Tocopherols, retinol, beta-carotene and fatty acids in fat globule membrane and fat globule core in cows'' milk

To develop and characterize a murine model for investigating the long-term effects of prenatal cocaine exposure, the present study established the route of drug administration and the doses to be used for pregnant C57BL/6 mice. Comparison of the effects of a high dose of cocaine (60 mg/kg) when gavaged or injected subcutaneously (SC) established patterns of pathology characteristic of administration route but no dominating logic for selecting one over the other route for prenatal studies; however, because of the fourfold greater brain levels, with no evidence of greater pathology, the SC route was selected. When injected daily during gestation days 12-18, the period of prenatal development of dopamine systems, cocaine at doses producing plasma concentrations consistent with its stimulatory effects reduced food ingestion and weight gains during pregnancy and fetal body and brain weights at term. The extent of these reductions was comparable to reports on babies exposed to cocaine prenatally. Furthermore, the present study suggests that maternal undernutrition is not a likely mediator of these perinatal effects and that differences in the amount of cocaine exposure may cause the contrasting effects of maternal cocaine noted in the human literature.     

Central administration of cocaine produces age-dependent effects on behavior in the fetal rat.

Rat fetuses were exposed to cocaine, lidocaine, or saline on Gestational Day 20 or 21 to provide information about cocaine effects on behavior during prenatal development. Cocaine was administered into the cisterna magna of individual fetal subjects to restrict effects to the CNS. Behavioral effects of cocaine were compared with lidocaine to help distinguish the effects of cocaine on monoamine systems in the brain from its properties as a local anesthetic. Cocaine promoted 3–5 fold increases in fetal motor activity in the absence of explicit sensory stimulation, in contrast to the slight suppressive effects of lidocaine. Cocaine and lidocaine also reduced coordinated behavioral responses to an artificial nipple. The behavioral effects of cocaine administered into the CNS of fetal subjects suggest specific mechanisms of action on developing neural and behavioral systems in the late prenatal period. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prenatal cocaine delays astroglial maturation: immunodensitometry shows increased markers of immaturity (vimentin and GAP-43) and decreased proliferation and production of the growth factor S-100

Exposure to cocaine during fetal development has been demonstrated to produce a variety of brain and behavioral changes. Cocaine is a potent releaser of a variety of neurotransmitters, such as serotonin, which act as developmental signals. Since serotonin plays an important role in astroglial maturation, migration, and growth factor production (e.g. S-100 beta), we proposed that these properties of astroglial cells will be altered in a brain prenatally exposed to cocaine. To observe cocaine's effects on astroglial development, we performed immunocytochemical analyses of a variety of developmental protein makers including BrdU, Gap-43, vimentin, and S100 beta. Our results demonstrate that prenatal cocaine administration produces decreased cell proliferation as measured by BrdU staining, retarded neurite outgrowth as ascertained by increased Gap-43 immunoreactivity, increased density of vimentin-positive radial glial cells, and diminished tissue S100 beta immunoreactivity. Overall, these results suggest that cocaine delays astroglial development. This delay would have profound effects on neuronal development and outgrowth and, thus, development of the entire brain.     

Prenatal cocaine, alcohol, and undernutrition differentially alter mineral and protein content in fetal rats

Alcohol exposure and undernutrition during pregnancy have been associated with altered fetal body composition. Recent observations suggest that cocaine exposure during pregnancy may impair delivery of nutrients to the fetus and could thereby alter body growth and composition. Such effects are important because they can adversely influence physical and neural development. Consequently, we investigated the dose-dependent effects of cocaine on fetal body composition in an animal (rat) model and compared such effects with those caused by prenatal alcohol exposure and undernutrition. Pregnant Sprague-Dawley rats received either 20, 30, 40, or 50 mg/kg cocaine HCl (SC) twice daily from gestation days 7 through 19. Pair-fed (undernutrition) and untreated control groups and a group receiving 3.0 g/kg alcohol (PO) twice daily served as comparison groups (n = 11 to 14/group). Females were sacrificed on gestation day 20. One male and one female fetus was removed from each dam. The fetuses were minced, dehydrated, defatted, and analyzed for content of protein and the minerals Zn, Ca, Fe, Mg, K, and Na. In terms of concentration per unit of fat-free dry solids, male fetuses in the cocaine groups showed significant decreases in protein compared to untreated controls (15+/-3 to 20+/-2 mg/g vs. 24+/-4 mg/g, p = 0.01). There was a significant treatment effect for Ca (p < 0.05), reflecting a trend for decreased Ca concentrations in the fetuses of the cocaine and undernutrition groups. Male fetuses in the alcohol group had significantly elevated Mg levels compared to male fetuses in the other groups (3.0+/-0.8 vs. 1.0+/-0.2 to 2.3+/-0.7 mg/g, p < 0.05). There were some sex differences, with female fetuses having significantly lower concentrations of Mg, Fe, K, and higher protein concentrations than male fetuses. Although the effects were few and modest, these results suggest that prenatal cocaine, alcohol, and undernutrition can differentially alter fetal body weight and composition and, therefore, adversely influence fetal development.     

Prenatal cocaine exposure and child development: what do we know and what do we do?

The literature remains unclear about the effects of prenatal cocaine exposure on child development. Meanwhile, the implications for public policy and treatment and for our scientific understanding of the toxicity of cocaine are substantial. In this article we describe; (1) our current understanding of the effects of prenatal cocaine use and child outcome, (2) the issues that need to be investigated, and (3) implications for treatment of cocaine exposed children. Findings from our database of the published literature shows that our knowledge is still limited, scattered, and compromised by methodological problems that mitigate any conclusions about whether or not or how prenatal cocaine exposure affects child outcome. The cocaine problem is more complicated than first envisioned--it is a multifactorial problem including the use of other drugs, parenting, and environmental lifestyle issues. However, we also show that, even though the effects may be more subtle than initially anticipated, prenatal cocaine exposure will substantially increase in the number of school age children who will need special education services. Clinicians working with these children and families need to be prepared to address psychosocial and environmental issues, as well as developmental performance, in order to optimize their assessment and intervention.     

Children's cognitive ability from 4 to 9 years old as a function of prenatal cocaine exposure, environmental risk, and maternal verbal intelligence.

This study examined the effects of prenatal cocaine exposure, environmental risk, and maternal verbal intelligence on children's cognitive ability. Gender and age were examined as moderators of potential cocaine exposure effects. The Stanford-Binet IV intelligence test was administered to 231 children (91 cocaine exposed, 140 unexposed) at ages 4, 6, and 9 years. Neonatal medical risk and other prenatal exposures (alcohol, cigarettes, and marijuana) were also examined for their unique effects on child IQ. Mixed models analysis indicated that prenatal cocaine exposure interacted with gender, as cocaine-exposed boys had lower composite IQ scores. Age at assessment did not moderate this relation, indicating that cocaine-exposed boys had lower IQs across this age period. A stimulating home environment and high maternal verbal IQ also predicted higher composite IQ scores. Cocaine-exposed boys had lower scores on the Abstract/Visual Reasoning subscale, with trends for lower scores on the Short-Term Memory and Verbal Reasoning subscales, as exposure effects were observed across domains. The findings indicate that cocaine exposure continues to place children at risk for mild cognitive deficits into preadolescence. Possible mechanisms for the Exposure × Gender interaction are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Choline supplementation following third-trimester-equivalent alcohol exposure attenuates behavioral alterations in rats.

Despite the known adverse consequences of prenatal alcohol exposure, some pregnant women continue to drink alcohol, making it imperative to identify treatments for children with fetal alcohol spectrum disorders. The authors recently reported that perinatal choline supplementation can reduce some fetal alcohol effects (J. D. Thomas, M. Garrison, & T. M. O'Neill, 2004), and the present study examined whether choline supplementation is effective when administered after third-trimester-equivalent ethanol treatment. Rat pups were exposed to 6.0 g/kg/day ethanol during the neonatal brain growth spurt (Postnatal Days [PD] 4-9) and treated with choline chloride (0, 10, 50, or 100 mg/kg) from PD 10-30. Behavioral testing occurred after choline treatment had ceased. Female subjects exposed to ethanol were overactive and exhibited spatial learning deficits, effects that were attenuated with all doses of choline supplementation. These data indicate that choline supplementation can alter brain development following a developmental insult. Moreover, the data suggest that early dietary interventions may reduce the severity of some fetal alcohol effects, even when administered after birth. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Human energy and work in a European village

In a mouse model of transplacental cocaine exposure we have demonstrated alterations in brain structure and function of offspring including disturbances of brain growth, disruption of neocortical cytoarchitecture, and transient as well as persistent behavioral deficits. One mechanism by which cocaine may alter fetal brain development is through cocaine-induced alpha-adrenergic-mediated (uterine) arterial vasoconstriction. In this study pregnant Swiss Webster (SW) mice were injected with cocaine HCl (20 or 40 mg/kg, SC) without any changes evident in mean arterial blood pressure (MAP) measurements. These physiology results suggest that in our mouse model, cocaine's transplacental effects on the fetus are not due to cocaine-induced maternal vasoconstriction, nor concomitant hypoperfusion of the fetus. In a separate series of experiments, pregnant SW dams were administered cocaine HCl at 40 mg/kg/day (COC 40), 20 mg/kg/day (COC 20), or 10 mg/kg/day (COC 10) [SC, divided in two daily doses, from embryonic day (E) 8 to E17 inclusive]. Additional groups of cocaine-treated dams were administered phentolamine (5 mg/kg, SC), a short-acting alpha-adrenergic antagonist, 15 min prior to each cocaine dose (Phent COC 40, Phent COC 20, Phent COC 10). Animals born to Phent COC 40 dams demonstrated transient postnatal brain growth retardation and behavioral deficits in first-order conditioning of P9 mice comparable to mice born to COC 40 dams, which received the same regimen of cocaine injections without phentolamine pretreatment. Like COC 40 offspring, Phent COC 40 offspring also demonstrated a persistent deficit in the blocking paradigm. The behavioral and growth findings confirm and extend the physiology data, and imply that in our rodent model, alpha-adrenergic mechanisms (including maternal vasoconstriction) are unlikely to mediate these toxic effects of transplacental cocaine exposure on developing brain.     

Alterations in the reinforcing efficacy of cocaine in adult rats following prenatal exposure to cocaine.

Adult male rats gestationally exposed to cocaine and nonexposed control offspring were examined for differences in operant responding for cocaine and sucrose reinforcement. Offspring were derived from dams that had received subcutaneous injections of 40 mg/kg/3cc cocaine hydrochloride daily on gestational Days 8–20 and nontreated control dams. Although no prenatal treatment differences were seen when the animals lever pressed for sucrose pellets on a progressive-ratio (PR) schedule, adult offspring prenatally exposed to cocaine were observed to exhibit an enhanced rate of cocaine intravenous self-administration on a fixed-ratio 5 (FR-5) schedule along with a marked decrease in break point on the PR reinforcement schedule. These results suggest that the reinforcing efficacy of cocaine may be reduced in animals with a prenatal history of cocaine exposure. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of prenatal ethanol exposure on parvalbumin-expressing GABAergic neurons in the adult rat medial septum

Exposure of human fetuses to ethanol often results in the fetal alcohol syndrome. Animal models of fetal alcohol syndrome have been developed and used to examine the consequences of prenatal ethanol exposure on the central nervous system. The objective of this study was to determine the long-term effects of prenatal ethanol exposure on parvalbumin-expressing (PA+) GABAergic neurons of the rat medial septum. Pregnant Long-Evans rats were maintained on 1 of 3 diets from gestational day 0 to 21: an ethanol-containing liquid diet in which ethanol accounted for 35% of the total calories, a similar diet with the isocaloric substitution of sucrose for ethanol, or a lab chow control diet. Offspring were killed on postnatal day 60, and their brains were prepared for parvalbumin immunocytochemistry. Female rats exposed to the ethanol-containing diet during gestation had 42% fewer PA+ neurons in the medial septum and reduced PA+ cell density when compared with female rats exposed to the sucrose diet. Ethanol females also had fewer PA+ neurons per unit volume than sucrose females. Male rats exposed to ethanol did not display a similar reduction in PA+ neurons or density. No effect of prenatal diet was found on the area or volume of the medial septum, nor were cell diameters affected. As such, prenatal exposure to ethanol seems to reduce permanently the number of PA+ neurons in the female rat medical septum without affecting area, volume, or neuronal size. Functional implications and possible relations to the fetal alcohol syndrome are discussed.     

Expression of sex-specific molecular markers in clones of bipartite allophenic nemertines produced by somatic embryogenesis from Lineus sanguineus male/female chimera fragments

Previous studies had demonstrated that in utero exposure to cocaine produces structural changes in the development of the rabbit's anterior cingulate cortex. Because the anterior cingulate cortex has been proposed to subserve a variety of cognitive processes including associative learning, we investigated the effects of intrauterine exposure to cocaine on the acquisition of the rabbit's classically conditioned nictitating membrane response. Adult, sexually mature rabbits born of dams that had received intravenous injections of either saline or cocaine (4 mg/kg, twice a day) from day 8 to day 29 of gestation were classically conditioned by pairing tone and light CSs with an airpuff US. Rabbits that had been exposed to cocaine in utero demonstrated a more rapid acquisition of CRs to a tone CS but not to a light CS as compared with saline controls. Control experiments indicated that the accelerated learning to the tone CS was not due to sensitization, pseudoconditioning, altered baseline rate of responding, an increased responsiveness to the airpuff US, or to a change in the intensity threshold of the tone CS for elicitation of CRs. We conclude that in utero exposure to cocaine alters the processing of auditory stimuli and this leads to an abnormally rapid acquisition of CRs. It is suggested that this functional consequence of prenatal exposure to cocaine is due to structural abnormalities in anterior cingulate cortex.     

Study of platelet-activating factor acetylhydrolase in the perioperative period of patients undergoing cardiac surgery

This study was conducted to determine whether brief, intermittent exposure to hypoxia with little change in nutrient intake would affect fetal growth. Pregnant rats were exposed to 1 or 2 h of hypoxia (FiO2 = 0.09-0.095) from days 15 to 19 of gestation. Exposure to 1 h of hypoxia decreased fetal body weight and length, liver weight and increased the brain/liver weight ratio (p < 0.05) as compared to controls. Two hours of hypoxia decreased fetal body weight and length, and heart, lung, kidney, gut, brain and liver weights (p < 0.01), but did not affect the brain/liver weight ratio. Two hours of hypoxia decreased maternal food intake and weight gain (p < 0.05), but fetal growth was not significantly altered in pair-fed controls. These data demonstrate that brief, intermittent periods of intrauterine hypoxia have significant effects on fetal growth.     

Changes in dopamine, serotonin and their metabolites in discrete brain areas of rat offspring after in utero exposure to cocaine or related drugs

The concentrations of dopamine (DA), serotonin (5HT) and their metabolites were quantified in 5 brain areas of rats exposed to saline, cocaine (15 mg/kg b.i.d.), amitriptyline (10 mg/kg), or amfonelic acid (AFA, 1.5 mg/kg) throughout gestation. Male pups from 3 similarly treated dams were fostered to 2 surrogate dams. The process of breeding and rearing was repeated 4 times with new dams to build the groups to 4-12, since only one pup per litter was used for any one measurement. AFA was used to mimic the dopamine (DA) uptake blockade and stimulant properties of cocaine and amitriptyline was used to mimic the other pharmacological effects of cocaine. At postnatal days (PND) 30, 60, and 180, one pup per litter was removed for HPLC analysis of monoamines. A second pup received 0.3 mg/kg haloperidol, catalepsy assessed after 1 hr, and the brain used for analysis. The cataleptic response to haloperidol was unaffected by any prenatal treatment. The striatum from PND 30 cocaine rats had decreased levels of DA without a decrease in DA metabolites. At PND 60 in cocaine exposed rats, DA and DOPAC concentrations were increased, and 5HT levels were decreased in the striatum. The amitriptyline-exposed group exhibited decreased 5HT and 5-HIAA levels in the striatum. The hypothalamus of the cocaine group had lower levels of 5-HIAA, and other brain areas had a trend for lower levels of 5HT and 5-HIAA. At PND 180, DOPAC was increased in the striatum and prefrontal cortex of the cocaine group. Haloperidol-induced altered monoamine metabolism was unaffected by any prenatal treatment at any age. These data suggest that age-related changes in the DA and 5HT neurotransmission systems occur in rats exposed prenatally to cocaine. However, the ability of the dopaminergic system to respond to a challenge by a DA receptor blocker is unaltered by these in utero treatments.     

Acute effects of cocaine on ornithine decarboxylase activity in fetal and neonatal rat heart: evidence for cardiotoxicity

Fetal exposure to cocaine is associated with increased perinatal cardiac risk. In the current study, we examined the effects of acute cocaine administration on ornithine decarboxylase (ODC) activity in fetal and neonatal rat heart. ODC is a key regulatory enzyme in the control of cell differentiation and growth, and rapid changes in ODC are associated with the response to cell injury. Administration of 30 mg/kg s.c. of cocaine to pregnant rats on the 20th day of gestation caused acute elevation of fetal cardiac ODC that persisted throughout the ensuing 24 h. In contrast, the same dose given directly to neonatal rats the day after birth evoked only a short-term (1-h) stimulation of ODC that was reversed by 4 h after treatment. By 4 days of age and subsequently, cocaine was unable to elicit acute stimulation of heart ODC and only evoked inhibition of enzyme activity. Elevated progesterone levels during pregnancy have been shown to sensitize the maternal myocardium to cocaine-induced catecholaminergic effects; the greater sensitivity of fetal heart ODC to cocaine, as compared to neonatal heart, supports the hypothesis that similar enhancement of fetal cardiac irritability can contribute to cocaine-induced cell damage.     

Prenatal cocaine but not prenatal malnutrition affects foster mother-pup interactions in rats

The separate and combined effects of prenatal cocaine exposure and malnutrition on mother-pup interactions in rats were assessed daily from postnatal day 2 to day 21. Sprague-Dawley dams were fed a diet of low protein content (6% casein), an isocaloric diet of adequate protein content (25% casein, control), or a laboratory chow diet prior to mating and throughout pregnancy. Within each diet group, rats received either cocaine injections (30 mg/kg IP two times per week prior to mating and then 30 mg/kg SC daily from days 3 to 18 of pregnancy) or saline injections. Litters were fostered on the day of birth to control mothers (i.e., nondrug-exposed dams fed the control or chow diet). Foster mothers fed the 25% casein diet showed increased contact with cocaine-exposed pups compared with nondrug-exposed pups in the second postnatal week but lower levels as the pups approached weaning. Passive nursing was increased in dams caring for prenatally malnourished, cocaine-exposed pups compared with those caring for similar pups with no drug exposure. Chow-fed mothers did not differ in their behavior towards pups with or without prenatal cocaine treatment. Prenatal cocaine and malnutrition independently compromised birth weight and various reflexive milestones but the attainment of physical milestones was affected only by prenatal cocaine. There were no additive effects of the two prenatal insults on any measure of mother-pup interaction or pup development.     

Schizophrenia: prenatal influenza and autoimmunity

The schizophrenic syndrome may represent a stereotyped response by the developing brain to various insults, including micro-organisms. We review studies that have examined the association between schizophrenia and infectious agents, and examine the current evidence for the hypothesis that exposure to influenza during fetal life increases the risk of later schizophrenia. A prenatal autoimmune basis for some cases of schizophrenia is proposed.     

Relationship of prenatal cocaine exposure and maternal postpartum psychological distress to child developmental outcome

Maternal cocaine use during pregnancy can affect the infant directly through toxic effects or indirectly through cocaine's influence on maternal psychological status. We followed 160 cocaine exposed and 56 nonexposed infants and their mothers identified at birth through interview and/or urine screen. Although cocaine exposure defined the groups, infant exposure to alcohol, marijuana, and tobacco was allowed to vary. Infants were 99% African American and poor. All mothers completed the Brief Symptom Inventory (BSI) and infants were given the Bayley Scales of Mental (MDI) and Motor (PDI) Development at a mean corrected age of 17 +/- 8 months. Both MDIs (94 +/- 17 vs. 103 +/- 16) and PDIs (101 +/- 16 vs. 108 +/- 12) were lower for cocaine exposed infants. Psychological distress was greater in cocaine using mothers. Hierarchical multiple regression was used to assess the relative effects of gestational age, maternal psychological distress, and cocaine and polydrug exposure on infant outcomes. Both psychological distress and cocaine and alcohol exposure predicted lower MDIs after controlling for prematurity. Neither psychological distress nor alcohol exposure predicted motor outcome, while cocaine had a significant effect. Tobacco and marijuana exposure were unrelated to outcome. These findings provide further support for direct effects of cocaine and alcohol on infant development as well as highlight the need for studies to document maternal psychological factors, which may increase child risk for poorer outcomes.     

Enduring Effects of Prenatal Cocaine Exposure on Selective Attention and Reactivity to Errors: Evidence From an Animal Model.

Adult Long-Evans rats, exposed prenatally to 1 of 4 doses of cocaine (0.0,0.5,1.0, or 3.0 mg/kg iv), were tested on a 3-choice visual attention task with an olfactory distractor presented unpredictably on one third of the trials. The performance of all 3 cocaine-exposed groups was significantly more disrupted than that of controls by the presentation of distractors. Results demonstrate that prenatal cocaine exposure increases susceptibility to distractors, using a task specifically designed to measure this function. In addition, the present study revealed that individuals exposed to cocaine in utero exhibit greater performance disruption after an error than controls, in certain types of tasks. Both areas of dysfunction, impaired selective attention and impaired arousal regulation, have important functional consequences in humans, possibly affecting the school performance and social development of cocaine-exposed children. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prolonged stress-induced elevation in plasma corticosterone during pregnancy in the rat: implications for prenatal stress studies

Experiments were conducted to test the hypothesis that exposure to uncontrollable stress during pregnancy results in a heightened elevation of plasma glucocorticoids. Rats were exposed to uncontrollable electric tail shocks every other day during the 3 weeks of pregnancy. Plasma corticosterone concentrations in stressed dams increased significantly from gestation days 4 to 20. Importantly, this increase in plasma corticosterone occurred 24- and 48-h after exposure to stress suggesting a prolonged elevation in stress-induced glucocorticoid secretion. In addition, the stress-induced rise in plasma corticosterone was accompanied by a significant decrease in maternal levels of corticosteroid binding globulin which suggests increased circulating levels of free corticosterone. Significant stress-induced elevations in plasma corticosterone also occurred in fetuses that were examined on gestation day 20. Furthermore, a significant positive correlation was found between maternal and fetal plasma corticosterone. Results demonstrate that repeated exposure to uncontrollable stress increases plasma concentrations of glucocorticoids throughout pregnancy. In the unbound state, corticosterone may be highly effective in producing alterations in brain development of offspring. These data have important implications for understanding the process underlying the effects of prenatal stress.     

Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome

The fetal hydantoin syndrome is a variable pattern of altered growth and performance which includes unusual facies, distal phalangeal hyoplasia, and other defects occurring in some infants exposed in utero to hydantoins. A prospective study of 35 infants exposed prenatally to this class of anticonvulsants showed that 11% had sufficient features to be classified as having the fetal hydantoin syndrome. An additional 31% displayed some features compatible with the prenatal effects of hydantoins. A case-control study of 104 infants whose mothers received hydantoins during pregnancy supports these conclusions. Reduction of intellectual ability in infants with the fetal hydantoin syndrome is the area of greatest concern. Women being treated with hydantoin anticonvulsants should be told of the nature and magnitude of risks to the developing fetus before considering a pregnancy.