Brucknerova I

Evaluation of developmental neurotoxicity: some important issues focused on neurobehavioral development

Evaluation of developmental neurotoxicity: some important issues focused on neurobehavioral development Exposure of the developing organism to industrial chemicals and physical factors represents a serious risk factor for the development of neurobehavioral disorders, such as attention-deficit hyperactivity disorder, autism and mental retardation. Appropriate animal models are needed to test potentially harmful effects and mechanisms of developmental neurotoxicity of various chemical substances. However, there are significant human vs. rat differences in the brain developmental profile which should be taken into account in neurotoxicity studies. Subtle behavioral alterations are hard to detect by traditional developmental toxicity and teratogenicity studies, and in many cases they remain hidden. They can however be revealed by using special behavioral, endocrine and/or pharmacological challenges, such as repeated behavioral testing, exposure to single stressful stimulus or drugs. Further, current neurobehavioral test protocols recommend to test animals up to their adulthood. However some behavioral alterations, such as anxiety-like behavior or mental deficiency, may become manifest in later periods of development. Our experimental and scientific experiences are highly suggestive for a complex approach in testing potential developmental neurotoxicity. Strong emphasis should be given on repeated behavioral testing of animals up to senescence and on using proper pharmacological and/or stressful challenges.

Teratology – past, present and future

ABSTRACT Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development. The authors present an updated overview of the most important milestones and stages of the development of modern teratology. Development of knowledge and society led to the recognition that causes of congenital developmental disorders (CDDs) might be caused by various mechanical effects, foetal diseases, and retarded or arrested development of the embryo and foetus. Based on the analysis of the historical development of hypotheses and theories representing a decisive contribution to this field, we present a survey of the six Wilson´s fundamental principles of teratology. The aim of observing these principles is to get insight into developmental relations and to understand mechanisms of action on the level of cell populations (elementary morphogenetic processes), tissues and organs. It is important to realise that any negative intervention into the normal course of these processes, either on genetic or non-genetic basis, inevitably leads to a sequence of subsequent changes resulting in CDDs. Moreover, the classical toxicologic monotonic doseresponse paradigm recently has been challenged by the so-called “low dose-hypothesis”, particularly in the case of endocrine active substances. These include some pesticides, dioxins, polychlorobiphenyls (PCBs), and bisphenol A. Despite modern approaches of molecular biology and genetics, along with top diagnostic techniques, we are still not able to identify the actual cause in more than 65 to 70% of all congenital defects classified as having an unknown etiology. Today CDDs include any birth defect, either morphological, biochemical, or behavioural.

Experimental modeling of hypoxia in pregnancy and early postnatal life

Experimental modeling of hypoxia in pregnancy and early postnatal life The important role of equilibrium of environmental factors during the embryo-fetal period is undisputable. Women of reproductive age are increasingly exposed to various environmental risk factors such as hypoxia, prenatal viral infections, use of drugs, smoking, complications of birth or stressful life events. These early hazards represent an important risk for structural and/or functional maldevelopment of the fetus and neonates. Impairment of oxygen/energy supply during the pre- and perinatal period may affect neuronal functions and induce cell death. Thus when death of the newborn is not occurring following intrauterine hypoxia, various neurological deficits, including hyperactivity, learning disabilities, mental retardation, epilepsy, cerebral palsy, dystonia etc., may develop both in humans and in experimental animals. In our animal studies we used several approaches for modeling hypoxia in rats during pregnancy and shortly after delivery, i.e. chronic intrauterine hypoxia induced by the antiepileptic drug phenytoin, neonatal anoxia by decreased oxygen saturation in 2-day-old pups. Using these models we were able to test potential protective properties of natural (vitamin E, melatonin) and synthetic (stobadine) compounds. Based on our results, stobadine was also able to reduce hypoxia-induced hyperactivity and the antioxidant capacity of stobadine exceeded that of vitamin E and melatonin, and contrary to vitamin E, stobadine had no adverse effects on developing fetus and offspring.

Early assessment of the severity of asphyxia in term newborns using parameters of blood count

Early assessment of the severity of asphyxia in term newborns using parameters of blood count Acute perinatal asphyxia is a major cause of death and neurological injury in newborn infants. Severe asphyxia can occur in infants around the time of birth for several reasons. The aim of our study was to find the most sensitive, easily obtainable and fast assessable parameter of the presence and quantification of asphyxia. In our study 39 term newborns (15 healthy term newborns and 24 asphyxial term newborns), from vaginal deliveries admitted within 24 hours of life were monitored and parameters of blood count from venous blood were assessed. Laboratory findings of blood count parameters revealed significant differences between term asphyxial and healthy newborns in erythrocyte count and hemoglobin and hematocrit values. Hematological changes observed early after delivery can determine the duration of hypoxemia (acute vs. chronic) and asphyxia of short duration may be accompanied without occurrence of polyglobulia.

Subchronic perinatal asphyxia in rats: Embryo–foetal assessment of a new model of oxidative stress during critical period of development

Approximately 3% of annual births suffer from birth asphyxia and one million of these newborns die. The aim of this study was to develop a model for studying subchronic perinatal asphyxia (SPA) in rats. Pregnant animals were exposed to 10.5% O2 during sensitive stages of brain development for 4h a day. Biochemical variables were analysed immediately and 24h after asphyxia. SPA caused significant reduction of foetal weight, produced abnormalities of distal parts of the skeleton, and anomalies in the development of brain ventricles. Time-dependent changes were observed in several parameters indicating adjustment of the developing organism to the delivery. Whereas lactate was elevated immediately after asphyxia, glucose mirrored high energy needs 24h after the insult. Immunohistochemical examination of the placentas revealed overgrowth of acidic glycoconjugates in the extracellular matrix of vascular walls in the animals exposed to asphyxia. We observed the presence of muscle fibres in chorionic plate arteries and also in intraplacental arteries. The present model proved to be useful for the study of asphyxial conditions during pregnancy. As it is non-invasive and allows to control asphyxial conditions, it appears suitable for the screening and investigation of indicators of asphyxia in the mother and foetus.

Safety assessment of the pyridoindole derivative SMe1EC2: developmental neurotoxicity study in rats.

Safety assessment of the pyridoindole derivative SMe1EC2: developmental neurotoxicity study in rats The present study deals with effect of prenatal and neonatal administration of the synthetic pyridoindole derivative SMe1EC2 (2-ethoxycarbonyl-8-methoxy-2,3,4,4a, 5,9b-hexahydro-1H-pyrido-[4,3b] indolinium chloride) on postnatal and neurobehavioral development of the rat offspring. The substance tested was administered to pregnant rats orally in the doses 5, 50 and 250 mg/kg from day 15 of gestation to day 10 post partum (PP). From the day 4 PP, the postnatal development and neurobehavioral characteritics of offspring were evaluated. The following variables were observed: body weight, pinna detachment, incisor eruption, ear opening, eye opening, testes descent and vaginal opening, righting reflex, negative geotaxia, startle reflex, dynamic air righting and exploratory behavior in a new environment. No maternal death, abortion or dead fetuses occurred either in the control or SMe1EC2 groups. Dynamic righting reflex was delayed one day in the groups of animals treated via their mothers with 5 and 50 mg/kg SMe1EC2. The delay in the development of this reflex was only transient. On day 20 PP, all pups tested had a positive score of the reflex. Administration of SMe1EC2 did not reveal any significant changes in other variables of somatic growth and maturation, reflex and neuromotor development and exploratory behavior, either of young or adult animals of both genders, assessed by analysis of variance.

How can the process of postnatal adaptation be changed by the presence of congenital abnormalities of lip and palate

Abstract Despite modern approaches in molecular biology and genetics, we are still not able to identify the actual cause in more than 50% of all congenital defects. One-half of the unidentified cases is referred to as “multifactorial”. Detailed prenatal investigation of the fetus can discover the presence of congenital abnormality, which can worsen the process of postnatal adaptation. Retrospective analysis of newborns admitted to the Neonatal Department of Intensive Medicine (NDIM) in 2012-2016 with the aim to analyze how the process of postnatal adaptation can be changed by the presence of congenital abnormalities of lip and palate. During a five-year period, 13 newborns were admitted to NDIM (2 premature; 11 term newborns). Chromosomal abnormality was confirmed in one patient (Down syndrome) and in one patient suspicion of Patau syndrome was found. Twelve newborns had complete cheilognathopalatoschisis. Two premature newborns and two term newborns had perinatal asphyxia. In this group of patients, 33% had respiratory insufficiency without the presence of congenital heart abnormality, 66% had congenital heart abnormality with respiratory insufficiency, and 2 patients had feeding problems. Only one patient had a positive family history. The diagnosis of complete cheilognathopalatoschisis was confirmed prenatally only in 9 patients. We confirmed that clinical consequences of congenital abnormalities of lip and palate depend on the nature, localization and range of abnormalities, as well as on the genetic background and accompanying congenital abnormalities. Prenatal confirmation of the presence of congenital abnormalities has an important influence on the postnatal management of a patient.

Red blood cell folate concentrations in term newborns: recent findings in the Slovak Republic

Folate plays one of the most important functions for nucleotide biosynthesis and cellular methylation reactions in cells. Folate-mediated one-carbon metabolism is essential for metabolic processes in the human body. During periods of rapid cell growth, such as perinatal period, increased amounts of folate are required. The determination of red blood cell (RBC) folate concentration levels is the most accurate indicator of long-term folate level status in the body. This prospective study determined RBC folate concentration levels on the first day of life from umbilical cord blood samples in the whole group of full-term newborns (n = 150), who were hospitalized at the Department of Neonatology at the University Hospital in Bratislava. Immunochemical analysis for the determination of folate levels in erythrocytes was performed (Roche Diagnostics, Germany). Mothers were asked to select different types of food and use folic acid or other multivitamin supplements containing also folic acid. Our results of RBC folate ranged from 625 to 1748 ng/mL (5th–95th percentile). The median was 935 ng/mL and deficiency was not observed in any sample. RBC folate concentration levels in newborns due to mother’s intake of multivitamin supplements were significantly increased (p = 0.02). No differences were observed in the levels of RBC folate concentration when mothers used only folic acid. The RBC folate concentration tended to change based on many factors on both the mother’s and the newborn’s sides. Our results showed different results of RBC folate when focused on neonatal period and maternal intake of vitamins during pregnancy.