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PubMed2005

Notch signaling, brain development, and human disease.

The Notch signaling pathway is central to a wide array of developmental processes in a number of organ systems, including hematopoiesis, somitogenesis, vasculogenesis, and neurogenesis. These processes involve maintenance of stem cell self-renewal, proliferation, specification of cell fate or differentiation, and apoptosis. Recent studies have led to the recognition of the role of the Notch pathway in early neurodevelopment, learning, and memory, as well as late-life neurodegeneration. This review summarizes what is currently known about the role of the Notch pathway in neural stem cells, gliogenesis, learning and memory, and neurologic disease.

Animals↗

PubMed2004

A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration.

Epidemiological studies and case reports show that even a relatively minor degree of maternal hypothyroxinemia during the first half of gestation is potentially dangerous for optimal fetal neurodevelopment. Our experimental approach was designed to result in a mild and transient period of maternal hypothyroxinemia at the beginning of corticogenesis. Normal rat dams received the goitrogen 2-mercapto-1-methyl-imidazole for only 3 d, from embryonic d 12 (E12) to E15. Maternal thyroid hormones decreased transiently to 70% of normal serum values, without clinical signs of hypothyroidism. Dams were injected daily with 5-bromo-2'-deoxyuridine (BrdU) during 3 d, from E14-E16 or E17-E19. Their pups were tested for audiogenic seizure susceptibility 39 d after birth (P39) and killed at P40. Cells that had incorporated BrdU were identified by immunocytochemistry, and quantified: numerous heterotopic cells were found, whether labeled at E14-E16 or E17-E19, that were identified as neurons. The cytoarchitecture and the radial distribution of BrdU-labeled neurons was significantly affected in the somatosensory cortex and hippocampus of 83% of the pups. The radial distribution of gamma-aminobutyric acidergic neurons was, however, normal. The infusion of dams with T4 between E13 and E15 avoided these alterations, which were not prevented when the T4 infusion was delayed to E15-E18. In total, 52% of the pups born to the goitrogen-treated dams responded to an acoustic stimulus with wild runs, followed in some by seizures. When extrapolated to man, these results stress the need for prevention of hypothyroxinemia before midpregnancy, however moderate, and whichever the underlying cause.

Animals↗

PubMed2006

Mechanisms of adaptation to iodine deficiency in rats: thyroid status is tissue specific. Its relevance for man.

Many animals, man included, live in areas providing insufficient iodine (I) for optimal health. Degrees of I deficiency (ID) vary from mild-moderate to very severe, with quali- and quantitatively different negative consequences. To understand the mechanisms involved in adaptation to different grades of ID, we fed rats a low-iodine diet, plus additions resulting in a 250-fold range of I daily available to the thyroid, ranging from 5 mug (adequate) down to 0.02 microg I. We measured thyroid weight, total I, T(4), T(3), and type I 5' iodothyronine deiodinase (D1) activity, TSH, T(4), free T(4), and T(3) in plasma, T(4) and T(3) in 11 tissues, and two 5' deiodinase isoenzymes in four. TSH-independent thyroid autoregulation plays an important role in addition to TSH-dependent mechanisms in the adaptation to ID, avoiding a decrease of T(3) in plasma and most tissues, despite a marked decrease of plasma T(4), whereas extrathyroidal responses of D2 mitigate T(3) deficiency in tissues in which T(3) is mostly generated from T(4). We focused on mild and moderate ID, the least investigated experimentally, despite its current frequency in industrialized countries. The novel and important finding of our study is that thyroid status cannot be defined for the animal as a whole: at all grades of ID, T(3) is simultaneously elevated, normal, and low in different tissues. Present findings in mild-moderate ID draw attention to the importance, for man, of the resulting hypothyroxinemia that may affect mental functions and neurodevelopment of the inhabitants, even when they do not have the increased TSH or clinical hypothyroidism, often wrongly attributed to them.

Analysis of Variance↗

PubMed2001

Distinct cytochrome P450 aromatase isoforms in zebrafish (Danio rerio) brain and ovary are differentially programmed and estrogen regulated during early development.

As a first step toward understanding estrogen's role in neurodevelopment, a PCR cloning strategy was used to isolate complementary DNAs encoding two distinct cytochrome P450 aromatase isoforms in adult zebrafish (Danio rerio) brain and ovary (termed P450aromB and P450aromA, respectively). Sequence and phylogenetic analysis showed that the zebrafish P450arom forms are orthologs of previously identified cyp19b and cyp19a genes in goldfish. On Northern blots, a single 4.4-kb transcript of the P450aromB subtype was identified in brain, and a 2.1-kb transcript of the P450aromA subtype in ovary, but RT-PCR showed a degree of overlapping expression. Both messenger RNA (mRNA) forms were detected in unfertilized eggs and 1.5 hpf (cleavage stage) embryos but declined by 12 hpf, indicating maternal transfer. A secondary rise in mRNAs between 12-24 hpf indicated the onset of embryonic cyp19b and -a transcription. Both mRNA species accumulated progressively to 120 hpf (early larval stage), but the relative magnitude and pattern of change was isoform specific. Estradiol (E(2,) 1 microM) advanced and amplified the developmentally programmed accumulation of P450aromB mRNA, and ICI164.384 decreased expressed levels, implying blockade of an endogenous estrogen mediated regulatory component. Conversely, E(2) had no effect or decreased P450aromA mRNA. The early embryonic expression of P450aromB and P450aromA isoforms, and differences in developmental programming and estrogen regulation, imply independent regulatory mechanisms and unique functions during major morphogenetic and differentiative events.

Aging↗

PubMed2007

Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society.

OBJECTIVE: Low birth weight remains a major cause of morbidity and mortality in early infancy and childhood. It is associated with an increased risk of health problems later in life, particularly coronary heart disease and stroke. A meeting was convened to identify the key health issues facing a child born small for gestational age (SGA) and to propose management strategies. PARTICIPANTS: There were 42 participants chosen for their expertise in obstetrics, peri- and neonatal medicine, pediatrics, pediatric and adult endocrinology, epidemiology, and pharmacology. EVIDENCE: Written materials were exchanged, reviewed, revised, and then made available to all. This formed the basis for discussions at the meeting. Where published data were not available or adequate, discussion was based on expert clinical opinions. CONSENSUS PROCESS: Each set of questions was considered by all and then discussed in plenary sessions with consensus and unresolved issues identified. The consensus statement was prepared in plenary sessions and then edited by the group chairs and shared with all participants. CONCLUSIONS: The diagnosis of SGA should be based on accurate anthropometry at birth including weight, length, and head circumference. We recommend early surveillance in a growth clinic for those without catch-up. Early neurodevelopment evaluation and interventions are warranted in at-risk children. Endocrine and metabolic disturbances in the SGA child are recognized but infrequent. For the 10% who lack catch-up, GH treatment can increase linear growth. Early intervention with GH for those with severe growth retardation (height sd score, <-2.5; age, 2-4 yr) should be considered at a dose of 35-70 microg/kg x d. Long-term surveillance of treated patients is essential. The associations at a population level between low birth weight, including SGA, and coronary heart disease and stroke in later life are recognized, but there is inadequate evidence to recommend routine health surveillance of all adults born SGA outside of normal clinical practice.

Adult↗

PubMed2005

Midazolam in neonatal seizures with no response to phenobarbital.

The outcome of 45 neonates with EEG-confirmed seizures (ESz) was analyzed with regard to treatment. ESz persisted in 17 of 32 neonates receiving phenobarbital/phenytoin (13 had a poor outcome, 4 died). In contrast, ESz were rapidly controlled in 13 of 13 nonresponders to phenobarbital/phenytoin treated with midazolam (4 had poor outcome, 2 died). Nonresponders to phenobarbital/phenytoin had a significantly worse outcome than responders did. Midazolam effectively controlled ESz in nonresponders to phenobarbital/phenytoin and correlated with significantly improved long-term neurodevelopment.

Age Factors↗

PubMed2005

The pro-apoptotic activity of a vertebrate Bar-like homeobox gene plays a key role in patterning the Xenopus neural plate by limiting the number of chordin- and shh-expressing cells.

Targeted disruption of effectors molecules of the apoptotic pathway have demonstrated the occurrence and magnitude of early programmed cell death (EPCD), a form of apoptosis that affects proliferating and newly differentiated cells in vertebrates, and most dramatically cells of the central nervous system (CNS). Little is known about the molecular pathways controlling apoptosis at these early developmental stages, as the roles of EPCD during patterning of the developing nervous system. We describe a new function, in Xenopus neurodevelopment, for a highly conserved homeodomain protein Barhl2. Barhl2 promotes apoptosis in the Xenopus neuroectoderm and mesoderm, acting as a transcriptional repressor, through a mechanism that cannot be attributed to an unspecific cellular stress response. We show that the pro-apoptotic activity of Barhl2 is essential during normal neural plate formation as it limits the number of chordin- and Xshh-expressing cells in the prospective notochord and floorplate, which act as organizing centers. Our findings show that Barhl2 is part of a pathway regulating EPCD. They also provide evidence that apoptosis plays an important role in regulating the size of organizing centers.

Amino Acid Sequence↗

PubMed2006

The neurodevelopmental abilities of very-low-birthweight children in Trinidad, West Indies.

Neurodevelopmental abilities of 33 very-low-birthweight (VLBW) Trinidadian children and randomly selected matched pairs of classmates who were of normal birth weight were tested in 1998 at ages 68-88 months, using the McCarthy Scales of Children's Abilities. The 1 min Apgar score was significantly lower in the VLBW children, 6.5 (SD 1.0) versus 7.7 (SD 1.27), P<or=0.001. Mean scores on the McCarthy Scales for study and control children were: (Table cannot be represented.) These differences may reflect a delay in the neurodevelopment of these children. However, the effect of child-rearing practices and the inappropriateness of the test for the population cannot be ruled out.

Apgar Score↗

PubMed2002

Investigations of methylmercury-induced alterations in neurogenesis.

Methylmercury (MeHg) has been an environmental concern to public health and regulatory agencies for over 50 years because of its toxicity to the human nervous system. Its association with nervous system toxicity in adults and infants near Minamata Bay, Japan, in the 1950s initiated environmental health research inquiries that continue to this day. Observations of greater neurotoxicity with gestational compared with adult exposure suggest a unique susceptibility of the developing nervous system to MeHg. Despite extensive research conducted over the last half century, determination of definitive molecular mechanisms underlying the observed neurotoxic effects of MeHg have not been identified. This paper summarizes results of a series of experiments conducted to examine the effects of MeHg on neuroepithelial cell proliferation, a hypothesized mode of action for its selective effects on neurogenesis. Observed effects of MeHg on cell cycle entry and progression were associated with alterations in a variety of cell cycle regulatory molecules, including p21 signaling pathways. We place these studies in the context of other cellular responses involved in signal transduction, including oxidative stress, altered protein phosphorylation, and altered intracellular calcium homeostasis. Although existing information suggests that no single mechanism underlies the diverse array of effects associated with MeHg-induced developmental neurotoxicity, we demonstrate characteristic effects of MeHg on cell signaling that contribute to observed effects on cell proliferation. Experimentally derived cell cycle kinetic and cytotoxicity data allowed development of a biologically based dose-response model of MeHg-induced alterations in neurodevelopment, which can form the basis for information synthesis and hypothesis testing and for use in assessing risks from environmental exposures.

Animals↗

PubMed2003

Effects of PCB exposure on neuropsychological function in children.

In the last decade advances in the analytic methods for quantification of polychlorinated biphenyls (PCBs) have resulted in widespread availability of congener-specific analysis procedures, and large amounts of data on PCB congener profiles in soil, air, water, sediments, foodstuffs, and human tissues have become available. These data have revealed that the PCB residues in environmental media and human tissues may not closely resemble any of the commercial PCB mixtures, depending on source of exposure, bioaccumulation through the food chain, and weathering of PCBs in the environment. At the same time, toxicological research has led to a growing awareness that different classes of PCB congeners have different profiles of toxicity. These advances in analytic techniques and toxicological knowledge are beginning to influence the risk assessment process. As the data from ongoing PCB studies assessing the mediators of neurobehavioral outcomes in children are published, the weight of evidence for PCB effects on neurodevelopment is growing. Studies in Taiwan, Michigan (USA), New York (USA), Holland, Germany, and the Faroe Islands have all reported negative associations between prenatal PCB exposure and measures of cognitive functioning in infancy or childhood. The German study also reported a negative association between postnatal PCB exposure and cognitive function in early childhood--a result that had not been found in previous studies. Only one published study in North Carolina (USA) has failed to find an association between PCB exposure and cognitive outcomes. Despite the fact that several more recent studies have used congener-specific analytic techniques, there have been only limited attempts to assess the role of specific PCB congeners or classes of congeners in mediating neurodevelopmental outcomes. From a statistical standpoint, attempts to determine the role of individual congeners in mediating outcomes are hampered by the fact that concentrations of most individual congeners are highly correlated with each other and with total PCBs. From a toxicological standpoint, these efforts are hampered by the fact that many of the PCB congeners present in human tissues have never been studied in the laboratory, and their relative potency to produce nervous system effects is unknown. More complete information on the health effects of various congeners or congener classes would allow more informed scientific and risk assessment decisions.

Child↗

PubMed2003

Exposure to indoor pesticides during pregnancy in a multiethnic, urban cohort.

Evidence is growing that indoor pesticide exposure is of considerable magnitude in the United States and that pesticide concentrations may be especially high in urban areas. Of particular concern is exposure of pregnant women because animal data suggest that exposure to pesticides during pregnancy and early life may impair neurodevelopment in the offspring. To investigate the relationship between prenatal exposure to indoor pesticides and infant growth and development, we are conducting a prospective, multiethnic cohort study of mothers and infants delivered at Mount Sinai Hospital in New York City. This article provides data on pesticide exposure based on questionnaire items and analysis of maternal urinary metabolite levels among 386 women. Both the questionnaire and laboratory data revealed that exposure to indoor pesticides was considerable. The proportion of women estimated from questionnaire data as having been exposed during pregnancy to indoor pesticides (approximately 70%) was somewhat lower than the 80-90% of American households who reportedly used pesticides in previous surveys, but some of the latter surveys included both indoor and outdoor pesticide use. Urinary metabolite levels of 3,5,6-trichloro-2-pyridinol (TCPy; median = 11.3 micro g/g creatinine), phenoxybenzoic acid (PBA; median =19.3 micro g/g creatinine), and pentachlorophenol (PCP; median =7.3 micro g/g creatinine) were higher than those reported in other studies of adults in the United States. Furthermore, no associations were evident between the pesticide questionnaire data and the urinary metabolites. Assessments of sociodemographic and building characteristics with questionnaire data and the metabolite levels revealed no consistent trends. Significant temporal variations were observed for urinary PBA but not TCPy or PCP. The temporal variations for PBA were consistent with seasonal spraying of pyrethroid pesticides. These data underscore the need to assess the potentially adverse effects of pesticide exposure on fetuses and infants and the importance of finding alternative methods for pest management to reduce pesticide exposures.

Adult↗

PubMed2003

Increased influence of genetic variation on PON1 activity in neonates.

PON1 (paraoxonase-1) detoxifies organophosphates by cleavage of active oxons before they have a chance to inhibit cholinesterases. The corresponding gene PON1 has common polymorphisms in both the promoter (-909, -162, -108) and the coding region (L55M, Q192R). The five PON1 genotypes were determined for maternal blood (n= 402) and cord blood (n= 229) as part of a study of the effects of organophosphate pesticide exposure on infant growth and neurodevelopment. PON1 enzymatic activities were determined for a majority of subjects. The population contained Caucasians, Caribbean Hispanics, and African Americans. PON1 activity was strongly dependent upon the promoter alleles in both maternal and cord blood. For example, PON1 activities for position -108CC, CT, and TT mothers were 146, 128, and 109 arylesterase U/mL (analysis of variance, p< 0.0001), whereas the same PON1 activities for the respective cord bloods were 49.0, 32.4, and 23.2 U/mL (p < 0.0001). Compared with adults, neonates had lower PON1 activity, implying reduced capacity to detoxify organophosphates. In addition there was a larger difference in activity between genotype groups in neonates than in adults. Because the five polymorphisms in PON1 occur in a short stretch of DNA, they were tested for linkage disequilibrium (LD). Significant LD was found among all three promoter polymorphisms as well as between promoter polymorphisms and L55M, with the strongest LD for Caucasians and the weakest for African Americans. The Caribbean Hispanics fall between these two groups. Surprisingly, significant LD also was observed between the promoter polymorphisms and C311S in PON2. LD between the promoter polymorphisms and Q192R was not significant.

Adult↗

PubMed2003

Polybrominated diphenyl ethers in maternal and fetal blood samples.

Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants in consumer goods, such as plastics, electronics, textiles, and construction material. PBDEs have been found in human milk, fat, and blood samples. Rodent studies indicate that PBDEs may be detrimental to neurodevelopment, possibly by lowering thyroid hormone concentrations in blood. In the present study, we determined concentrations of PBDEs and thyroid hormones in human fetal and maternal serum. Patients presenting in labor to Indiana University and Wishard Memorial County hospitals in Indianapolis, who were older than 18 years, were recruited to participate. Twelve paired samples of maternal and cord blood were obtained and analyzed using gas chromatographic mass spectrometry; thyroid hormone concentrations were determined by radioimmunoassay. Six congeners of PBDE were measured in maternal and fetal serum samples. The concentrations of total PBDEs found in maternal sera ranged from 15 to 580 ng/g lipid, and the concentrations found in fetal samples ranged from 14 to 460 ng/g lipid. Individual fetal blood concentrations did not differ from the corresponding maternal concentrations, indicating that measurement of maternal PBDE blood levels is useful in predicting fetal exposure; similarly, other reports have shown a high correlation between PBDE in mother's milk and fetal exposure. In accord with reports on other biologic samples, the tetrabrominated PBDE congener BDE-47 accounted for 53-64% of total PBDEs in the serum. The concentrations of PBDEs found in maternal and fetal serum samples were 20-106-fold higher than the levels reported previously in a similar population of Swedish mothers and infants. In this small sample, there was no apparent correlation between serum PBDEs and thyroid hormone concentrations. Our study shows that human fetuses in the United States may be exposed to relatively high levels of PBDEs. Further investigation is required to determine if these levels are specific to central Indiana and to assess the toxic potential of these exposure levels.

Adult↗

PubMed2005

Air pollution exposure assessment for epidemiologic studies of pregnant women and children: lessons learned from the Centers for Children's Environmental Health and Disease Prevention Research.

The National Children's Study is considering a wide spectrum of airborne pollutants that are hypothesized to potentially influence pregnancy outcomes, neurodevelopment, asthma, atopy, immune development, obesity, and pubertal development. In this article we summarize six applicable exposure assessment lessons learned from the Centers for Children's Environmental Health and Disease Prevention Research that may enhance the National Children's Study: a) Selecting individual study subjects with a wide range of pollution exposure profiles maximizes spatial-scale exposure contrasts for key pollutants of study interest. b) In studies with large sample sizes, long duration, and diverse outcomes and exposures, exposure assessment efforts should rely on modeling to provide estimates for the entire cohort, supported by subject-derived questionnaire data. c) Assessment of some exposures of interest requires individual measurements of exposures using snapshots of personal and microenvironmental exposures over short periods and/or in selected microenvironments. d) Understanding issues of spatial-temporal correlations of air pollutants, the surrogacy of specific pollutants for components of the complex mixture, and the exposure misclassification inherent in exposure estimates is critical in analysis and interpretation. e) "Usual" temporal, spatial, and physical patterns of activity can be used as modifiers of the exposure/outcome relationships. f) Biomarkers of exposure are useful for evaluation of specific exposures that have multiple routes of exposure. If these lessons are applied, the National Children's Study offers a unique opportunity to assess the adverse effects of air pollution on interrelated health outcomes during the critical early life period.

Air Pollutants↗

PubMed1998

Developmental neurotoxicology of endocrine disruptors and pesticides: identification of information gaps and research needs.

There is increasing evidence that some environmental chemicals can interrupt neurodevelopmental processes during critical periods of development, resulting in effects on sensory, motor, and cognitive function. It is now generally accepted that developing organisms are differentially sensitive to chemical exposure because of toxicokinetic and/or toxicodynamic factors. Regulatory mechanisms have been implemented to protect humans from over- or inappropriate exposures to environmental chemicals. Current regulatory practices, however, may be insufficient because of the possibility that some environmental chemicals interfere with endocrine function at key periods of neurodevelopment. In addition, a recent National Research Council (NRC) report on pesticide contamination in the diets of infants and children concluded that current regulatory practices may not sufficiently protect infants and children from the risk of pesticide exposure. The NRC report indicates that regulatory agencies might underestimate the actual exposure of infants and children to pesticides and rely too heavily on data from adults in the risk assessment of pesticides. Consideration of endocrine-disrupting chemicals and the differential susceptibility of infants and children has led to identification of a number of information gaps and research needs that should be addressed in order to improve future risk assessments for these chemicals.

Adult↗

PubMed1999

Association of prenatal maternal or postnatal child environmental tobacco smoke exposure and neurodevelopmental and behavioral problems in children.

We review the potential neurodevelopmental and behavioral effects of children's prenatal and/or postnatal exposure to environmental tobacco smoke (ETS). Children's exposure to ETS has been assessed in epidemiologic studies as a risk factor for a variety of behavioral and neurodevelopmental problems including reduced general intellectual ability, skills in language and auditory tasks, and academic achievement, and behavioral problems such as hyperactivity and decreased attention spans. We review 17 epidemiologic studies that have attempted to separate the effects of maternal active smoking during pregnancy from passive ETS smoke exposure by the pregnant mother or the child. Based on the available data, we found that ETS exposure could cause subtle changes in children's neurodevelopment and behavior. However, studies to date are difficult to interpret because of the unknown influence of uncontrolled confounding factors, imprecision in measurements of smoking exposure, and collinearity of pre- and postnatal maternal smoking. Although some evidence suggests that maternal smoking during pregnancy may be associated with deficits in intellectual ability and behavioral problems in children, the impact of prenatal or postnatal ETS exposure remains less clear.

Child Behavior Disorders↗

PubMed2000

Ultrarapid opioid detoxification of two children with congenital heart disease.

The cases of two children with congenital heart disease and severe opioid dependency who underwent ultrarapid opioid detoxification are presented. This technique entails rapid opioid reversal with the opioid antagonist naloxone while under general anesthesia. The procedures were not technically difficult to perform and both children were successfully detoxified at the end of the procedure. In the weeks following the procedure, the first child exhibited accelerated neurodevelopment. Ultrarapid opioid detoxification is possible in children and may have a neurodevelopmental advantage over a prolonged wean.

Analgesics, Opioid↗

PubMed2006

Awareness of fish advisories and mercury exposure in women of childbearing age.

Methylmercury crosses the placenta and increases the risk of impaired neurodevelopment in the fetus. Federal guidelines for fish intake and fish advisories are in place to help people of all ages limit their exposure to mercury from fish. However, recent studies suggest that the awareness of fish advisories is low among women of childbearing age. Fish intake is strongly correlated with hair mercury concentrations. In women in states with fish advisories, hair mercury concentrations were 7-fold higher in women who consumed 20 or more servings of fish than in those who reported nofish consumption in the past 3 months (0.59 vs. 0.08 microg/g). Among this high fish consumption group, the 75th and 95th percentile of hair mercury concentrations were 0.99 and 2.29 microg/g, respectively. This is of concern because the US Environmental Protection Agency (EPA) recommends that hair mercury be less than 1 microg/g. Public health campaigns to reduce mercury exposure need further refinement to reach women of childbearing age.

Adult↗