Metabolite profiling of the effect of prenatal stimuli across postnatal treatments in the liver.

The aim of the present study was to investigate the effects of hypothyroidism induced during the pre- and postnatal periods of life on ovarian function and structure in offspring (pups) 120 days of age. Three groups were used. In the prenatal group, treatment was given from conception to parturition. In the postnatal group, treatment was given from parturition to 25 days postpartum. Hypothyroidism was induced by administration of 0.1% 6-n-propyl-2-thiouracil (PTU) in the drinking water of mothers. Body weights of the offspring were measured weekly. In each group, ten offspring were sacrificed at 120 days of age. Postnatal PTU treated pups showed delay in eye opening, teething, fur development, and weaning (35-37 days) compared to control animals (28-30 days). Body weight of offspring in the postnatal PTU treatment group was significantly decreased (P < 0.001), while the prenatal PTU treatment group showed a significant increase (P < 0.0001) compared to control animals. There was a significant (P < 0.05) reduction in paired ovarian weight of offspring in the postnatal PTU treatment group compared to control animals. Diameter of the ovaries was not affected by any treatment. Regarding the morphometery, only offspring in the prenatal PTU treatment group showed a significant (P < 0.001) increase in the diameter of graafian follicles. No significant difference was observed in morphometery of the granulosa layer, primary, and developing follicles of control and all treated groups. Number of primary, developing, and graafian follicles of all the treated groups was similar to that of the control group. The corpora lutea of the postnatal PTU treated group contained a population of large numbers of luteal cells compared to the control group. The prenatal PTU treated group did not exhibit a profound effect on ovarian morphology, histology, and morphometery. No difference was found in the serum estradiol concentration of control and PTU treated groups. J. Exp. Zool. 293:407-413, 2002.

Animals prenatally exposed to ethanol typically exhibit hypothalamic-pituitary-adrenal (HPA) hyperresponsiveness to stressors. In contrast to previous studies that have investigated effects of prenatal ethanol exposure on HPA responses to acute or intermittent stressors, our study investigated HPA responses to a chronic continuous stressor, cold stress (4 degrees C for 0, 1, or 3 days). We tested the hypothesis that prenatal ethanol exposure would result in increased plasma corticosterone (CORT) and adrenocorticotropin (ACTH) responses and increased peptide [corticotropin-releasing factor and vasopressin] mRNA levels in the paraventricular nucleus (PVN) of the hypothalamus compared to that in control animals. In addition, CORT and ACTH responses were measured after exposure to an acute stressor (i.p. isotonic saline injection), superimposed during chronic cold exposure, to examine possible sensitization of the HPA response to the acute stress. Thus, blood samples were collected at the end of each of the three periods of cold exposure, either before (0 min) or 15 min after acute stress. The subjects were adult male and female Sprague-Dawley rat offspring from prenatal ethanol (E), pair-fed (PF), and ad libitum-fed control (C) treatment groups. Exposure to cold stress resulted in significant body weight loss in E males at 1 day and in both males and females of all prenatal treatment groups by 3 days of cold stress. Males in all prenatal groups also exhibited significant increases in adrenal weight:body weight ratios. Cold stress alone (0 min condition) increased CORT levels in E males and overall ACTH levels in E males and females compared to controls. ACTH levels were also higher overall in E compared to control males after acute stress (15 min condition). Sensitization of the CORT response to acute stress was observed in males but not females across all prenatal treatment groups. Corticotropin-releasing factor and vasopressin mRNA levels in the PVN were not significantly affected by prenatal treatment or chronic cold stress in either males or females. In contrast, both males and females displayed increases in PVN thyrotropin-releasing hormone (TRH) mRNA levels after cold stress. These data support and extend previous work demonstrating differential effects of prenatal ethanol exposure on HPA responsiveness of male and female offspring, and suggest that E males may be more vulnerable to the effects of chronic cold stress than E females.

Periventricular leukomalacia (PVL), a common neonatal brain white matter (WM) lesion, is frequently associated with cerebral palsy. Growing evidence has indicated that in addition to ischemia/reperfusion injury, cytokine-induced brain injury associated with maternal or fetal infection may also play an important role in the pathogenesis of PVL. Recent studies have shown that administration of lipopolysaccharide (LPS) to pregnant rats causes enhanced expression of the cytokines, i.e., IL-1β, TNF-α, and IL-6, in fetal brains. In recent years, it has been shown that erythropoietin (EPO) has a critical role in the development, maintenance, protection and repair of the nervous system. In the present study we investigated the effect of EPO on LPS-induced WM injury in Sprague-Dawley rats. LPS (500 µg/kg) suspension in pyrogen-free saline was administered intraperitoneally to pregnant rats at 18 and 19 days of gestation. The control group was treated with pyrogen-free saline. They were given 5,000 U/kg recombinant human EPO. Seven-day-old Sprague-Dawley rat pups were divided into four groups: control group, LPS-treated group, prenatal maternal EPO-treated group (5,000 U/kg, intraperitoneally given to pregnant rats at 18 and 19 days of gestation), and postnatal EPO-treated group (5,000 U/kg, intraperitoneally given to 1-day-old rat pups). Cytokine induction in the postnatal 7-day-old (P7) rat brain after maternal administration of LPS was determined by the ELISA method. The proinflammatory cytokine levels (IL-1β, TNF-α, and IL-6) in P7 rat pup brains were significantly increased in the LPS-treated group as compared with the control group. Prenatal maternal EPO treatment significantly reduced the concentration of TNF-α and IL-6 in the newborn rat brain following LPS injection. The concentration of IL-1β was decreased in the intrauterine EPO treatment group. Postnatal EPO treatment significantly decreased only the IL-6 concentration in the newborn rat brain following LPS injection. The concentration of cytokines, IL-1β and TNF-α, was reduced in the postnatal EPO treatment group. We demonstrated here that LPS administration in pregnant rats at gestational day 18 and 19 induced WM injury in P7 progeny characterized by apoptosis. Prenatal maternal and postnatal EPO treatment significantly reduced the number of apoptotic cells in the periventricular WM. Using immunohistochemistry techniques, we investigated the effects of maternal administration of LPS on myelin basic protein (MBP) staining, as a marker of myelination in the periventricular area in the neonatal rat brain. MBP staining was significantly less and weaker in the brains of the LPS-treated group as compared with the prenatal maternal EPO-treated group. However, the postnatal EPO treatment did not prevent LPS-stimulated loss of MBP-positive staining. In conclusion, especially prenatal maternal EPO treatment attenuates LPS-induced injury by reducing the expression of inflammatory cytokines and sparing MBP in the neonatal rat brain. While the postnatal EPO treatment prevented LPS-induced brain injury this effect was partial. To our knowledge, this is the first study that demonstrates a protective effect of EPO on LPS-induced WM injury in the developing brain. Regarding the wide use of EPO in premature newborns, this agent may be potentially beneficial in treating LPS-induced brain injury in the perinatal period.

Prenatal cocaine exposure increases the behavioral sensitivity of neonatal rat pups to ligands active at opiate receptors

Prenatal or postnatal corticosteroids favor clinical, respiratory, metabolic outcomes and oxidative balance of preterm lambs corticotherapy for premature neonatal lambs

This study was designed to determine whether exposure to low-dose endotoxin (lipopolysaccharide; LPS) during gestation can enhance immunity to a subsequent LPS challenge in piglets after weaning. Pregnant sows (parity: 2.6 ± 1.4) were assigned to prenatal immune stimulation (PIS; n = 7; administered 2.5 µg/kg BW LPS, i.m.) or saline treatment groups (CON; n = 7) administered at day 78 ± 1.8 of gestation. From the two prenatal treatment groups, barrows (n = 17 PIS, 17 CON) were identified at weaning (21 ± 1.3 day of age) to subsequently receive a post-weaning LPS challenge. On day −1, the pigs were fitted with indwelling jugular catheters and subcutaneous temperature loggers. On day 0, the pigs were challenged i.v. with LPS (10 µg/kg BW), and blood samples were collected at −2, 0, 1, 2, 4, 6, 8, 12, and 24 h relative to LPS challenge. There was a treatment × time interaction for subcutaneous temperature (P &amp;lt; 0.01), where the temperature increased more quickly at 1 and 2 h post-challenge in PIS compared to CON pigs. There was a tendency (P = 0.08) for less change in white blood cells, relative to baseline values, in PIS compared to CON pigs. There was a treatment × time interaction (P = 0.01) for lymphocyte concentrations where the concentrations were reduced in PIS compared to CON pigs at 8 h post-challenge. There was also a treatment × time interaction (P = 0.01) for the change in eosinophil concentrations, where there was less change in eosinophil concentrations from 1 to 12 h in PIS compared to CON pigs. There was a tendency (P ≤ 0.06) for a treatment × time interaction for serum interleukin-6 (IL-6) and IL-8. Granulocyte-macrophage colony-stimulating factor tended to be greater, and tumor necrosis factor-α tended to be reduced in PIS compared to CON pigs (P ≤ 0.08). These data suggest that exposure to endotoxin in utero may influence the postnatal innate immune response to endotoxin. More research is necessary to further understand the mechanism behind the differences observed and the potential long-term influence of prenatal immune stimulation on pig offspring.

One of the most lacking areas where improvements can be made in swine production is in the area of swine health. This study was designed to determine whether exposure to low dose endotoxin (lipopolysaccharide; LPS) during gestation can enhance immunity to a subsequent LPS challenge in piglets after weaning. Pregnant Camborough sows (parity: 2.6 ± 1.4) were assigned to prenatal immune stimulation (LPS; n = 7; administered 2.5 µg/kg BW LPS i.m. at d 78 ± 1.8 of gestation) or saline treatment groups (CON; n = 7). From the 2 prenatal treatment groups, barrows (n = 17 LPS, 17 CON) were identified at weaning (21 ± 1.3 d of age) to subsequently receive a post-weaning LPS challenge. On d -7, barrows were transported to the USDA-ARS Livestock Issues Research Unit in Lubbock, TX where they were housed in individual pens in an environmentally controlled building with ad libitum access to water and a starter ration. On d -1, pigs were fitted with indwelling jugular catheters and subcutaneous temperature loggers. On d 0, pigs were challenged i.v. with LPS (10 µg/kg BW) and blood samples were collected at -2, 0, 1, 2, 4, 6, 8, 12, and 24 h relative to LPS challenge. Data were analyzed using PROC MIXED in SAS, specific for repeated measures. There was a treatment × time interaction for subcutaneous temperature (P &amp;lt; 0.01), where temperature increased more quickly at 1 and 2 h post-challenge in LPS compared with CON pigs. There was a tendency (P = 0.08) for less change in white blood cells, relative to baseline values, in LPS compared with CON pigs. There was a treatment × time interaction (P = 0.01) for lymphocyte concentrations where concentrations were reduced in LPS compared with CON pigs at 8 h post-challenge. There was also a treatment × time interaction (P = 0.01) for the change in eosinophil concentrations, where there was less change in eosinophil concentrations from 1 to 12h in LPS compared with CON pigs. There was a tendency (P = 0.08) for a treatment × time interaction for serum interleukin-6 (IL-6), where concentrations were reduced in LPS compared with CON pigs at 2h (P = 0.01) and tended to be reduced at 1 and 4h post-challenge (P ≤ 0.11). There was a tendency (P = 0.06) for a treatment × time interaction for IL-8, where concentrations were reduced in LPS compared with CON pigs at 1 and 4h (P ≤ 0.01) and tended to be reduced at 2h post-challenge (P = 0.06). Granulocyte macrophage colony stimulating factor and tumor necrosis factor-α tended (P ≤ 0.08) to be reduced in LPS compared with CON pigs. These data suggest that exposure to endotoxin in utero can influence the postnatal innate immune response to endotoxin. Thus, it is possible to influence the innate immune response of pigs in utero, which may serve as a method to positively influence postnatal immune responsiveness.

Neurons in the rat hippocampal formation (the dentate gyrus and the hippocampus) are born over a protracted period, from gestational day (G) 15 into adulthood. Dentate gyral neurons born prenatally are generated from the ventricular zone, whereas those born postnatally are derived from a secondary proliferative zone, the intrahilar zone. In contrast, hippocampal pyramidal neurons are generated only prenatally from the ventricular zone. In the neocortex, ethanol depresses the proliferation of cells in the ventricular zone and stimulates the proliferation of cells in the secondary proliferative zone. The present study tests the hypotheses that prenatal treatment with ethanol has a different effect on the generation of dentate gyral neurons than does postnatal ethanol treatment, and that these differences are determined by the timing of the ethanol exposure relative to the period and site of neuronal generation. Rats were treated with ethanol between G6 and G21 or between postnatal day (P) 4 and P12. They were given an injection of [3H]thymidine on G15, G18, G21, P6, P9, or P12. Rats were killed on P30-P35. The tissue was processed by standard autoradiographic methods and assessed using rigorous stereological procedures. The total number of neurons and the density of radiolabelled neurons in both the dentate gyrus and the CA1 region of the hippocampus were determined. Prenatal ethanol treatment decreased the total number of neurons in the CA1 segment of the hippocampus and had little impact on neuronal number in the dentate gyrus. Likewise, the number of hippocampal and dentate gyral neurons generated daily was significantly lower in ethanol-treated rats than in controls. Postnatal treatment to ethanol, however, significantly increased the total number of dentate gyral neurons and the density of neurons generated postnatally. These postnatal changes depended on the blood ethanol concentration (BEC). At moderate BECs, the total number of neurons in the dentate gyrus and the number of neurons generated was increased. At high BECs, however, neuronal number and neuronal generation were decreased. Postnatal ethanol treatment had no effect on the number of (total or radiolabeled) CA1 neurons. Thus, pre- and postnatal exposure to ethanol have opposite effects both on the number of neurons in the dentate gyrus and on the generation of neurons. These paradoxical effects likely result from three causes: the differential effects of ethanol on the two proliferative zones, the critical period of neuronal development, and the potentially opposite effects of moderate and high BEC.

Background. Congenital toxoplasmosis, a vertical infection caused by Toxoplasma gondii, can result in neurological and ocular sequelae that may manifest even years postnatally. Although standardized postnatal treatments have been implemented, clinical recurrences, particularly ocular ones, are anticipated to persist during extended follow-up periods. Consequently, prenatal treatment may potentially mitigate these recurrences; however, the evidence supporting this is currently limited and dispersed. Aim: To conduct a meta-analysis on the recurrence rate in children with congenital toxoplasmosis, considering their history of prenatal and postnatal treatment (spanning at least one year), and incorporating long-term clinical follow-up (extending for a minimum of two years). Methods. The databases utilized for the study selection process included PubMed, Web of Science, and Google Scholar. The Medical Subject Headings (MeSH) terms employed were “Toxoplasmosis AND Congenital” and "Toxoplasmosis AND Ocular.” The search was refined using the filters “clinical trial” and “randomized controlled trial.” Additionally, the references of the identified articles were scrutinized to identify other pertinent studies, employing the snowball technique. Experts in the field were consulted to provide relevant published or unpublished data. Studies were included if they reported a minimum of two years of follow-up and presented the results of ophthalmological follow-up. Data concerning prenatal treatment were extracted and systematically organized in an Excel database. The recurrence rate was determined by dividing the number of relapses among untreated patients over the follow-up period by 100. Results. Following revision, only three studies documented the incidence of new retinochoroiditis episodes during extended ophthalmological follow-up. All children in these cohorts received a minimum of one year, with some receiving up to two years of postnatal anti-Toxoplasma treatment. The adjusted recurrence rate in prenatally treated children was 2.6 (n = 229), whereas in untreated children, it was 16.2 (n = 185). The overall adjusted risk of recurrence in prenatally treated children was 0.23 (95% CI: 0.09–0.56; p = 0.001). Conclusions. There is a paucity of research concerning the impact of prenatal treatment on the ocular recurrence of congenital toxoplasmosis. A meta-analysis of three studies revealed that the absence of prenatal treatment heightened the risk of new episodes, even after one year of comprehensive postnatal treatment.

A 2 x 3 factorial arrangement of treatments was used to elucidate the mechanism(s) by which prenatal androgenization improves postnatal rate and efficiency of growth and composition of gain in beef heifers. Fifteen control (C) and 15 prenatally androgenized (PA) Angus x Simmental heifers (prenatal treatment, Pretrt) received no (N), estrogen (E), or estrogen and testosterone (ET) implants postnatally (postnatal treatment, Posttrt) to evaluate whether the postpubertal growth response after prenatal androgenization could be induced in prepubertal heifers. Blood was collected from the heifers at 6 +/- 1, 9 +/- 1, and 12 +/- 1 mo of age and analyzed from serum concentrations of growth hormone (GH), IGF-I, IGF-II, insulin, thyroxine (T4), and triiodothyronine (T3). Season of the year had a greater effect on hormone concentrations than either Pretrt or Posttrt, and there were no Pretrt x Posttrt interactions. Prenatal treatment, PA, had no effect on GH; however, Posttrt E and ET increased (P < .001) GH concentrations. Prenatal treatment, PA, increased (P < .05) IGF-I concentrations, and there was a nonsignificant increase (P = .11) in IGF-I concentrations with Posttrt E and ET. Concentrations of IGF-II were unaffected by Pretrt PA; however, they were lower (P < .01) in the Posttrt E and ET groups. Insulin, T4, T3, BW, and ADG were not affected by Pretrt and Posttrt. Concentrations of GH and IGF-I were increased in heifers that received Pretrt PA and(or) Posttrt E and ET in a manner to support improved growth performance; however, BW and ADG were similar. In prepubertal beef heifers, factors in addition to increased GH and IGF-I seem to be necessary for improved growth performance.

Neonatal choline supplementation ameliorates the effects of prenatal alcohol exposure on a discrimination learning task in rats

Adequate choline supply during the perinatal period is critical for proper brain formation when robust neurogenesis and neuronal maturation are occurring. To examine the impact of perinatal choline on neurodevelopment, sows (n = 8) were fed a choline deficient (CD) or sufficient (CS) diet during the last 65 d of the 114 d gestation period. At 2 d of age, piglets from sows within each prenatal treatment group were stratified into postnatal treatment groups and provided either a CD or CS milk replacer, resulting in a 2 x 2 factorial arrangement (N = 32, n = 6‐9 piglets treatment). At 30 d of age, piglets underwent magnetic resonance imaging procedures to examine brain morphology and metabolite concentrations. Fractional anisotropy (FA) values, obtained from diffusion tensor imaging, revealed an interaction (P = 0.02) between prenatal and postnatal treatments in the right hippocampus. Pigs of a continuous perinatal CD status exhibited lower FA values than CS/CD and CD/CS piglets, highlighting the importance of perinatal choline supplementation for white matter development. Voxel‐based morphometry illustrated differences (P 蠄 0.01) between prenatal choline status in grey and white matter volumes of cortical, cerebellar, and hippocampal regions. Volumes of whole brain, cortical, and subcortical regions were greater (P 蠄 0.05) in prenatal CS compared with prenatal CD piglets. Hippocampal metabolites, assessed using single‐voxel spectroscopy, indicated a decrease (P &lt; 0.01) in glycerophosphocholine + phosphocholine concentration in postnatal CD piglets and a decrease (P = 0.01) in glutamate + glutamine concentration in prenatal CD piglets. These results suggest that adequate dietary choline provided prenatally or postnatally, promotes neuronal growth and maturation.

After completing this article, readers should be able to: 1. Describe the standard of care for prenatal corticosteroids for women in preterm labor prior to 34 weeks’ gestation. 2. Describe the effects of prenatal corticosteroids on the fetus. 3. List the preferred corticosteroid for prenatal treatments. 4. Explain the recommendation regarding not using repetitive courses of prenatal corticosteroids. Prenatal glucocorticoids are standard of care for women at high risk of preterm delivery prior to 34 weeks’ gestation because randomized, controlled trials and extensive meta-analyses demonstrate decreased death and improved outcomes, primarily related to less respiratory distress syndrome (RDS) and a decreased incidence of intraventricular hemorrhages (IVH) (Fig. 1). (1) However, it is worth remembering that the benefits of prenatal corticosteroids initially were demonstrated in 1972, and most of the trials were completed before 1985. Most infants in the trials were delivered after 28 weeks’ gestation and in the presurfactant era, when mortality rates for infants whose birthweights were less than 1 kg were high and when obstetric management differed from current practice. Maternal corticosteroid therapy is validated practice, but care strategies proven to be effective may lose effectiveness as other aspects of care change and the target population most likely to benefit changes. This review asks a series of questions to frame the overriding question of how antenatal corticosteroids should be used in 2006. Figure 1. Meta-analysis of randomized controlled trials of prenatal corticosteroids. Adapted from Crowley. (1) The current recommendations come from the 1994 National Institutes of Health (NIH) Consensus Conference and were reinforced by a second NIH Consensus Conference in 2000. (2) The key points from the guidelines are: 1. The benefits of prenatal corticosteroids outweigh any risks that have been identified. The benefits include decreased death and decreased incidence of RDS and IVH. 2. All fetuses at 24 to 34 weeks’ gestation are candidates …

The behavioral response to stress is altered in adult rats exposed prenatally to cocaine

Comparative effects of maternal prenatal and postnatal exposures to astemizole on reproductive parameters of rats