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Evaluation of the developmental effects on mice after prenatal, or pre- and postnatal exposure to 2,3-dimercaptopropane-1-sulfonic acid (DMPS).

The sodium salt of 2,3-dimercaptopropane-1-sulfonic acid (DMPS), a water soluble metal complexing agent, was administered to four groups of pregnant Swiss mice at 0, 70, 210, and 630 mg/kg/day by two dosing schedules: gestation day 14 until birth (prenatal exposure), and gestation day 14 until postnatal day 21 (pre- and postnatal section). Dams were allowed to deliver and the number of live and dead pups recorded. Each pup was sexed and weighed on days 0, 4, 14, and 21. Also, pinna detachment, incisor eruption and eye opening were monitored. No adverse effects on offspring survival or development were evident in either exposures at doses employed in this study. The "no observable effect level" (NOEL) for health hazard to the developing fetus or pup was 630 mg DMPS/kg/day. This dose is much higher than the amounts of DMPS usually administered in human heavy metal poisoning.

Animals↗

Unusual patterns of somatic embryogenesis in the domesticated carrot: developmental effects of exogenous auxins and auxin transport inhibitors.

The effects of various exogenous auxins and polar auxin transport inhibitors on somatic embryogenesis in carrot cultures were investigated. Indole-3-acetic acid and 2,4-dichlorophenoxyacetic acid do not disrupt the sequence or the polarity of individual stages in embryo development, but tend to cause developing embryos to revert to undifferentiated callus, with increasing frequency in later embryo stages. The transport inhibitors, N-(1-naphthyl)phthalamic acid and 2,3,5-triiodobenzoic acid, block morphological transitions to the subsequent stage; for example, they cause the formation of enlarged globular and oblong embryos. Heart embryos in these treatments usually develop additional lateral growth axes. These results shed light on the role of auxin and its polar transport in somatic embryogenesis.

2,4-Dichlorophenoxyacetic Acid↗

Behavioral and developmental effects in suckling mice following maternal exposure to the mycotoxin secalonic acid D.

Pregnant mice (dams) were gavaged once on gestational day 13 with 4 ml/kg of dimethylsulfoxide vehicle containing 0 (groups 15, 25 and negative control) or 25 (positive behavioral teratogenic control group) mg/kg of secalonic acid D (SAD). While nursing their offspring, dams were gavaged on postgestational days 1 to 10 with vehicle containing 0 (negative and positive control groups), 15 (group 15) or 25 (group 25) mg/kg/day of SAD. Gestational lengths, maternal pregnancy weights, litter sizes, neonatal sex ratios, neonatal physical appearance and female birth weights were unaffected by prenatal treatment, but male pups born to positive control dams weighed less (p less than 0.05) than negative control group. Compared to negative control, the positive control dams gained significantly more weight while nursing their offspring. Prenatal (positive control) and postnatal (15, 25) SAD exposure delayed ontogeny of surface righting, olfactory discrimination and hindlimb grip behaviors in males and females, and testes descent in males. Negative geotaxis in male and female offspring of group 25 and male offspring of positive control group, as well as times of incisor eruptions of both sexes in groups 15 and 25 were delayed. A significant dose-response effect in olfactory discrimination existed between the groups exposed to postnatal SAD. SAD was behaviorally teratogenic following both prenatal and early postnatal exposure.

Animals↗

Developmental effects of maternal stress in the CD-1 mouse induced by restraint on single days during the period of major organogenesis.

Maternal stress during gestation can produce significant fetal and/or postnatal effects, and can enhance the teratogenicity of other agents. We have previously shown that restraint stress on gestational day 8 in CD-1 mice produces significant increases in encephaloceles and supernumerary and fused ribs. In the present study we have examined the effects of stress induced by restraint on individual days during the period of major organogenesis (days 6-14). Weight loss and stress-induced analgesia as assessed by the tail-flick method were used to determine the degree of stress induced by a 12-h restraint period. Restrained animals lost significantly more weight and had longer tail-flick latencies than the concurrent food and water deprived controls on all gestational days. Significant increases in embryo/fetal mortality were also observed in the offspring of restrained animals. An increased incidence of supernumerary ribs was found in mice restrained on days 7 and 8. Since maternal toxicity induced by chemical teratogens may be accompanied by a general increase in maternal stress, our data suggest that such stress may be an etiological factor in teratology bioassays in which dose levels are sufficiently high to induce overt maternal toxicity.

Analgesia↗

Developmental effects of neonatal sex hormones on spatial and activity skills in the white rat.

The purpose of this experiment is to extend these experiments by using varying neonatal hormonal differentiation processes and to examine the effects of these different methods of neonatal feminization on changes in spatial and activity skills. The experiment involved three neonatally feminized groups of male rats: 'castration alone', 'estrogen alone', and 'estrogen injected castrates' together with one female sample, 'testosterone injected castrates', while treated and untreated male and female controls were also used. The data provide partial support for the major hypotheses that neonatal gonadectomy and opposite sex hormones administered to male and female castrated rats (together and independently for males) would reverse the normal sex-associated abilities of the white rate (higher male spatial learning and higher female activity). However, the feminization effect for the male 'estrogen alone' and 'castration alone' experimental groups was much greater than for the male estrogen injected castrates. The masculinized females, testosterone injected castrates, also had higher spatial learning and lower activity levels, while the feminized male's spatial and activity skills were also reversed. This confirmed in part the extent to which neonatal gonadal sex hormones are effective at critical periods of development in programming the brain in terms of sex-associated spatial and activity skills. Adult hormonal replacement therapy was also administered at 12 months and supported the hypothesis that sex hormones in adults would be mainly activational and have less marked effects than the significant directional changes obtained by these neonatal sex hormones and castration techniques.

Age Factors↗

Developmental effects of vitamin B-6 restriction on the locomotor behavior of rats.

The nocturnal spontaneous locomotor behavior of vitamin B-6 restricted and control rats was measured using activity chambers. The results show a generalized hypoactivity in indices of horizontal and vertical activity in neonatal rats fed vitamin B-6 restricted diets during gestation and lactation. This pattern of locomotor behavior changed in the postweaning period to a gradual increase in indices of locomotor activity to a pronounced hyperkinesis in vitamin B-6 restricted young adult rats. This study suggests that long-term vitamin B-6 restriction results in damage and/or abnormal development of neuronal system(s) associated with locomotor behavior.

Aging↗

Behavioral and developmental effects of two 3,4-methylenedioxymethamphetamine (MDMA) derivatives.

The effects of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstacy') and two structurally related compounds, N-methyl-1-(3,4-methylenedioxyphenyl)-1-ethanamine (MDM1EA) and N-methyl-1-(3,4-methylenedioxyphenyl)-3-butanamine (HMDMA) were examined in two preparations: (i) a drug discrimination procedure in MDMA-trained rats and (ii) the chicken embryo, for determination of the direct effects of these compounds on the developing organism. The highest doses of MDM1EA and HMDMA partially substituted for MDMA, whereas higher (30-60 mg/kg) doses of HMDMA evoked clonic seizures in a separate group of rats. In chicken embryos MDMA had no effect on body, brain or liver weight, while the highest dose of MDM1EA decreased body weight and the 2 lowest doses of HMDMA increased body weight. All doses of HMDMA decreased liver weight (expressed as % body weight) when compared with contemporaneous water-treated controls. Taken together, the results of these experiments suggest that structurally related compounds share some stimulus properties with MDMA and may therefore share abuse liability. Furthermore, both MDMA-related compounds produced adverse effects on the developing organism, whereas MDMA did not.

3,4-Methylenedioxyamphetamine↗

"Population" characteristics of birthweight in an animal model of alcohol-related developmental effects.

A retrospective analysis of a large database of maternal and litter variables in rats collected over several years evaluated the robustness of fetal alcohol effects on birthweight. Pregnant rats were fed a liquid diet in which 35% of the calories were derived from alcohol. Control dams were pairfed an isocaloric liquid diet or were fed lab chow ad lib. Alcohol exposure produced large, highly significant, and reliable decreases in birthweight of male and female pups. Multiple regression analyses indicated that alcohol exposure per se, much more than restricted caloric intake alone, caused these effects. Litters of pairfed dams weighed less than chowfed controls but the effects were less consistent, varying with season and requiring more litters to discriminate the effects of restricted caloric intake. Power analyses indicated that 7 to 12 litters per group are needed for detecting a statistically significant reduction in birthweight due to prenatal alcohol exposure, even with single pups selected at random from each litter. Alcohol-exposed pups also weighed consistently and significantly less than both the chowfed and pairfed pups, whereas differences between chowfed and pairfed groups were much smaller and inconsistent. The results imply that decreased birthweight is a consistent characteristic of prenatal alcohol exposure.

Animals↗

Radiobiological studies with the nematode Caenorhabditis elegans. Genetic and developmental effects of high LET radiation.

The biological effects of heavy charged particle (HZE) radiation are of particular interest to travellers and planners for long-duration space flights where exposure levels represent a potential health hazard. The unique feature of HZE radiation is the structured pattern of its energy deposition in targets. There are many consequences of this feature to biological endpoints when compared with effects of ionizing photons. Dose vs response and dose-rate kinetics may be modified, DNA and cellular repair systems may be altered in their abilities to cope with damage, and the qualitative features of damage may be unique for different ions. The nematode Caenorhabditis elegans is being used to address these and related questions associated with exposure to radiation. HZE-induced mutation, chromosome aberration, cell inactivation and altered organogenesis are discussed along with plans for radiobiological experiments in space.

Animals↗

Developmental effects of in vivo and in vitro inhibition of nitric oxide synthase in neurons.

The diffusible chemical messenger nitric oxide (NO) is involved in neuronal plasticity and it is, therefore, supposed to play a role in brain development. A shortage of NO during the critical period of brain maturation may theoretically have long-lasting consequences on the organization of the adult brain. We have performed in neonatal rats a chronic inhibition of the enzyme responsible for NO production, nitric oxide synthase (NOS), from postnatal day 3 to postnatal day 23, through administration of the competitive antagonist N-nitro-L-arginine methylester (L-NAME). The calcium-dependent catalytic activity resulted almost completely inhibited throughout the period of treatment and it took more than 4 days after its suspension to get a full recovery. The expression of the neuronal isoform of the enzyme (nNOS), revealed by immunoblotting, was unchanged during the treatment and after it. The histochemical reaction for NADPH diaphorase was reduced at the end of the treatment and recovered in concomitance with the recovery of the catalytic NOS activity. No gross structural alterations were detected in brain morphology. The levels of three neurotransmitter-related and one astrocytic marker were unchanged in the cerebellum, hippocampus and cortex of 60-day-old rats which had been neonatally treated. A similar lack of significant effects on neurochemical brain maturation was also noticed in a parallel series of experiments, in which a short pulse of NOS inhibition was performed at a critical prenatal time of brain development, from gestational day 14 to gestational day 19. In vitro, chronic exposure of cerebellar granule cells to L-NAME (500 microM) resulted in slight decrease of surviving neurons after 8 days in culture and in better resistance to the challenge of stressful culture conditions. The present results suggest that the basic plan of brain organization can be achieved despite an almost complete NOS inhibition during the maturation period. In vitro, NOS inhibition may bring to more pronounced consequences on neuronal viability and function.

Animals↗