradiol benzoate (2.5, 10, and 25 micrograms) and progesterone (200 micrograms). The results demonstrate that a single injection of TP administered at either 1 or 24 hr after birth can significantly increase the capacity of female rats to exhibit ejaculation patterns and that the amount of androgen that is administered is critical in determining the levels of ejaculatory responding. Similarly, the females given high doses (50 and 500 micrograms) of TP at either 1 or 24 hr neonatally were almost completely defeminized. In contrast, however, the females treated with 5 micrograms TP at 1 and 24 hr showed different levels of lordotic performance indicating a greater sensitivity to androgen immediately after birth than at 24 hr in female rats as has been shown in male rats.