Phencyclidine during pregnancy in the rat: effects on locomotor activity in the offspring

Either 5 or 10 mg/kg of phencyclidine hydrochloride (PCP) was administered by gastric intubation to gravid rats during the last two weeks of gestation. Intubation controls received the vehicle and all offspring were fostered to untreated controls at birth. PCP produced a decrement in maternal weight gain and a small but nonsignificant reduction in birth weight that was no longer evident at weaning. There were no maternal deaths nor were resorptions or stillbirths increased by PCP exposure. Offspring were tested for differences in locomotor activity from birth to weaning at 30 days of age and during adulthood. No behavioral differences were found among the preweanling or adult offspring. Results are compared with other prenatal studies of PCP toxicity and teratogenicity.     

Maternal exposure to diphenhydramine during the fetal period in rats: effects on physical and neurobehavioral development and on neurochemical parameters

Previous research from our laboratory suggested that the administration of antihistaminics (H(1) receptor antagonists) to pregnant Wistar rats throughout pregnancy altered brain sexual differentiation and dopaminergic physiology of the offspring. In the present study, we assessed the effects of 20 mg/kg diphenhydramine (DPH) administration to pregnant rats during the fetal period of pregnancy [Gestation Days (GDs) 16-21], a critical period for brain sexual differentiation and central nervous system (CNS) maturation. Maternal body weight and water and food consumption were measured during pregnancy and offspring physical and behavioral development were evaluated during lactation. Offspring open-field behavior was assessed at 21 and 100 days of age. After the final open-field test, male and female sexual behavior, stereotypy following an apomorphine challenge, striatal content of dopamine (DA), the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA), serotonin (5-HT) and the serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA) were assessed. There were no significant treatment-related changes in maternal reproductive parameters, but DPH treatment decreased maternal body weight gain during the treatment period. Offspring physical parameters were not altered in the treated group, and no significant treatment-related changes were found in female open-field measures, sexual behavior or in striatal neurochemical measurements. However, delayed testis descent and altered patterns of sexual behavior occurred in male offspring accompanied by increased striatal DA, decreased striatal DOPAC as well as reduced DOPAC/DA, HVA/DA and 5-HIAA/5-HT ratios. Taken together, these data suggest that exposure to DPH during the fetal period of rat development altered postnatal CNS maturation and sexual development of male offspring via changes in striatal bioamine systems.     

Biomarkers in assessing residential insecticide exposures during pregnancy and effects on fetal growth

The Columbia Center for Children's Environmental Health is using a combination of environmental and biologic measures to evaluate the effects of prenatal insecticide exposures among urban minorities in New York City. Of the 571 women enrolled, 85% report using some form of pest control during pregnancy and 46% report using exterminators, can sprays, and/or pest bombs. Chlorpyrifos, diazinon, and propoxur were detected in 99.7-100% of 48-h personal air samples collected from the mothers during pregnancy (n = 394) and in 39-70% of blood samples collected from the mothers (n = 326) and/or newborns (n = 341) at delivery. Maternal and newborn blood levels are similar and highly correlated (r = 0.4-08, P < 0.001). Levels of insecticides in blood samples and/or personal air samples decreased significantly following the 2000-2001 U.S. Environmental Protection Agency's regulatory actions to phase out residential use of chlorpyrifos and diazinon. Among infants born prior to 1/1/01, birth weight decreased by 67.3 g (95% confidence interval (CI) -116.6 to -17.8, P = 0.008) and birth length decreased by 0.43 centimeters (95% CI, -0.73 to -0.14, P = 0.004) for each unit increase in log-transformed cord plasma chlorpyrifos levels. Combined measures of (ln)cord plasma chlorpyrifos and diazinon (adjusted for relative potency) were also inversely associated with birth weight and length (P 0.8). Results support recent regulatory action to phase out residential uses of these insecticides.     

Chronic cadmium exposure during pregnancy in the mouse: influence of exposure levels on fetal and maternal uptake

The uptake and distribution of orally administered cadmium-109 was studied in pregnant mice. Female outbred QS mice were given cadmium (Cd) supplemented drinking water for 1 mo before pregnancy and for the duration of pregnancy. The water contained either 0.0015 ppm Cd, 0.24 ppm Cd, or 40 ppm Cd. For the duration of pregnancy, 1.48 micrograms Cd/l (0.0015 ppm) in each solution was in the form of 109Cd (1 mCi/l). Control mice were given distilled/deionized water. On the day before term the mice were killed and a variety of adult and fetal tissues were examined in a gamma counter to determine their 109Cd concentrations. For each group the 109Cd concentration was highest in the maternal gastrointestinal tract, liver, and kidneys and lowest in the central nervous system (CNS) and blood. In general, the 109Cd concentrations in each organ were similar for each group of mice and were therefore independent of the overall oral Cd dose. A notable exception was the lower level in the duodenum in the 40 ppm group. In the fetal unit the chorioallantoic placenta contained the highest concentration of 109Cd. Concentrations in the fetuses were very low, comparable to those in the adult CNS. The 109Cd levels in the fetuses from group A were about fivefold greater than those of the fetuses from group C. There was no statistically significant evidence of specific localization in the fetal brain, kidney, or liver.     

Asthma, asthma medications and their effects on maternal/fetal outcomes during pregnancy

Maternal asthma may increase the risk of adverse fetal and maternal outcomes such as low birth weight, perinatal mortality, preterm birth, preeclampsia, hypertensive disorders, maternal mortality, uterine hemorrhage, and gestational diabetes. Controlling asthma during pregnancy with appropriate medications leads to improved intrauterine growth of the fetus and fewer adverse perinatal outcomes. Prospective population or birth cohort studies have shown that the medications used to treat asthma, such as bronchodilators (short-acting β2-agonists) and controller medications (inhaled corticosteroids, cromones, theophylline, leukotriene inhibitors), have no or minimal effects on fetal growth, and perinatal complications are reduced when maternal asthma is adequately controlled. However, taking oral corticosteroids during pregnancy may confer increased risk of lower birth weight and congenital malformations. Therefore, managing pregnant asthmatics requires a careful benefit–risk analysis, and when indicated, the benefits of a medication that may have increased risks can dictate its use in severe uncontrolled asthma.     

Maternal passive smoking during pregnancy and fetal developmental toxicity. Part 1: gross morphological effects.

1. Prenatal exposure of human fetus to tobacco smoke through maternal passive smoking has been epidemiologically linked to reduced birth weight, enhanced susceptibility to respiratory diseases and changes in immune system. However, no data exists indicating teratogenicity of involuntary smoking. Since sidestream smoke of cigarettes makes the most constituent of whole smoke inhaled by nonsmokers, we performed experiments to determine whether passive inhalation of sidestream smoke by rats causes malformations in newborns. 2. Pregnant 230 - 300 g Wistar rats were each placed in a 150 dm3 glass chamber with two holes, each 3 cm in diameter in two opposite walls to provide unforced exchange of fresh air. A third hole was connected to an automatic smoking machine. The head of a commercial filter blond cigarette (13 mg Tar, 0.9 mg Nicotine) was introduced to the chamber through this later hole. Cigarettes were smoked by smoking machine at the rate and volume resembling human smoking and the mainstream smoke was separately collected and discarded. Each rat thus received the sidestream smoke self-diluted in the chamber air. Experiments were performed with either 1, 2, 3 or 4 cigarettes/day during either first, second or third week of a total 21-day pregnancy period. The interval between smoking of cigarettes was 2 h. 3. COHb in blood of negative controls was about 1.2% and after exposure to 1 or 4 cigarettes were 6% and 12.2%, respectively. A dose-dependent reduction of birth weight was observed in newborns (P<0.001); bitemporal diameters and body lengths were reduced accordingly. No macroscopically visible gross anomaly could be observed. After removing the fat tissue and staining the skeleton with alizarin, a widespread ossification retardation could be observed in all exposed groups regardless of the dose. Such a retardation was not limited to a particular bone. 4. These results support epidemiologic data on developmental toxicity of passive smoking and further provide evidence on an unfavorable osteopathic effect of sidestream exposure of mother on fetal development.     

Smoking and carbon monoxide levels during pregnancy

Self-reports of smoking status and breath tests for carbon monoxide were collected in prenatal outpatients. The breath test for carbon monoxide appeared to be a valid and specific measure of smoking status during pregnancy. Of the 179 patients surveyed, 99 reported they had smoked during the present pregnancy. Nineteen of the smokers reported they had quit during the present pregnancy and 46 reported that they smoked fewer cigarettes than at the beginning of their pregnancy. Most of the quitters and reducers stated that they had stopped or reduced their intake early in pregnancy and for pregnancy-related reasons; however, neither parity, nausea or vomiting, marital status, nor requests of physicians or family were associated with higher rates of smoking cessation or reduction. Most of the pregnant smokers were interested in stopping smoking, but few attended a free treatment program.     

Dapsone therapy for malaria during pregnancy: maternal and fetal outcomes.

The need to consider using dapsone in pregnant women for its antimalarial activity is becoming greater in areas where Plasmodium falciparum resistance to chloroquine and pyrimethamine-sulfadoxine is rapidly increasing. Dapsone in combination with other antimalarials might provide a valuable alternative for both treatment and prophylaxis. This review assesses the clinical pharmacology of dapsone and its adverse drug reactions in relation to haemolysis, glucose-6-phosphate dehydrogenase (G6PD) deficiency, blood dyscrasias and methaemoglobinaemia. Studies are summarised reporting its use in leprosy, dermatological and other conditions, and malaria, in relation to maternal and infant outcomes. A total of 924 pregnancies were identified during which dapsone therapy was taken. Only limited data are available and this precludes a meaningful quantitative benefit-risk analysis.Mild degrees of haemolysis consistently occur with continued therapy, although adverse effects may be less likely with intermittent treatment, as most reported adverse effects have occurred with long-term use of dapsone. There are a number of gaps in knowledge where more data are needed. These include no data on pharmacokinetics in pregnancy and whether these are altered with co-administration of chlorproguanil. Potential complications in women with severe anaemia are unknown and there is no information on haemolytic effects in women or the fetus with G6PD deficiency. The use of dapsone in HIV-infected women in malarious areas could carry increased risks because of the immunosuppressive actions of the drug. Trials of dapsone therapy in pregnancy should be considered in malarious areas where there is good reason for its deployment. Controlled trials have provided data on maternal tolerance, and dapsone in combination with other antimalarial drugs can offer clear benefit in terms of improved birthweight. The use of dapsone combinations should be considered when no good alternative is available and the threat of malaria is the greater risk.     

Alterations in brain catecholamines during pregnancy

During pregnancy mice are more susceptible to flurothyl-induced seizures than are non-pregnant controls. The potential role of brain catecholamines in mediating this behavior was examined in the present study. The concentration and turnover of norepinephrine (NE) and dopamine (DA) were measured in hippocampus, striatum, midbrain and cortex in control, pregnant and delivery-day mice. There were no significant changes from control in DA levels during pregnancy and parturition. The turnover of DA was not altered during pregnancy, except for a small increase in turnover rate in the hippocampus. The concentration of NE decreased during pregnancy, and rose at parturition. This effect was most striking in the hippocampus. The turnover of NE was markedly depressed during pregnancy, with the hippocampus again being most affected. These data imply a role for NE, but not DA in the mediation of increased seizure susceptibility during pregnancy.     

Phencyclidine: Effects on motor activity and brain biogenic amines in the guinea pig

Previous reports suggesting that the behavioral response of the guinea pig to phencyclidine (PCP) administration is more similar to the effects of PCP observed in higher animals than those observed in mice and rats prompted us to investigate the effects of PCP on spontaneous motor activity and brain biogenic amine levels in the guinea pig. Doses of 2.5 and 5.0 mg/kg PCP were found to significantly elevate spontaneous motor activity; however, 7.5 mg/kg PCP produced highly variable results which were not significantly different from control. The concentrations of tryptophan, serotonin, 5-hydroxyindoleacetic acid, and norepinephrine were measured in the forebrain and hindbrain of previously drug naive animals 30min after administration of 5 mg/kg PCP. As compared to saline injected control animals, PCP was observed to have no effect on any of the neurochemical determinants measured. Contrary to previous reports, these data suggest that PCP produces behavioral effects in the guinea pig which are not unlike those observed in mice and rats. Furthermore, the effects which we report on spontaneous motor activity are not related to changes in the regional concentration of any of the neurochemical variables which were measured.     

Ortho-iodosobenzoic acid: its acute toxicity and neurobehavioral effects in mice

o-Iodosobenzoic acid (IBA), in a surfactant micellar medium, is a rapid and efficient catalyst for the hydrolysis of organophosphate (OP) esters. Since little is known about the toxicity of IBA, a primary screen of neurobehavioral toxicity was evaluated in male ICR mice. IBA was administered intraperitoneally in a pH 7.4 phosphate buffer solution containing 8% dimethylformamide. The predominant overt signs of toxicity included an immediate and transient writhing reflex and/or persistent spasmodic myotwitching of the abdomen, and conspicuous suppression of orienting/exploratory behavior and emotional defecation. The dose ranges for ED50 of writhing response, suppression of rearing and spontaneous motor activity overlapped at levels of about one-tenth the acute LD50, 742 (633-856) mumol/kg, being 94.9 (74.5-122.5), 69.8 (47.9-105.4) and 71.1 (49.9-101.3) mumol/kg, respectively; the dose ranges for ED50 of abdominal myotwitching and depression of emotional defecation in a novel environment also overlapped but at levels of about one-fifth the acute LD50, being 138.4 (115.3-167.2) and 146.2 (110.7-196.3) mumol/kg, respectively. Morphine (1.25-10 mg/kg s.c.) antagonized the IBA-induced writhing response and abdominal myotwitching in a dose-dependent manner, with a PD50 of 4.2 and 4.9 mg/kg, respectively. The present report demonstrates that acute intraperitoneal administration of IBA produces an intriguing, non-specific behavioral syndrome, probably resulting from nociceptive stimulation. This implies that IBA might be irritating to the skin and mucosa.     

Effects of caffeine administered during pregnancy on fetal development and subsequent function in the adult rat: prolonged effects on a second generation

Caffeine, when administered in moderate (30 mg/kg X d) or high (60 mg/kg X d) doses during pregnancy, was shown to cause significant fetal growth retardation of both sexes. Mortality rate at or soon after birth was significantly higher and litter size significantly lower in the litters treated with 60 mg. The subsequent growth rates were also affected. The experimental pups grew more slowly, with growth plateauing at the same age resulting in smaller adults. The male offspring when subjected to short-term stress (one session) in adulthood showed an intact emergency response, demonstrating an adequate ability to react to a sudden environmental change. A significant decrease in 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity, and consequent reduction in testosterone biosynthesis, in the fetal testes at d 18 and 20 of gestation was also found for both doses of caffeine. Low 3 beta-HSD activity persisted to adulthood in the group receiving 60 mg. Lingering effects were observed in a second litter bred 8 wk after the discontinuation of caffeine consumption. In this second breeding, the offspring of both sexes from both caffeine doses were born significantly smaller when compared to the controls. Persistent effects of caffeine were also found in second-generation rats bred from females who were exposed to caffeine in utero. The pups of both sexes were born significantly heavier after a significantly longer gestation. The subsequent growth did not differ from that of the controls. It was suggested that a changed genetic program in the ovarian germ cells of the first generation and/or a changed uterine environment in the second generation may be implicated.     

Phencyclidine Ingestion: Drug Abuse and Psychosis

Phencyclidine (PCP) is a popular illicit drug often misrepresented as some other hallucinogenic substance and distributed in widely varying dosage forms and strengths. Users of hallucinogenic drugs may present with unintentional PCP overdoses. Toxicological laboratory analyses are essential to establish the diagnosis. In nine admitted overdose patients, the consciousness level ranged from alert to comatose on presentation, and all showed a prolonged recovery phase with agitation and toxic psychosis. Severe behavior disorder, paranoid ideation, and amnesia for the entire period of in-hospital stay are characteristic. In very high dose patients, shallow respiratory excursions and periods of apnoea and cyanosis coincided with generalized extensor spasm and spasm of neck muscles. Excessive bronchial secretions, gross ataxia, opisthotonic posturing, and grimacing occur. PCP toxic psychosis should be considered in drug-abusing patients presenting with schizophrenic-like symptoms, psychosis, or other bizarre behavior, whether or not they admit to taking PCP.     

A comparison of active and passive smoking during pregnancy: long-term effects

Previous research has determined that maternal smoking during pregnancy is associated with negative effects for the child at birth and throughout childhood. Much less is known about the consequences of exposure to secondary smoke during fetal development. The present study investigates and compares the long-term consequences of active and passive smoking during pregnancy. Ninety-one children between the ages of six and nine years were tested using a comprehensive neuropsychological test battery. After considering potential confounds, children of nonsmoking mothers generally were found to perform better than the two smoking groups on tests of speech and language skills, intelligence, visual/spatial abilities and on the mother's rating of behavior. The performance of children of passive smokers was found, in most areas, to be between that of the active smoking and nonsmoking groups. It was concluded that there is a continuum of long-term smoking effects and that, although active maternal smoking is associated with effects of greater breadth and magnitude than passive maternal smoking, children of passive smokers are also at risk for a pattern of negative developmental outcomes.