Effects Of Prenatal Treatment Research Articles

S.02.01 Genetic models of psychiatric disorders: phenotyping mutant mice

The effects of prenatal treatment with the antimitotic agent methylazoxymethanol (MAM; 25 mg/kg i.v., gestation day 15) on the development of monoamine neurons and their receptors have been investigated by neurochemical techniques. The MAM treatment led to a forebrain microencephaly with an approximately 50% weight reduction of the cerebral cortex and hippocampus, 30% of the striatum while the other CNS regions were reduced by about 5–15%. Endogenous noradrenaline (NA) dopamine (DA) and 5-hydroxytryptamine (5-HT) concentrations in the cerebral cortex and hippocampus were increased by about 100% and to a similar extent for all amines, whereas the total amine content in each brain region analyzed was more or less unchanged after MAM treatment. The DA concentration in the striatum was increased by 40% without any change in the total DA content. The subcellular distribution of NA and DA in the cerebral cortex and striatum was similar in MAM-treated and control rats. The effect of the NA denervation agent DSP4 was identical in MAM-treated and controls, showing very pronounced NA reductions in the cerebral cortex, hippocampus, cerebellum and the spinal cord, while the DA levels in various brain regions were not or only to a minor degree affected. Analysis of [3H]NA and [3H]5-HT uptake in slices from the cerebral cortex in vitro, demonstrated an approximate doubling of the uptake (calculated per weight) for both amines after MAM, while total uptake was not notably changed. MAM treatment also led to a significant reduction of the in vitro binding of various radioligands for monoamine (α, β, 5-HT) receptors. The most pronounced reduction was observed for β-receptors. Administration of a tyrosine-hydroxylase (α-methyl-p-tyrosine) or a tryptophan hydroxylase (α-propyldopacetamide) inhibitor led to marked NA/DA and 5-HT reductions after MAM in all regions analyzed, indicating that the monoamine neurons are active in synthesizing and releasing their neurotransmitter. The results suggest that

Prenatal dexamethasone selectively decreases calretinin expression in the adult female lateral amygdala

Exposure to high levels of glucocorticoids (GCs) during early development results in lasting disturbances in emotional behavior in rodents. Inhibitory GABAergic neurons, classified by their expression of calcium binding proteins (CBPs), also contribute to stress-related behaviors and may be GC sensitive during development. Therefore, in the present study we investigated the effects of prenatal treatment with the glucocorticoid receptor agonist dexamethasone (DEX) on expression of calbindin and calretinin in brain areas critical to emotional regulation (basolateral/lateral amygdala and hippocampal CA1 and CA3 regions). Late gestational treatment with DEX (gestational days 18–22) significantly decreased the density of calretinin immunoreactive cells in the lateral amygdala of adult female offspring with no differences in the basolateral amygdala, hippocampal CA1, or CA3 regions. Moreover, there were no effects of gestational DEX treatment on calretinin expression in males. Calbindin expression in adulthood was unaltered within either amygdala or hippocampal subregion of either sex following prenatal DEX treatment. Together these findings indicate that late gestational DEX treatment causes a targeted reduction of calretinin within the lateral amygdala of females and this may be one mechanism through which developmental glucocorticoid exposure contributes to lasting alterations in emotional behavior.

Maternal treatment with dexamethasone at minimal therapeutic doses inhibits neonatal bone development in a gender-dependent manner

The structural quality of bone is genetically determined, and remains under the influence of hormonal modification. A gender-dependent effect of prenatal treatment with multiple therapeutic minimal doses of dexamethasone (DEX) on the growth and mineralisation of the skeletal system of piglets at weaning was considered in undertaking this study. Sows were treated i.m. with DEX at the dose of 0.03mgkg−1 body weight every second day during the last 45 days of pregnancy. Prenatal treatment with DEX resulted in decreased weight, length, geometric parameters and histomorphometry of limb bones and influenced bone quality which was expressed by decreased values of bone mineral density (BMD), ultimate and maximum elastic strengths about 40%, 60% and 40%, respectively. Prenatal DEX administration to male piglets via their mothers significantly enhanced the concentration of leptin and decreased the concentration of GH and insulin. Additionally, the negative effect of DEX treatment on bone tissue was connected with changes of the free amino acid pool of male piglets. In addition, female pigs had unaffected mass and length of bones. This result showed that maternal DEX action was multifactorial and differently influenced postnatal bone development in the female and male piglets.

Antenatal screening forToxoplasma gondiiinfection at a tertiary care hospital in Riyadh, Saudi Arabia

BACKGROUND AND OBJECTIVES:Congenital toxoplasmosis is associated with significant morbidity and mortality. This study investigates the prevalence of toxoplasmosis among pregnant women.DESIGN AND SETTING:A retrospective study at King Khalid University Hospital, Riyadh from September 2009 to August 2010.PATIENTS AND METHODS:Laboratory data of 2176 pregnant women screened for Toxoplasma gondii in the antenatal care unit were assessed during the study period. The mean (SD) age of the women and the duration of pregnancy were 25 (7.3) years and 18 (7.7) weeks, respectively. Data were extracted for the presence or absence of anti-T gondii immunoglobulin G (IgG) and IgM antibodies.RESULTS:Of 2176 sera tested, 1351 (62%) did not show any evidence of exposure to T gondii. The remaining 825 (38%) samples tested positive for anti-T gondii IgG antibodies, and none was found to have anti-T gondii IgM antibodies in the serum. These data reveal that a significantly high number of women in the antenatal care unit at King Khalid University Hospital in Riyadh had been exposed to T gondii.CONCLUSION:A high prevalence of toxoplasmosis among pregnant women warrants multicenter community-based investigations for assessment of T gondii infection and identification of risk factors for transmission of toxoplasmosis in general, and particularly during pregnancy.

Postnatal effects of prenatal treatment of amorphous nanosilica

Postnatal effects of prenatal treatment of amorphous nanosilica

Prenatal Glucocorticoid Overexposure Causes Permanent Increases in Renal Erythropoietin Expression and Red Blood Cell Mass in the Rat Offspring

Glucocorticoids promote maturation of fetal systems, including erythropoiesis, in preparation for extrauterine life. However, recent studies have shown that prenatal glucocorticoid excess can cause long-term deleterious cardiometabolic and other consequences to the offspring. Here, we examined the effect of prenatal treatment with the synthetic glucocorticoid dexamethasone (DEX) during the last week of gestation on red blood cell (RBC) mass in the rat offspring. DEX-treated offspring at 9 months of age had significantly higher RBC count (9.4 ± 0.1 vs. 8.8 ± 0.2 × 10(12) liter; P = 0.02), hematocrit (50.0 ± 0.5 vs. 46.7 ± 0.7%; P=0.004), hemoglobin (17.3 ± 0.2 vs. 16.2 ± 0.2 g/dl; P = 0.02) and number of reticulocytes (258.2 ± 8.8 vs. 235.7 ± 5.6 × 10(9) liter; P = 0.04), compared with offspring of vehicle-treated control pregnancies. White blood cells and platelets were unaltered. Renal mRNA expression and plasma concentrations of erythropoietin, the main regulator of erythropoiesis, were increased by nearly 100% in both newborn and adult DEX-treated rats (P < 0.01). This increase was accompanied by marked elevation in renal expression of hepatocyte nuclear factor 4α mRNA, whereas other erythropoietin-regulating transcription factors, such as hypoxia-inducible factor 1, hypoxia-inducible factor 2, and GATA2 were unchanged. These data indicate that RBC mass can be programmed by prenatal glucocorticoid excess, and if extrapolatable to humans, provide a novel mechanism for fetal origins of polycythemia and its associated complications.

Efectos de la administración de glucocorticoides prenatales en el desarrollo de la enterocolitis necrosante en neonatos de rata wistar

Necrotizing enterocolitis (NEC) is a frequent problem in preterm infants. Prenatal treatment with steroids proved to be effective for lung maturation and it is thought to have a protective effect on the immature bowel. To study the effects of prenatal treatment with steroids at the onset, clinical course and histological pattern of NEC in an animal model. Pregnant rats received treatment with intraperitoneal hydrocortisone (5 mg/kg) 24 and 48 hrs prior to the expected date of delivery (group S). Control pregnant rats were injected with normal saline, at the same timing (group P). After term delivery by cesarean section, both groups were kept in identical conditions in a neonatal incubator at 35ºC, away from their mothers to prevent any exposure to breast milk. Pups were fed every three hours with neonatal formula via an orogastric tube. To further increase the susceptibility to NEC, pups were exposed to hypoxia followed by hypothermia three times a day for 72 hrs (H-H) or until development of clinical signs of NEC. At that point, each animal was anesthetized and euthanized. The intestine was fixed for histological analysis. Those animals which died before 72 hours were excluded to prevent false positive results in the histopathological exam. The clinical signs of NEC include oral intolerance, gastric residuals, respiratory distress, abdominal distension, wall erythema and hematochezia; 60% of animals in group P (n= 16) presented with at least one clinical sign, vs. 40% of pups in group S (n= 15). The onset of clinical signs and clinical course in group S was more benign than in group P. Mortality rate was 40% for pups in group P vs. 20% for group S (NS). Histological analysis indicated that 80% of the animals from group P showed signs of NEC, of which 50% reached grade 3-4 (maximum score of damage), whereas only 40% of the animals in group S presented with signs of NEC (p<0.05), all were of grade 0-1 (minimum histological damage). Prenatal treatment with steroids was effective for amelioration of the onset and clinical presentation in this model of experimental NEC.

Prenatal Treatment for Serious Neurological Sequelae of Congenital Toxoplasmosis: An Observational Prospective Cohort Study

The effectiveness of prenatal treatment to prevent serious neurological sequelae (SNSD) of congenital toxoplasmosis is not known. Congenital toxoplasmosis was prospectively identified by universal prenatal or neonatal screening in 14 European centres and children were followed for a median of 4 years. We evaluated determinants of postnatal death or SNSD defined by one or more of functional neurological abnormalities, severe bilateral visual impairment, or pregnancy termination for confirmed congenital toxoplasmosis. Two-thirds of the cohort received prenatal treatment (189/293; 65%). 23/293 (8%) fetuses developed SNSD of which nine were pregnancy terminations. Prenatal treatment reduced the risk of SNSD. The odds ratio for prenatal treatment, adjusted for gestational age at maternal seroconversion, was 0.24 (95% Bayesian credible intervals 0.07-0.71). This effect was robust to most sensitivity analyses. The number of infected fetuses needed to be treated to prevent one case of SNSD was three (95% Bayesian credible intervals 2-15) after maternal seroconversion at 10 weeks, and 18 (9-75) at 30 weeks of gestation. Pyrimethamine-sulphonamide treatment did not reduce SNSD compared with spiramycin alone (adjusted odds ratio 0.78, 0.21-2.95). The proportion of live-born infants with intracranial lesions detected postnatally who developed SNSD was 31.0% (17.0%-38.1%). The finding that prenatal treatment reduced the risk of SNSD in infected fetuses should be interpreted with caution because of the low number of SNSD cases and uncertainty about the timing of maternal seroconversion. As these are observational data, policy decisions about screening require further evidence from a randomized trial of prenatal screening and from cost-effectiveness analyses that take into account the incidence and prevalence of maternal infection. Please see later in the article for the Editors' Summary.

Effect of prenatal treatment with maximal therapeutic dexamethasone dose on structure of piglets bones

Effect of prenatal treatment with maximal therapeutic dexamethasone dose on structure of piglets bones

Prise en charge de la toxoplasmose congénitale en France : données actuelles

Congenital toxoplasmosis is caused by transplacental contamination of the fetus withToxoplasma gondiifollowing maternal primary infection. The risk of mother-to-child transmission depends on the term of pregnancy at the time of maternal infection. The risk is lower than 5% in the first trimester but can reach 90% in the last days of pregnancy. Inversely, however, fetal disease is more severe when contamination occurs early in pregnancy. The French prevention program officially recommends monthly serological screening of susceptible women during pregnancy and information about hygiene and dietary rules. Prenatal diagnosis of congenital toxoplasmosis is based on a combination of examinations: PCR testing for the parasite in amniotic fluid, mouse inoculation, fetal ultrasonography, and magnetic resonance imaging. Neonatal screening consists of PCR of the placenta, mouse inoculation, detection of specific IgM and IgA in the newborn, ocular fundus examinations by indirect ophthalmoscopy, and transfontanellar ultrasonography. As soon as maternal infection is suspected, preventive treatment with spiramycin begins; the treatment is changed to a combination of pyrimethamine-sulfonamide if fetal infection is proved. Some teams are using this combination as first-line treatment after 30 weeks of gestation, without performing amniocentesis. Recent European multicenter studies raise questions about the effectiveness of prenatal treatment on mother-to-child transmission and on the reduction in the number and severity of fetal sequelae. A randomized controlled trial is required to prove the efficacy of prenatal treatment in general and of specific drugs, in particular. As soon as infection is confirmed, infected children are treated with the pyrimethamine-sulfonamide combination for 12 to 24 months. Recent multicenter studies show that postnatal treatment does not prevent ocular lesions: 5% of treated children had choroiditis lesions at birth, 20% at 5 years, and 30% at 8 years of age. Furthermore no consensus exists about the duration of postnatal treatment (3 months in Denmark versus 12 months in France). A multicenter randomized controlled trial is necessary to assess the efficacy of postnatal treatment and determine its duration. A surveillance system was set up in 2007 by the National Reference Center for Toxoplasmosis to determine the perinatal burden of this infection and to assess the national policy.

Delayed effects of prenatal treatment with synthetic glucocorticoids on the structural organization of the substantia nigra

Delayed effects of prenatal treatment with synthetic glucocorticoids on the structural organization of the substantia nigra

Long-term follow-up of prenatally treated children at risk for congenital adrenal hyperplasia: does dexamethasone cause behavioural problems?

To investigate the long-term effects of prenatal treatment of congenital adrenal hyperplasia (CAH) with emphasis on behavioural problems and temperament. A population-based long-term follow-up study of Swedish children at risk for virilising CAH, who had received treatment prenatally with dexamethasone (DEX). The questionnaire-based follow-up was performed when the children had reached school age. Standardised parent-completed questionnaires were used to evaluate adaptive functioning, behavioural/emotional problems and psychopathology, social anxiety and temperament in DEX-exposed school-aged children (n=26) and matched controls (n=35). In addition, the association between parental questionnaires and children's self-ratings was investigated. There were no statistically significant differences between DEX-exposed children and controls in measures of psychopathology, behavioural problems and adaptive functioning. In a questionnaire on temperamental traits, DEX-exposed children were described by their parents as being more sociable than controls (P=0.042). The correlation analysis showed only modest parent-child agreement on social anxiety, i.e. the increased social anxiety in children's self-ratings was not confirmed by their parents. DEX-treated children showed good overall adjustment. The parent-child agreement with respect to social anxiety was modest, highlighting the importance of multiple information sources and assessment methods. The clinical significance of the observed difference in sociability cannot be determined within the frameworks of this study. Additional studies of larger cohorts are essential to make more decisive conclusions on the safety of the treatment. Until then, it is important that parents are thoroughly informed about the benefits and potential risks and uncertainties of this controversial treatment.

Predictors of Retinochoroiditis in Children With Congenital Toxoplasmosis: European, Prospective Cohort Study

By school age, 20% of children infected with congenital toxoplasmosis will have > or = 1 retinochoroidal lesion. We determined which children are most at risk and whether prenatal treatment reduces the risk of retinochoroiditis to help clinicians decide about treatment and follow-up. We prospectively studied a cohort of children with congenital toxoplasmosis identified by prenatal or neonatal screening in 6 European countries. We determined the effects of prenatal treatment and prognostic markers soon after birth on the age at first detection of retinochoroiditis. Of 281 children with congenital toxoplasmosis, 50 developed ocular disease, and 17 had recurrent retinochoroiditis during a median follow-up of 4.1 years. Prenatal treatment had no significant effect on the age at first or subsequent lesions. Delayed start of postnatal treatment did not increase retinochoroiditis, but the analysis lacked power. Older gestational age at maternal seroconversion was weakly associated with a reduced risk of retinochoroiditis. The presence of nonocular clinical manifestations of congenital toxoplasmosis at birth strongly predicted retinochoroiditis. For 92% (230 of 249) of children with no retinochoroiditis detected before 4 months of age, the probability of retinochoroiditis by 4 years was low, whether clinical manifestations were present or not 8.0%. Prenatal treatment did not significantly reduce the risk of retinochoroiditis in this European cohort. If children have no retinochoroiditis in early infancy, the low risk of subsequent ocular disease may not justify postnatal treatment and repeated ophthalmic assessments during childhood. Controlled trials are needed to address the lack of evidence for the effectiveness of postnatal treatment.

Effectiveness of Prenatal Treatment for Congenital Toxoplasmosis: A Meta-analysis of Individual Patients’ Data

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The effect of prenatal treatment with steroids and preterm delivery in a model of myelomeningocele on the rabbit foetus

Damage of neural elements (spinal cord and encephalus) in myelomeningocele (MMC) seems to be progressive during gestation because of amniotic fluid chemical contact and continuous leakage of CSF. We studied the effect of preterm delivery and steroid treatment in a model of MMC in the rabbit foetus. Twelve New Zealand White rabbits underwent laparotomy and hysterotomy at 23 days of gestation. Fifty-nine out of 107 foetuses underwent lumbar laminectomy (three to four levels). Dura was opened to expose the neural elements to the amniotic fluid. Six rabbits underwent caesarean section on gestational day 31 for fetal harvest; three of them had no treatment (group T) and three received corticosteroid treatment (group TC). The other six rabbits underwent caesarean section on gestational day 29 for fetal harvest (preterm delivery); three of them had no treatment (group P) and three received corticosteroid treatment (group PC). Alive newborns were clinically, neurophysiologically and histologically analysed. None of mothers died during the procedure. After birth, animals in group preterm showed statistically significant less deformity than animals in group at term. Lower kyphosis was observed in group PC (preterm and steroids). Pain related and spontaneous mobility of lower extremities was higher in groups treated with corticosteroids (TC and PC). Only newborns at term (T and TC groups) showed response to evoked potentials (CMEPs). The response was earlier and higher in group treated with steroids (TC). Histologically, we observed progressive lesion of the spinal cord. Groups treated with steroids (TC and PC) show less inflammatory response. Arnold-Chiari malformation was present in all groups. Animals in group preterm with steroids show statistically significant less herniation than those group at term. Preterm delivery and prenatal steroid therapy seem to be an effective treatment to get less neural injury (spinal cord and encephalus) in myelomeningocele foetuses.

Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients' data

Despite three decades of prenatal screening for congenital toxoplasmosis in some European countries, uncertainty remains about the effectiveness of prenatal treatment. We did a systematic review of cohort studies based on universal screening for congenital toxoplasmosis. We did a meta-analysis using individual patients' data to assess the effect of timing and type of prenatal treatment on mother-to-child transmission of infection and clinical manifestations before age 1 year. Analyses were adjusted for gestational age at maternal seroconversion and other covariates. We included 26 cohorts in the review. In 1438 treated mothers identified by prenatal screening, we found weak evidence that treatment started within 3 weeks of seroconversion reduced mother-to-child transmission compared with treatment started after 8 or more weeks (adjusted odds ratio [OR] 0.48, 95% CI 0.28-0.80; p=0.05). In 550 infected liveborn infants identified by prenatal or neonatal screening, we found no evidence that prenatal treatment significantly reduced the risk of clinical manifestations (adjusted OR for treated vs not treated 1.11, 95% CI 0.61-2.02). Increasing gestational age at seroconversion was strongly associated with increased risk of mother-to-child transmission (OR 1.15, 95% CI 1.12-1.17) and decreased risk of intracranial lesions (0.91, 0.87-0.95), but not with eye lesions (0.97, 0.93-1.00). We found weak evidence for an association between early treatment and reduced risk of congenital toxoplasmosis. Further evidence from observational studies is unlikely to change these results and would not distinguish whether the association is due to treatment or to biases caused by confounding. Only a large randomised controlled clinical trial would provide clinicians and patients with valid evidence of the potential benefit of prenatal treatment.

Association between prenatal treatment and clinical manifestations of congenital toxoplasmosis in infancy: A cohort study in 13 European centres

To determine the effectiveness of prenatal treatment for clinical manifestations of congenital toxoplasmosis. We prospectively identified 255 live-born infants with congenital toxoplasmosis using prenatal or neonatal screening. We determined the effect of prenatal treatment on the risks of intracranial or ocular lesions in infancy, accounting for gestational age at maternal seroconversion. Prenatal treatment within 4 wk of seroconversion reduced the risk of intracranial lesions compared with no treatment (odds ratio, OR 0.28; 95% CI: 0.08-0.75), but there was no significant effect when initiated after 4 wk (OR 0.76; 95% CI: 0.35-1.59; overall p-value 0.19). Compared to spiramycin alone, no treatment doubled the risk of intracranial lesions (OR 2.33; 95% CI: 1.04-5.50), but the risk did not differ with pyrimethamine-sulphonamide treatment (overall p-value 0.52). There was no consistent relationship between the type or timing of treatment and the risk of ocular lesions. Gestational age at maternal seroconversion was inversely associated with the risk of intracranial but not ocular lesions. Only early versus no prenatal treatment for intracranial lesions showed a statistically significant benefit. A large randomized controlled trial and/or meta-analysis of individual patient data from cohort studies is required to confirm these findings.

Sex-Specific Effects of Prenatal Low-Protein and Carbenoxolone Exposure on Renal Angiotensin Receptor Expression in Rats

Experimental models have shown the developing cardiovascular and renal systems to be sensitive to mild shifts in maternal nutrition, leading to altered function and risk of disease in adult life. The offspring of Wistar rats fed a low-protein diet during pregnancy exhibit a reduced nephron number and hypertension in postnatal life, providing a useful tool to examine the mechanistic basis of programming. Evidence indicates that upregulation of the renin-angiotensin system plays an important role, in particular through receptor-mediated changes in angiotensin II activity. However, although programmed hypertension has proven dependent on maternal glucocorticoids, there appear to be conflicting effects of prenatal low-protein and glucocorticoid exposure on postnatal angiotensin receptor expression. This study aimed to resolve this issue by comparing the effects of low-protein and glucocorticoid exposures on postnatal nephron number and angiotensin receptor expression. In addition, this study examined the modulation of prenatal treatment effects by postnatal inhibition of type 1 angiotensin receptor. The data demonstrates that whereas prenatal low-protein and glucocorticoid exposure have a similar effect in reducing nephron number, there are age- and gender-related differences in their effects on postnatal angiotensin receptor expression. In addition, this study provides novel evidence of a substantial upregulation of type 2 angiotensin receptor expression in low-protein- and glucocorticoid-exposed female offspring at 20 weeks of age, with implications for subsequent renal remodeling and function. Despite being targeted to the postnephrogenic period, inhibition of type 1 angiotensin receptor had an inhibitory effect on renal and somatic growth, additionally indicating its unsuitability during early life.

Identification and Characterization of Engrafted Human Cells in Human/Goat Xenogeneic Transplantation Chimerism

We have injected human CD34+lin- cells derived from cord blood (CB) into the goat fetuses via in utero at 45-55 days gestation under guidance of B-scan ultrasonograph. Sixty out of 68 fetuses injected survived to full term. The long-term survival of the human cells in transplant goat has been tested by various experimental methods, including FACS analysis, real-time PCR, RT-PCR, Southern-blot hybridization, FISH, as well as immunohistochemical assays. All the 60 transplant goats demonstrated engrafted human cells, including myeloid, B-lymphoid, and erythroid lineages. The yield of the human CD34+ cells varied, but was not linked with sex and age. High numbers of human cells could be detected for at least 16 months after birth. Immunohistochemical analyses revealed that the human cells were present not only in blood but also in other tissues, such as liver, of the transplant goats. In addition, a human-specific serum albumin and the hepatocyte nuclear factor (hHNF-3beta) mRNAs specific to human hepato-antigen could be readily detected in the livers of the transplant goats. Our results demonstrate that this in utero xenograft model should be useful for expansion of human HSC and possibly for the evaluating the effectiveness of prenatal treatment of human genetic diseases.

D-Amphetamine-related reinforcing effects are reduced in mice exposed prenatally to estrogenic endocrine disruptors

Estrogenic endocrine disruptors are hormonally active compounds that can bind to estradiol receptors. Central dopamine pathways have been reported to be affected by early developmental exposure to estrogenic endocrine disruptors. In the present study, pregnant female CD-1 mice were allowed to drink spontaneously either oil or environmentally relevant low doses of two estrogenic compounds, methoxychlor (20 μg/kg) or bisphenol-A (10 μg/kg) during gestation days 11–18. Their adult offspring were assessed for conditioned place preference produced by d-amphetamine (0, 1 or 2 mg/kg). Interestingly, prenatal treatment effects were sex-dependent and no changes in conditioned place preference emerged for the male offspring. Conversely, a clear-cut profile of d-amphetamine-induced conditioned place preference was only shown by oil-exposed females, whereas exposure to bisphenol-A or methoxychlor resulted in little or no place conditioning. Locomotor effects of acute d-amphetamine were not affected by prenatal exposure to bisphenol-A or methoxychlor. As a whole, prenatal exposure to estrogenic endocrine disruptors affected some steps in the organization of the brain dopaminergic systems in the female offspring, thus leading to long-term alterations in neurobehavioral function. These data confirm that exposure to weak environmental estrogens in the period of brain sexual differentiation can influence adult behavior.