Concentration In Fetal Brain Research Articles

Considering developmental neurotoxicity invitro data for human health risk assessment using physiologically-based kinetic modeling: deltamethrin case study.

Developmental neurotoxicity (DNT) is a potential hazard of chemicals. Recently, an in vitro testing battery (DNT IVB) was established to complement existing rodent in vivo approaches. Deltamethrin (DLT), a pyrethroid with a well-characterized neurotoxic mode of action, has been selected as a reference chemical to evaluate the performance of the DNT IVB. The present study provides context for evaluating the relevance of these DNT IVB results for the human health risk assessment of DLT by estimating potential human fetal brain concentrations after maternal exposure to DLT. We developed a physiologically based kinetic (PBK) model for rats which was then translated to humans considering realistic in vivo exposure conditions (acceptable daily intake [ADI] for DLT). To address existing uncertainties, we designed case studies considering the most relevant drivers of DLT uptake and distribution. Calculated human fetal brain concentrations were then compared with the lowest benchmark concentration achieved in the DNT IVB. The developed rat PBK model was validated on in vivo rat toxicokinetic data of DLT over a broad range of doses. The uncertainty based case study evaluation confirmed that repeated exposure to DLT at an ADI level would likely result in human fetal brain concentrations far below the in vitro benchmark. The presented results indicate that DLT concentrations in the human fetal brain are highly unlikely to reach concentrations associated with in vitro findings under realistic exposure conditions. Therefore, the new in vitro DNT results are considered to have no impact on the current risk assessment approach.

Evaluation of a rapid, generic human gestational dose model

Chemical risk assessment considers potentially susceptible populations including pregnant women and developing fetuses. Humans encounter thousands of chemicals in their environments, few of which have been fully characterized. Toxicokinetic (TK) information is needed to relate chemical exposure to potentially bioactive tissue concentrations. Observational data describing human gestational exposures are unavailable for most chemicals, but physiologically based TK (PBTK) models estimate such exposures. Development of chemical-specific PBTK models requires considerable time and resources. As an alternative, generic PBTK approaches describe a standardized physiology and characterize chemicals with a set of standard physical and TK descriptors – primarily plasma protein binding and hepatic clearance. Here we report and evaluate a generic PBTK model of a human mother and developing fetus. We used a published set of formulas describing the major anatomical and physiological changes that occur during pregnancy to augment the High-Throughput Toxicokinetics (httk) software package. We simulated the ratio of concentrations in maternal and fetal plasma and compared to literature in vivo measurements. We evaluated the model with literature in vivo time-course measurements of maternal plasma concentrations in pregnant and non-pregnant women. Finally, we prioritized chemicals measured in maternal serum based on predicted fetal brain concentrations. This new model can be used for TK simulations of 859 chemicals with existing human-specific in vitro TK data as well as any new chemicals for which such data become available. This gestational model may allow for in vitro to in vivo extrapolation of point of departure doses relevant to reproductive and developmental toxicity.

High Accumulation of Methadone Compared with Buprenorphine in Fetal Rat Brain after Maternal Exposure.

Experimental animal studies are valuable in revealing a causal relationship between prenatal exposure to opioid maintenance treatment (OMT) and subsequent effects; however, previous animal studies of OMT during pregnancy have been criticized for their lack of clinical relevance because of their use of high drug doses and the absence of pharmacokinetic data. Hence, the aim of this study was to determine blood and brain concentrations in rat dams, fetuses, and offspring after continuous maternal exposure to methadone or buprenorphine during gestation and to examine the offspring for neonatal outcomes and withdrawal symptoms. Female rats were implanted with a 28-day osmotic minipump delivering methadone (10 mg/kg per day), buprenorphine (1 mg/kg per day) or vehicle 5 days before mating. Continuous exposure to methadone or buprenorphine induced stable blood concentrations in the dams of 0.25 ± 0.02 µM and 5.65 ± 0.16 nM, respectively. The fetal brain concentration of methadone (1.89 ± 0.35 nmol/g) was twice as high as that in the maternal brain, whereas the fetal brain concentration of buprenorphine (20.02 ± 4.97 pmol/g) was one-third the maternal brain concentration. The opioids remained in the offspring brain several days after the exposure ceased. Offspring prenatally exposed to methadone, but not buprenorphine, displayed reduced body weight and length and increased corticosterone levels. No significant changes in ultrasonic vocalizations were revealed. Our data in rat fetuses and neonates indicate that OMT with buprenorphine may be a better choice than methadone during pregnancy. SIGNIFICANCE STATEMENT: Concern has been raised about the use of opioid maintenance treatment during pregnancy because of the important role of the endogenous opioid system in brain development. Here, we show that the methadone concentration in the fetal rat brain was twice as high as that in the maternal brain, whereas the buprenorphine concentration was one-third the maternal concentration. Furthermore, buprenorphine allowed more favorable birth outcomes, suggesting that buprenorphine may be a better choice during pregnancy.

Maternal Glucose Supplementation in a Murine Model of Chorioamnionitis Alleviates Dysregulation of Autophagy in Fetal Brain.

Fetal brain injury induced by intrauterine inflammation is a major risk factor for adverse neurological outcomes, including cerebral palsy, cognitive dysfunction, and behavioral disabilities. There are no adequate therapies for neuronal protection to reduce fetal brain injury, especially new strategies that may apply promptly and conveniently. In this study, we explored the effect of maternal glucose administration in a mouse model of intrauterine inflammation at term. Our results demonstrated that maternal glucose supplementation significantly increased survival birth rate and improved the neurobehavioral performance of pups exposed to intrauterine inflammation. Furthermore, we demonstrated that maternal glucose administration improved myelination and oligodendrocyte development in offspring exposed to intrauterine inflammation. Though the maternal blood glucose concentration was temporally prevented from decrease induced by intrauterine inflammation, the glucose concentration in fetal brain was not recovered by maternal glucose supplementation. The adenosine triphosphate (ATP) level and autophagy in fetal brain were regulated by maternal glucose supplementation, which may prevent dysregulation of cellular metabolism. Our study is the first to provide evidence for the role of maternal glucose supplementation in the cell survival of fetal brain during intrauterine inflammation and further support the possible medication with maternal glucose treatment.

Positive modulation of α5 GABAA receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide

We previously demonstrated that lipopolysaccharide (LPS) administered intraperitoneally (i.p.) to pregnant Wistar rat dams, at embryonic days 15 and 16 (E15/16), induced a decrease of baseline locomotor activity and diminished reactivity to amphetamine in adult female offspring. In the present study we aimed to assess the duration of LPS-induced maternal immune activation (MIA) and investigate possible changes in levels of main neurotransmitters in fetal brain during MIA. We hypothesized that the observed behavioral changes may be linked with MIA-induced disturbance of prenatal GABAergic system development, especially with α5 GABAA receptors (α5GABAARs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of α5GABAARs in offspring’s preadolescence (from postnatal day 22–28) could prevent the deficit in locomotor reactivity to amphetamine observed in adulthood, at postnatal day P60. The elevation of IL-6 in amniotic fluid 6h after LPS treatment (100μg/kg, i.p.) at E15 was concurrent with a significant increase of GABA and decrease of glutamate concentration in fetal brain. Moreover, repeated administration of MP-III-022, a selective positive allosteric modulator of α5GABAARs, at a dose (2mg/kg daily, i.p.) derived from a separate pharmacokinetic study, prevented the LPS-induced decrease in locomotor reactivity to amphetamine (0.5mg/kg, i.p.) in adult females. These results were not mirrored in the parallel set of experiments with male offspring from LPS-treated rats. The results suggest that pharmacological potentiation of α5GABAARs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero.

The Role of Norbuprenorphine in Buprenorphine‐Induced Neonatal Abstinence Syndrome: A Pilot Study

Opioid abuse during pregnancy may cause drug dependence in the fetus, and the abrupt discontinuation of opioid exposure at birth may induce neonatal abstinence syndrome (NAS) during the first week of life. NAS is characterized by inconsolable high‐pitched crying, tremor, vomiting, diarrhea, hypersensitivity, and sleep disturbances. Buprenorphine (BUP), a mu‐opioid receptor partial agonist, is administered as a substitution therapy to treat opioid use disorder during pregnancy. BUP improves neonatal outcome compared with methadone or no treatment, but BUP exposure often leads to NAS. Furthermore, NAS severity is independent of maternal BUP dose throughout pregnancy, suggesting that individual differences in maternal‐fetal BUP pharmacology may increase NAS susceptibility in some newborns. One possible explanation is that fetal exposure to norbuprenorphine (NorBUP), a metabolite of BUP that has high affinity and efficacy at the mu‐opioid receptor, differs across the BUP‐treated population and drives individual differences in the development of opioid dependence. This study tested the hypothesis that NorBUP can induce NAS. To test this hypothesis, we developed a novel model of NAS in which exposure to opioids occurs continuously across fetal development. Pregnant rats were implanted with subcutaneous minipumps containing NorBUP (0.1 or 0.3 mg/kg*day) or vehicle (5 % Emulphor) on gestation day (GD) 9. Treatment continued until delivery. Upon delivery, half of the pups were observed and scored for signs of precipitated withdrawal for 10 minutes after administration of the mu‐opioid receptor antagonist naltrexone (1 or 10 mg/kg, i.p.) or saline (10 ml/kg). Because of the CNS immaturity of the neonatal rat pup relative to the human newborn, this group models opioid dependence in preterm newborns. To model NAS at term, the other half of each litter was fostered to an untreated dam and received subcutaneous injections of NorBUP (0.05 mg/kg or 1.5 mg/kg) every 12 hours (BID) until they were tested for precipitated opioid withdrawal on postnatal day (PD) 7. Few withdrawal signs were observed in the pups tested within 24 hours of delivery, but PD7 pups exposed to the high dose of NorBUP in utero and after birth exhibited significantly more “wall climbing” and less “quiet” signs when challenged with naltrexone, indicating opioid withdrawal. The results of these preliminary studies suggest that NorBUP can induce opioid dependence in the neonatal pup. Ongoing experiments will determine fetal brain concentrations of NorBUP after maternal exposure to NorBUP (GD 9‐ GD20). Results of this experiment will be used to determine additional doses of NorBUP to be tested in the novel rat model of NAS.Support or Funding InformationSupport for this study was provided by the UAMS Fellow to Faculty award and the UAMS Tobacco Research Committee Tobacco Settlement Funds

The pharmacokinetic profile of methylphenidate use in pregnancy: A study in mice

The purpose of this study was to quantify the amounts of the d- and l-threo enantiomers of methylphenidate in maternal plasma, placenta, and maternal and fetal brain tissue following prenatal exposure and to establish a pharmacokinetic profile for MPH during pregnancy. Due to increasing rates of use of methylphenidate amongst females of childbearing age, it is important to understand the extent of exposure to the fetus. Briefly, pregnant mice were injected with 5mg/kg methylphenidate at 18days gestation, and tissue was collected 1, 5, 10, 30, 60, and 120min following injection. Methylphenidate was extracted from tissue via solid phase extraction, and concentrations were determined using liquid chromatography–mass spectrometry (LC–MS). Because methylphenidate is administered as a racemic mixture of d- and l-threo enantiomers and the d-enantiomer is more pharmacologically active, the enantiomers were quantified separately. Interestingly, we found that methylphenidate does cross the placenta and enter the fetal brain. Although the highest concentrations were achieved in maternal brain, the concentrations of d- and l-methylphenidate in fetal brain were comparable to those of maternal plasma. Additionally, both d- and l-methylphenidate had longer half-lives in placenta than in maternal or fetal brain. Interestingly, there was a bimodal peak in maternal brain concentrations, at 5min and again at 60min, which was not observed in maternal plasma. Finally, the total exposure (as represented by area under the curve) was statistically significantly higher for the active d-enantiomer than the l-enantiomer in maternal brain tissue. In conclusion, methylphenidate crosses the placenta and reaches measurable concentrations in fetal brain. Although long-term behavioral and developmental studies are needed to determine specific outcomes of prenatal exposure, discussion with pregnant patients on the potential risks of methylphenidate exposure is warranted.

Increased Levels of Monoamine-Derived Potential Neurotoxins in Fetal Rat Brain Exposed to Ethanol

Pregnant SD rats were exposed to ethanol (25 % (v/v) ethanol at 1.0, 2.0 or 4.0 g/kg body weight from GD8 to GD20) to assess whether ethanol-derived acetaldehyde could interact with endogenous monoamine to generate tetrahydroisoquinoline or tetrahydro-beta-carboline in the fetuses. The fetal brain concentration of acetaldehyde increased remarkably after ethanol administration (2.6 times, 5.3 times and 7.8 times as compared to saline control in 1.0, 2.0 and 4.0 g/kg ethanol-treated groups, respectively) detected by HPLC with 2,4-dinitrophenylhydrazine derivatization. Compared to control, ethanol exposure induced the formation of 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol, Sal), N-methyl-salsolinol (NMSal) and 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline (6-OH-MTHBC) in fetal rat brains. Determined by HPLC with electrochemical detector, the levels of dopamine and 5-hydroxytryptamine in whole fetal brain were not remarkably altered by ethanol treatment, while the levels of homovanillic acid and 5-hydroxyindole acetic acid in high dose (4.0 g/kg) of ethanol-treated rats were significantly decreased compared to that in the control animals. 4.0 g/kg ethanol administration inhibited the activity of mitochondrial monoamine oxidase (51.3 % as compared to control) and reduced the activity of respiratory chain complex I (61.2 % as compared to control). These results suggested that ethanol-induced alteration of monoamine metabolism and the accumulation of dopamine-derived catechol isoquinolines and 5-hydroxytryptamine-derived tetrahydro-beta-carbolines may play roles in the developmental dysfuction of monoaminergic neuronal systems.

Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy

To design a new class of selective neuronal nitric oxide synthase (NOS) inhibitors, and demonstrate that administration in a rabbit model for cerebral palsy (CP) prevents hypoxia-ischemia-induced deaths and reduces the number of newborn kits exhibiting signs of CP. We used a novel computer-based drug design method called fragment hopping to identify new chemical entities, synthesized them, and conducted in vitro enzyme inhibition studies with the three isozymes of NOS and in vivo experiments to monitor cardiovascular effects on pregnant rabbit dams, NOS activity, and NO(x) (NO and NO(2)) concentration in fetal brain, and assess neurobehavioral effects on kits born to saline- and compound treated dams. The computer-based design led to the development of powerful and highly selective compounds for inhibition of neuronal NOS over the other isozymes. After maternal administration in a rabbit model of CP, these compounds were found to distribute to fetal brain, to be nontoxic, without cardiovascular effects, inhibit fetal brain NOS activity in vivo, reduce NO concentration in fetal brain, and dramatically ameliorate deaths and number of newborn kits exhibiting signs of CP. This approach may lead to new preventive strategies for CP.

3,4-Methylenedioxy-N-methamphetamine (ecstasy) promotes the survival of fetal dopamine neurons in culture

The current study examined whether modest concentrations of MDMA could increase the survival and/or neurite outgrowth of fetal midbrain dopamine (DA) neurons in vitro since increased DA neurite outgrowth has been previously observed in vivo from prenatal exposure. MDMA concentrations in fetal brain were quantified to determine relevant in vivo concentrations to employ in vitro. A dose response study in vitro demonstrated that MDMA, at concentrations observed in vivo, resulted in increased, DA-specific, neuron survival. Higher doses resulted in non-specific neurotoxicity. MDMA application immediately after culture establishment resulted in greater survival than delayed application, however both were superior to control. MDMA significantly increased the expression of the slc6a3 gene (dopamine transporter; DAT) in culture. Co-application of the DAT reuptake inhibitor methylphenidate (MPH) with MDMA attenuated this effect. Progressive reductions in MPH concentrations restored the MDMA-induced survival effect. This suggests that MDMA's action at DAT mediates the survival effect. Neurite density per neuron was unaffected by MDMA in vitro suggesting that MDMA promotes DA neuron survival but not neurite outgrowth in culture. Finally, animals prenatally exposed to MDMA and examined on postnatal day 35 showed an increase in tyrosine hydroxylase-positive (TH+) neurons in the substantia nigra but not in the ventral tegmental area. These data suggest that during development, MDMA can increase the survival of DA neurons through its action at its transporter. Understanding how MDMA increases DA neuron survival may provide insight into normal DA neuron loss during development.

Using measurement error models to assess effects of prenatal and postnatal methylmercury exposure in the Seychelles Child Development Study

Studies of the effects of environmental exposures on human health typically require estimation of both exposure and outcome. Standard methods for the assessment of the association between exposure and outcome include multiple linear regression analysis, which assumes that the outcome variable is observed with error, while the levels of exposure and other explanatory variables are measured with complete accuracy, so that there is no deviation of the measured from the actual value. The term measurement error in this discussion refers to the difference between the actual or true level and the value that is actually observed. In the investigations of the effects of prenatal methylmercury (MeHg) exposure from fish consumption on child development, the only way to obtain a true exposure level (producing the toxic effect) is to ascertain the concentration in fetal brain, which is not possible. As is often the case in studies of environmental exposures, the measured exposure level is a biomarker, such as the average maternal hair level during gestation. Measurement of hair mercury is widely used as a biological indicator for exposure to MeHg and is the only indicator that has been calibrated against the target tissue, the developing brain. Variability between the measured and the true values in explanatory variables in a multiple regression analysis can produce bias, leading to either over or underestimation of regression parameters (slopes). Fortunately, statistical methods known as measurement error models (MEM) are available to account for measurement errors in explanatory variables in multiple regression analysis, and these methods can provide an (either “unbiased” or “bias-corrected”) estimate of the unknown outcome/exposure relationship. In this paper, we illustrate MEM analysis by reanalyzing data from the 5.5-year test battery in the Seychelles Child Development Study, a longitudinal study of prenatal exposure to MeHg from maternal consumption of a diet high in fish. The use of the MEM approach was made possible by the existence of independent, calibration data on the magnitude of the variability of the measurement error deviations for the biomarker of prenatal exposure used in this study, the maternal hair level. Our reanalysis indicated that adjustment for measurement errors in explanatory variables had no appreciable effect on the original results.

Placental transfer of mercury in pregnant rats which received dental amalgam restorations

Mercury vapor released from one, two and four amalgam restorations in pregnant rats and mercury concentrations in maternal and fetal organs were studied. Dental treatment was given on day 2 of pregnancy. Mercury concentration in air samples drawn from each metabolism chamber with a rat were measured serially for 24 h on days 2, 8 and 15 of pregnancy. On each day of pregnancy, the amount of mercury in 24 h air samples was in proportion to the amalgam surface areas. Linear regression analysis showed relatively high correlation coefficients between the mercury content and amalgam surface areas, and the coefficients were statistically significant. A highly significant correlation was also found between the number of amalgam fillings and their surface areas. Mercury concentrations in major maternal organs with one, two and four amalgam fillings tended to increase with the increasing amalgam surface areas. Spearman's rank correlation test revealed significant correlations in the brain, liver, kidneys and placenta but not in the lung. Furthermore, significant correlations were also found between the mercury concentrations in all maternal organs and the amount of mercury in 24 h air samples on day 15 of pregnancy. Mercury concentrations in fetal brain, liver and kidneys were much lower than those of the dams but liver and kidneys showed positive correlations between the mercury content and maternal amalgam surface areas. Similar correlations were observed between the mercury concentrations in fetal organs and the amount of mercury in 24 h air samples on day 15 of pregnancy. In fetal brain, no significant correlations were found between either maternal amalgam surface areas or the amount of mercury in 24 h samples on day 15 of pregnancy but significant uptake of mercury was found in the samples from the dams given four amalgam fillings. The results of the present study demonstrated that mercury vapor released from the amalgam fillings in pregnant rats was distributed to maternal and fetal organs in dose-dependent amounts of the amalgam fillings.

High-affinity sodium-vitamin C co-transporters (SVCT) expression in embryonic mouse neurons.

The sodium-vitamin C co-transporters SVCT1 and SVCT2 transport the reduced form of vitamin C, ascorbic acid. High expression of the SVCT2 has been demonstrated in adult neurons and choroid plexus cells by in situ hybridization. Additionally, embryonic mesencephalic dopaminergic neurons express the SVCT2 transporter. However, there have not been molecular and kinetic analyses addressing the expression of SVCTs in cortical embryonic neurons. In this work, we confirmed the expression of a SVCT2-like transporter in different regions of the fetal mouse brain and in primary cultures of neurons by RT-PCR. Kinetic analysis of the ascorbic acid uptake demonstrated the presence of two affinity constants, 103 microM and 8 microM. A K(m) of 103 microM corresponds to a similar affinity constant reported for SVCT2, while the K(m) of 8 microM might suggest the expression of a very high affinity transporter for ascorbic acid. Our uptake analyses also suggest that neurons take up dehydroascorbic acid, the oxidized form of vitamin C, through the glucose transporters. We consider that the early expression of SVCTs transporters in neurons is important in the uptake of vitamin C, an essential molecule for the fetal brain physiology. Vitamin C that is found at high concentration in fetal brain may function in preventing oxidative free radical damage, because antioxidant radical enzymes mature only late in the developing brain.

Effect of metyrapone administration in pregnant rats on monoamine concentration in fetal brain

Studies performed in our laboratory indicate that the adrenal deprivation during gestation can greatly influence the fetal catecholamines development in several cerebral areas. The present study was undertaken to determine wether the administration of metyrapone to pregnant rats affects the content of monoamines in fetal brain at term. To test wether the content of monoamines in fetal brain is regulated, at least in part, by endogenous glucocorticoids, pregnant rats were injected for 5 days prior to delivery with metyrapone, an adrenal 11-β-steroid hidroxylase inhibitor wich crosses the placenta and blocks endogenous glucocorticoid synthesis, or saline. On day 21 of gestation, delivery of all animals was accomplished by cesarean section. The encephalons were extracted and immediately dissected in metencephalon, mesencephalon, diencephalon and telencephalon. Monoamine determination was carried out using HPLC-ED. The results obtained indicate that the metyrapone treatment increases both DA and 5-HT and their metabolites in the brain studied areas.

Cocaine concentrations in fetal C57BL/6 mouse brain relative to maternal brain and plasma.

Cocaine concentrations in maternal plasma and brain and fetal brain of mice were evaluated as a model for fetal brain exposure during maternal cocaine use. On days 12-18 of gestation, mice (C57BL/6; N = 5-7/group) received SC cocaine-HCI: 20 or 40 mg/kg. Maternal plasma and brain (accumbens and caudate nuclei removed), and fetal brain were collected at 0.5, 1, and 2 h following the last injection. Analysis was by GC-MS. Brain cocaine levels in the dams declined from 9.6 to 3.4 and 20.9 to 12.5 micrograms/g [corrected] during the 0.5-1-h period after the low and high doses, respectively, and were 7.5-14.3 times greater than plasma levels. The corresponding fetal brain concentrations changed from 1.6 to 1.3 and 2.9 to 3.4 micrograms/g [corrected]. By 2 h, brain cocaine concentrations in dams declined to approximately 10% of their 0.5-h values, with a slower drug decay occurring in fetal brain. Maternal plasma cocaine concentrations correlated with those of maternal brain (r = 0.94, p < 0.01) and fetal brain (r = 0.69, p < 0.01). The present results indicate that cocaine accumulates to a lesser extent in fetal brain than in maternal brain of C57BL/6 mice; however, the duration of exposure appears to be more sustained in the fetus, a phenomenon that may have toxicological implications for human in utero cocaine exposure.

Ethanol-induced changes in insulin-like growth factors and IGF gene expression in the fetal brain.

Brain growth retardation is a major feature of the fetal alcohol syndrome (FAS). Insulin-like growth factors (IGF-I and IGF-II) have been shown to exert significant metabolic and growth-promoting effects. Previously, we showed that circulating levels of IGF-I as well as hepatic gene expression of both IGFs were decreased in newborn offspring of rats fed ethanol during pregnancy. This study investigated the effects of maternal ethanol ingestion on fetal rat brain growth and on levels of IGF-I and IGF-II, as well as their mRNAs, in fetal brain. IGF-binding protein (IGFBP) levels also were determined. Rats were fed 5% w/v ethanol in a liquid diet during gestation (EF group). Weight-matched animals were pair-fed equicaloric control diet (PF group) or were fed ad libitum (AF group). The mean fetal brain weight of EF offspring was 13% and 16% lower (P < 0.01) than that of PF and AF offspring, respectively. Body weight of EF pups was decreased to a greater extent, resulting in higher brain to body weight ratios in EF pups than in either control group (P < 0.05). IGF-I levels in EF pups decreased by 33% and 41% compared with the corresponding PF and AF values (P < 0.01). IGF-I mRNA levels decreased by 27% and 40% compared with PF and AF values, respectively. A positive correlation was observed between brain IGF-I level and brain weight (r = 0.561, P < 0.01). IGF-II levels were not affected despite a 50% decrease in IGF-II expression. In PF animals, the fetal brain IGF-I and IGF-II mRNA levels were reduced by 28% and 21%, apparently in response to undernutrition. IGF-binding proteins levels were low in the EF group but not statistically significant compared with control values. The diminished fetal brain concentration of IGF-I and decreased gene expression of IGFs may play a role in brain growth retardation associated with FAS.

Behavioral and neurochemical sequelae in young rats of antenal hypoxia

To test the hypothesis that perinatal hypoxia may have postnatal consequences via à vis learning memory, and neurochemical sequelae, we exposed pregnant Sprague-Dawley rats to 10.5% O 2 for 4 h per day (0800–1200 h) or continuously from gestional day E15 to E20. On E20 we quantified ornithine decarboxylase activity and polyamine concentrations in fetal brain. We also conducted behavioral tests from postnatal day P3 to PI 10. Relatively mild antenatal hypoxia resulted in altered learning, memory, and delayed maturation of early developmental sensorimotor function. These behavioral changes disappeared at various postnatal ages, depending on the function. Perinatal hypoxia also altered the pharmacological response to dopaminergic drugs. In addition, antenatal hypoxia feminized a male nonreproductive sexual behavior, that of saccharin preference. Acute hypoxia also resulted in an increase in the enzyme ornithine decarboxylase and polyamines, which may affect brain development.

Prenatal exposure to benzodiazepine—I. Prenatal exposure to lorazepam in mice alters open-field activity and GABA A receptor function

Prenatal exposure to benzodiazepines may lead to developmental abnormalities in humans and animals. To assess the behavioral and neurochemical effects of such exposure, pregnant mice were treated with lorazepam, 2 mg/kg/day, from days 13–20 of gestation, and open-field activity was assessed in offspring at 3 and 6 weeks of age and the function of GABA A receptors at 6 weeks of age. Activity was increased in mice exposed to lorazepam, compared to untreated or vehicle-treated controls at 3 weeks, but was unchanged at 6 weeks. Muscimol-stimulated uptake of chloride was decreased in lorazepam-treated mice, compared to controls, with a decrease in maximum uptake but no change in the EC 50, for muscimol. Concentrations of lorazepam in maternal plasma and brain showed a similar brain: plasma ratio as previously reported and concentrations in fetal brain were about 50% of maternal levels. Lorazepam persisted for 48 hours after birth in dams but not in the offspring. These results indicate persistent behavioral and neurochemical alterations after prenatal exposure to lorazepam. This model may be useful in assessing other effects of prenatal exposure to benzodiazepine.

Fetal and maternal brain and plasma levels of cocaine and benzoylecgonine following chronic subcutaneous administration of cocaine during gestation in rats

The distribution of cocaine and the cocaine metabolite benzoylecgonine (BE) in brain and plasma of Sprague-Dawley rat dams and their near-term fetuses was assessed 0.5 and 2 h post-injection on gestational day 20 following chronic daily subcutaneous injections of 10, 20, or 40 mg/kg/3 ml cocaine hydrochloride beginning on gestational day 8. Plasma concentrations of cocaine reached in the dams were found to be in the range of, or to exceed, those reported in human cocaine users. Dose-related increases in plasma and brain levels of cocaine in the dams and the fetuses were observed, particularly at 2 h post-injection. Fetal concentrations of cocaine in brain and plasma were approximately 2-3-fold less than those of the dams, suggesting that the placenta may somewhat restrict cocaine entry into fetal circulation. Brain/plasma cocaine ratios, however, were generally equivalent in the dams and fetuses, suggesting that once cocaine enters the circulation, its affinity for brain tissue is similar in the fetus and dam. Whereas plasma levels of BE, like cocaine levels per se, were greater in the dams than fetuses, BE concentrations in fetal brain were greater than those observed in maternal brain. These high levels of BE may contribute to the production of neurobehavioral alterations in cocaine-exposed offspring, given that this active cocaine metabolite has been shown to form molecular complexes with calcium ions (Misra and Mule 1975), thereby having the potential to influence a multiplicity of calcium-regulated developmental events.(ABSTRACT TRUNCATED AT 250 WORDS)

Maternal-Fetal Distribution of Bupivacaine in the Rabbit

Bupivacaine was infused i.v. in nine anaesthetized pregnant rabbit does near term. Pups were removed at 10–15 min intervals and bupivacaine concentrations measured in fetal plasma, brain, placenta, amniotic fluid, maternal plasma sampled synchronously and maternal brain at the end of the experiment. Mean maximum fetal: maternal (F: M) ratio was 0.31 (SD 0.16) (range 0.18–0.64). Mean fetal brain: plasma ratios ranged from 2.04 to 5.09. There was no progressive increase in fetal brain bupivacaine concentration with time. Maternal brain: plasma ratio was 1.62 (0.81). However, maximum fetal brain concentration was only 0.27–0.86 of maternal. Concentrations increased with time in amniotic fluid, but did not exceed those in maternal plasma. Although there was some accumulation of bupivacaine in rabbit fetuses, tissue uptake could not account for low F: M ratios persisting beyond 80 min.