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Polyfluorinated chemicals (PFCs) are a series of endocrine disruptors (EDCs) generated from industrial production and existing in environment of daily life. PFCs can be accumulated in animal tissues, and perform reproductive toxicity through different mechanisms such as disrupting steroidogenesis, inducing apoptosis of reproductive cells and acting as antagonism of hormone receptors. In male, PFCs were found to be associated with the decreased sperm quality and concentration, and the increased rate of sperm deformation, and to disturb sexual hormones such as testosterone. In female, PFCs increased in blood or follicular fluid were related to the decreased fertility. Moreover, the exposure to PFCs during pregnancy may affect the health and fertility of offspring. The molecular mechanisms of this kind of chemicals have been studied in many animal experiments. In conclusion, we should pay attention to the reproductive toxicity of PFCs. [ABSTRACT FROM AUTHOR]

Introduction: Despite a wealth of epidemiological evidence that cumulative parental lifetime stress experiences prior to conception are determinant of offspring developmental trajectories, there is a lack of insight on how these previous stress experiences are stored and communicated intergenerationally. Preconception experiences may impact offspring development through alterations in transcriptional regulation of the placenta, a major determinant of offspring growth and sex-specific developmental outcomes. We evaluated the lasting influence of maternal and paternal preconception stress (PCS) on the mid-gestation placenta and fetal brain, utilizing their transcriptomes as proximate readouts of intergenerational impact., Methods: To assess the combined vs. dominant influence of maternal and paternal preconception environment on sex-specific fetal development, we compared transcriptional outcomes using a breeding scheme of one stressed parent, both stressed parents, or no stressed parents as controls., Results: Interestingly, offspring sex affected the directionality of transcriptional changes in response to PCS, where male tissues showed a predominant downregulation, and female tissues showed an upregulation. There was also an intriguing effect of parental sex on placental programming where paternal PCS drove more effects in female placentas, while maternal PCS produced more transcriptional changes in male placentas. However, in the fetal brain, maternal PCS produced overall more changes in gene expression than paternal PCS, supporting the idea that the intrauterine environment may have a larger overall influence on the developing brain than it does on shaping the placenta., Discussion: Preconception experiences drive changes in the placental and the fetal brain transcriptome at a critical developmental timepoint. While not determinant, these altered transcriptional states may underlie sex-biased risk or resilience to stressful experiences later in life., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We investigated if greenness and air pollution exposure in parents' childhood affect offspring asthma and hay fever, and if effects were mediated through parental asthma, pregnancy greenness/pollution exposure, and offspring exposure. We analysed 1106 parents with 1949 offspring (mean age 35 and 6) from the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) generation study. Mean particulate matter (PM 2.5 and PM 10 ), nitrogen dioxide (NO 2 ), black carbon (BC), ozone (O 3 ) (µg/m 3 ) and greenness (normalized difference vegetation index (NDVI)) were calculated for parents 0-18 years old and offspring 0-10 years old, and were categorised in tertiles. We performed logistic regression and mediation analyses for two-pollutant models (clustered by family and centre, stratified by parental lines, and adjusted for grandparental asthma and education). Maternal medium PM 2.5 and PM 10 exposure was associated with higher offspring asthma risk (odds ratio (OR) 2.23, 95%CI 1.32-3.78, OR 2.27, 95%CI 1.36-3.80), and paternal high BC exposure with lower asthma risk (OR 0.31, 95%CI 0.11-0.87). Hay fever risk increased for offspring of fathers with medium O 3 exposure (OR 4.15, 95%CI 1.28-13.50) and mothers with high PM 10 exposure (OR 2.66, 95%CI 1.19-5.91). The effect of maternal PM 10 exposure on offspring asthma was direct, while for hay fever, it was mediated through exposures in pregnancy and offspring's own exposures. Paternal O 3 exposure had a direct effect on offspring hay fever. To conclude, parental exposure to air pollution appears to influence the risk of asthma and allergies in future offspring.

Using a mouse model, our group recently described an association between chronic paternal alcohol use prior to conception and deficits in offspring growth. Here, we sought to determine the impact of alcohol exposure on male reproductive physiology and the association of sperm-inherited noncoding RNAs with the transmission of the observed growth defects. Alcohol exposure did not appreciably alter male reproductive physiology or fertility. However, chronic alcohol use reproducibly induced late-term fetal growth restriction in the offspring, which correlated with a shift in the proportional ratio of transfer RNA-derived small RNAs to Piwi-interacting RNAs, as well as altered enrichment of microRNAs miR21, miR30, and miR142 in alcohol-exposed sperm. Although our dataset share similarities to prior works examining the impact of paternal stress on offspring phenotype, we were unable to identify any changes in plasma corticosterone, indicating alcohol may alter sperm-inherited noncoding RNAs through distinct mechanisms., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Autism spectrum disorder (ASD), one of the most common childhood neurodevelopmental disorders (NDDs), is diagnosed in 1 of every 68 children. ASD is incredibly heterogeneous both clinically and aetiologically. The etiopathogenesis of ASD is known to be complex, including genetic, environmental and epigenetic factors. Normal epigenetic marks modifiable by both genetics and environmental exposures can result in epigenetic alterations that disrupt the regulation of gene expression, negatively impacting biological pathways important for brain development. In this chapter we aim to summarize some of the important literature that supports a role for epigenetics in the underlying molecular mechanism of ASD. We provide evidence from work in genetics, from environmental exposures and finally from more recent studies aimed at directly determining ASD-specific epigenetic patterns, focusing mainly on DNA methylation (DNAm). Finally, we briefly discuss some of the implications of current research on potential epigenetic targets for therapeutics and novel avenues for future work.

Background: Alcohol-related mortality and morbidity among women has increased over recent decades, especially in areas of higher deprivation. Pre-pregnancy alcohol use is associated with continued consumption in pregnancy. We assessed whether general population alcohol consumption patterns were reflected among pregnant women in two Scottish areas with different deprivation levels., Methods: Cross-sectional study in two health boards (HB1, lower deprivation levels, n = 274; HB2, higher deprivation levels, n = 236), using face-to-face 7-day Retrospective Diary estimation of peri-conceptual and mid-pregnancy alcohol consumption., Results: A greater proportion of women in HB2 (higher deprivation area) sometimes drank peri-conceptually, but women in HB1 (lower deprivation area) were more likely to drink every week (49.6 vs 29.7%; p < 0.001) and to exceed daily limits (6 units) at least once each week (32.1 vs 14.8%; p < 0.001). After pregnancy recognition, consumption levels fell sharply, but women in HB2 were more likely to drink above recommended daily limits (2 units) each week (2.5 vs 0.0%; p < 0.05). However, women in HB1 were more likely to drink frequently. Women with the highest deprivation scores in each area drank on average less than women with the lowest deprivation scores., Conclusions: Heavy episodic and frequent consumption was more common in the lower deprivation area, in contrast with general population data. Eliciting a detailed alcohol history at the antenatal booking visit, and not simply establishing whether the woman is currently drinking, is essential. Inconsistent messages about the effects of alcohol in pregnancy may have contributed to the mixed picture we found concerning peri-conceptual and mid-pregnancy alcohol consumption., (© 2016 Wiley Periodicals, Inc.)

Background: Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene., Methods: We examined DNA from umbilical cord blood leukocytes from 79 newborns, born between July 2005 and November 2006 at Duke University Hospital, Durham, NC. Their mothers participated in the Newborn Epigenetics Study (NEST) during pregnancy. Parental characteristics were obtained via standardized questionnaires and medical records. DNA methylation patterns at two DMRs were analyzed by bisulfite pyrosequencing; one DMR upstream of IGF2 (IGF2 DMR), and one DMR upstream of the neighboring H19 gene (H19 DMR). Multiple regression models were used to determine potential associations between the offspring's DNA methylation patterns and parental obesity before conception. Obesity was defined as body mass index (BMI) ≥30 kg/m²., Results: Hypomethylation at the IGF2 DMR was associated with paternal obesity. Even after adjusting for several maternal and newborn characteristics, we observed a persistent inverse association between DNA methylation in the offspring and paternal obesity (β-coefficient was -5.28, P = 0.003). At the H19 DMR, no significant associations were detected between methylation patterns and paternal obesity. Our data suggest an increase in DNA methylation at the IGF2 and H19 DMRs among newborns from obese mothers, but a larger study is warranted to further explore the potential effects of maternal obesity or lifestyle on the offspring's epigenome., Conclusions: While our small sample size is limited, our data indicate a preconceptional impact of paternal obesity on the reprogramming of imprint marks during spermatogenesis. Given the biological importance of imprinting fidelity, our study provides evidence for transgenerational effects of paternal obesity that may influence the offspring's future health status.

Adverse condition of rat development during the prenatal period (rearing by mother survived brain injury) or during the early post-natal period (cross fostering), causes impairment of motor behavior and a lipid turnover in adult rats. Such rats under severe stress showed decrease of adaptation (as expressed or low indexes of motor impellent behavior and lipid metabolism) in comparison with rats that were grown up by own mother. The psychoemotional stress caused the most expressed deficient behavior in males that were grown up by mothers with brain injury (decrease in serum level of HC and HDL and depressively - similar behavior).

Background: Obesity and related conditions, notably subfertility, are increasingly prevalent. Paternal influences are known to influence offspring health outcome, but the impact of paternal obesity and subfertility on the reproductive health of subsequent generations has been overlooked., Methods: A high-fat diet (HFD) was used to induce obesity but not diabetes in male C57Bl6 mice, which were subsequently mated to normal-weight females. First-generation offspring were raised on a control diet and their gametes were investigated for signs of subfertility. Second-generation offspring were generated from both first generation sexes and their gametes were similarly assessed., Results: We demonstrate a HFD-induced paternal initiation of subfertility in both male and female offspring of two generations of mice. Furthermore, we have shown that diminished reproductive and gamete functions are transmitted through the first generation paternal line to both sexes of the second generation and via the first generation maternal line to second-generation males. Our previous findings that founder male obesity alters the epigenome of sperm, could provide a basis for the developmental programming of subfertility in subsequent generations., Conclusions: This is the first observation of paternal transmission of diminished reproductive health to future generations and could have significant implications for the transgenerational amplification of subfertility observed worldwide in humans.

Aim: Observation of identical genetic changes in leukemia cells from monozygotic twin pairs has provided evidence for the in utero single clonal origin hypothesis of leukemia, with intraplacental metastasis the basis for concordance. Investigation of this rare mixed lineage leukemia (MLL) cytogenetic abnormality aims to provide further evidence of the genetic changes that underpin this aggressive form of leukemia in infants., Method: The clinical features of a monozygotic infant twin pair with acute lymphoblastic leukemia (ALL) are reported. Banded chromosomal analysis and fluorescent in situ hybridization were used for cytogenetic characterization of the leukemic cells. Immunophenotype was determined by flow cytometry and polymerase chain reaction was used to determine the presence of FLT3-D835/I836 and FLT3-internal tandem duplication (ITD) mutations., Results: The twins were seven weeks of age at diagnosis. Both had cytogenetic evidence for the t(1;11)(p32;q23) translocation. Trisomy X was present in a subpopulation of cells in one twin. Immunophenotypic profile at diagnosis was consistent with B precursor ALL (CD19, CD24, CD33 positive, weak CD13 positivity, CD10 negative) and both were negative for FLT3-D835/I836 and FLT3-ITD mutations., Conclusions: This is the first report of monochorionic monozygotic twins harboring the t(1;11)(p32;q23) translocation. Identification of this rare translocation in both twins, indicates a common stem line and provides further evidence for the intrauterine monoclonal origin for infant ALL with concordance explained by the shared circulation. Genetic diversity was observed in a subpopulation of cells from one twin at diagnosis. We must now utilize the sophisticated molecular biology tools available to capture changes at the genome-wide level to gain further insight into the complex events contributing to MLL leukemogenesis in infants., (Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.)

The authors proved relationship between congenital abnormalities in children and influence of chemical factors (methanol and formaldehyde production) on the parents. Higher risk of congenital abnormalities was seen: PR = 5.6 (chi2 = 3.54; p = 0.00001), EF = 0.95. These disorders could be connected with work conditions--exceeded MAC for methanol 3.9-fold, that for formaldehyde--2.4-fold.

Objective: We reviewed the evidence for three theories of how preconceptional psychosocial stress could act as a contributing determinant of excess preterm birth risk among African American women: early life developmental plasticity and epigenetic programming of adult neuroendocrine systems; blunting, weathering, or dysfunction of neuroendocrine and immune function in response to chronic stress activation through the life course; individuals' adoption of risky behaviors such as smoking as a response to stressful stimuli., Methods: Basic science, clinical, and epidemiologic studies indexed in MEDLINE and Web of Science databases on preconceptional psychosocial stress, preterm birth and race were reviewed., Results: Mixed evidence leans towards modest associations between preconceptional chronic stress and preterm birth (for example common odds ratios of 1.2-1.4), particularly in African American women, but it is unclear whether this association is causal or explains a substantial portion of the Black-White racial disparity in preterm birth. The stress-preterm birth association may be mediated by hypothalamic-pituitary-adrenal axis dysfunction and susceptibility to bacterial vaginosis, although these mechanisms are incompletely understood. Evidence for the role of epigenetic or early life programming as a determinant of racial disparities in preterm birth risk is more circumstantial., Conclusions: Preconceptional stress, directly or in interaction with host genetic susceptibility or infection, remains an important hypothesized risk factor for understanding and reducing racial disparities in preterm birth. Future studies that integrate adequately sized epidemiologic samples with measures of stress, infection, and gene expression, will advance our knowledge and allow development of targeted interventions., (© 2011 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2011 Nordic Federation of Societies of Obstetrics and Gynecology.)

SENTIERI Project (Mortality study of residents in Italian polluted sites) studies mortality of residents in 44 sites of national interest for environmental remediation (Italian polluted sites, IPSs). A development of the Project is the investigation of adverse reproductive effects. This issue is of the utmost importance in the field of environmental epidemiology, both in analytical studies and in surveillance activity. An environmental factor can be at play either as a preconception mutagen (maternal or paternal exposure) or as a postconceptional teratogen. The US-Agency for Toxic Substances and Disease Registry (ATSDR) and the US-Environmental Protection Agency (USEPA), indicate as a priority the study of congenital anomalies (CA) and reproductive disorders. The choice of congenital anomalies to be included in the study is mainly based on the results of the evaluation of the epidemiological evidence completed for SENTIERI Project. The epidemiological knowledge on congenital anomalies in polluted sites is lacking, therefore main groups of CA will also be included for descriptive purposes. Data on CA are produced by seven registers located in Italy, either in regional or sub-regional areas, which are included in the National Committee of Congenital Malformations Registers hosted by the National Center for Rare Diseases at Istituto Superiore di Sanità. The study periods are: a) 1995-2002 (1996-2002 for the Region Campania), namely the same years as SENTIERI mortality study; b) for the years 2003-2008 different time windows will be chosen on the basis of data availability in single registers. Registers of CA are active in 16 out of 44 polluted sites included in SENTIERI, for a total of 119 municipalities. In each polluted site the number of expected cases for each CA will be estimated from the prevalence at birth of the same anomaly as from regional registers active in the polluted site at study. For a description of SENTIERI, refer to the 2010 Supplement of Epidemiology & Prevention devoted to the Project.

Multiple sclerosis is a common disease of young adults in which accidental and unplanned pregnancies under disease modifying or immunosuppressive therapies may occur. The experience with mitoxantrone (MIX) especially in the first trimenon is very limited, until now only one case of a pregnant woman with MS who was exposed to MIX in early pregnancy and delivered a growth restricted but healthy child was published. We report a case of a secondary progressive MS patient who was exposed periconceptionally to MIX and delivered a child with Pierre Robin Sequence (PRS), a syndrome with the main features of glossoptosis, micrognathia, and palate clefts. PRS is a very rare defect and therefore a causal relation with MIX seems possible., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Developmental exposure to polychlorinated biphenyls (PCBs) disrupts reproduction in animals. Human data are lacking. We measured PCBs in preserved mothers' serum samples collected during 1960-1963, 1-3 days after their daughters' birth. We recorded time to pregnancy (TTP) in 289 daughters 28-31 years later. PCB congeners 187, 156, and 99 in mother's serum were associated with longer TTP in their daughters while PCB congeners 105, 138 and 183 were associated shorter TTP. Probability of pregnancy fell by 38% (95% CI 17-53%) and infertility was higher (30% not pregnant after 13 cycles versus 11% not pregnant after 13 cycles) among women whose mothers had a higher proportion of PCB congeners associated with longer TTP (75th percentile versus 25th percentile). This study demonstrates, for the first time, that developmental exposure to PCBs may disrupt pregnancy in humans., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To evaluate the effect of pregestational metformin administration on abortion risk in polycystic ovary syndrome (PCOS) patients., Design: Systematic review and meta-analysis., Setting: Academic Department of Obstetrics and Gynecology in Italy., Patient(s): Women affected by PCOS receiving pregestational metformin., Intervention(s): Systematic review of randomized controlled trials (RCTs) published up to June 2008 and subsequent meta-analysis., Main Outcome Measure(s): Abortion rate., Result(s): Seventeen RCTs were included in the final analysis. Overall, no effect of the metformin administration was detected on the abortion risk. No statistically significant effect of metformin on the abortion risk was observed in any comparison when subgrouping the RCTs according to received treatment., Conclusion(s): Metformin has no effect on the abortion risk in PCOS patients when administered before pregnancy.

Background: Consumption of fish contaminated with polychlorinated biphenyls (PCBs) and prenatal PCB serum concentrations have been associated with a longer time-to-pregnancy (TTP). However, the relationship between preconception serum PCBs concentrations and TTP has not been previously studied., Methods: Eighty-three women (contributing 442 menstrual cycles) planning pregnancies completed daily diaries regarding menstruation, intercourse, home pregnancy test results, and reported use of alcohol and cigarettes. TTP denoted the number of observed menstrual cycles required for pregnancy. Preconception blood specimens underwent toxicologic analysis for 76 PCB congeners via gas chromatography with electron capture; serum lipids were quantified with enzymatic methods. A priori, PCB congeners were summed into a total and three groupings-estrogenic, anti-estrogenic and other-and entered into discrete analogs of Cox models with time-varying covariates to estimate fecundability odds ratios (FOR) and corresponding 95% confidence intervals (CIs)., Results: Estrogenic and anti-estrogenic PCB concentrations (ng/g serum) conferred reduced FORs in fully adjusted models (0.32; 95% CI 0.03, 3.90 and 0.01: 95% CI < 0.00, 1.99, respectively). Reduced FORs (0.96) were observed for alcohol consumption standardized to a 28-day menstrual cycle in the same adjusted model (FOR = 0.96; 95% CI 0.93, 1.00)., Conclusions: These data suggest that environmental exposures including those amenable to change, such as alcohol consumption, may impact female fecundity. The findings are sensitive to model specification and PCB groupings, underscoring the need to further assess the impact of chemical mixtures on sensitive reproductive outcomes, such as TTP, especially in the context of lifestyle factors which are amenable to change, thereby improving reproductive health.

Radiation and other agents can cause germ-cell mutations in animal systems. No human germ-cell mutagen has been identified, but this does not mean that human germ-cells are not vulnerable to mutagenesis. There has been particular concern about the possible health effects on offspring following parental preconception exposure to ionizing radiation-both occupational and therapeutic. A strong association with preconception radiation exposure in the fathers of the cases was found in a case-control study of young people with leukaemia living near the Sellafield nuclear plant in the UK. Subsequent studies of workers occupationally exposed to ionizing radiation have failed to confirm these findings. No statistically significant effects have been reported from studies of possible indicators of germ-cell mutagenesis in the A-bomb survivors. Studies of offspring of cancer survivors who receive radiotherapy and mutagenic chemotherapy have found no evidence of germ-cell mutagenesis. Failure to detect human germ-cell mutagenic agents may be a consequence of inadequate study sizes or insufficiently sensitive laboratory techniques.

Despite being one of the most common congenital defects in boys, the etiology of hypospadias remains largely unknown. In this case-referent study, we evaluated a wide spectrum of potential risk factors for hypospadias. Cases were identified from the hospital information system, and referents were recruited through the parents of the cases. Both parents of cases and referents completed written questionnaires that they received through the mail. Logistic regression analyses were used to assess the independent contribution of different factors to the risk of hypospadias. The final database included 583 cases and 251 referents. Hypospadias more often occurred in children whose father had hypospadias (OR=9.7; 95%CI: 1.3-74.0) and in children with a low birth weight (OR=2.3; 95%CI: 1.2-4.2). Indications for elevated risks were found when mothers were DES-daughters (OR=3.5; 95%CI: 0.8-15.6), fathers were subfertile (OR=1.8; 95%CI: 0.7-4.5), the parents had undergone fertility treatment (OR=2.3; 95%CI: 0.9-5.8), and in twin or triplet pregnancies (OR=2.0; 95%CI: 0.8-5.1). Maternal use of iron supplements (OR=2.2; 95%CI: 0.8-6.0), maternal smoking (OR=1.5; 95%CI: 1.0-2.4), paternal prescriptive drug use (OR=2.6; 95%CI: 1.1-6.6), and paternal exposure to pesticides (OR=2.1; 95%CI: 0.6-7.1) during the 3 months immediately prior to conception or in the first trimester of pregnancy also appeared to increase the risk of hypospadias. The associations found in this study support the hypothesis that genetic predisposition, placental insufficiency, and substances that interfere with natural hormones play a role in the etiology of hypospadias.

A preconditioning sciatic nerve crush promotes the capacity of adult sensory neurons to regenerate following a subsequent injury to their axons. The increase in regeneration is detected in cultures of dissociated neurons, as an earlier and enhanced rate of neurite elongation. We compare neurotrophin-stimulated neurite outgrowth from sensory neurons on laminin and fibronectin. There is a poor response of sensory neurons to fibronectin in comparison to laminin, but this is enhanced by a preconditioning lesion to the sciatic nerve 7 days prior to culture. By using specific integrin-binding fibronectin fragments and function-blocking antibodies, we demonstrate that the enhanced preconditioned neurite outgrowth on fibronectin is largely mediated by alpha5beta1 integrin. Preconditioning injury alter the subcellular localisation of alpha5 integrin in preconditioned neurites. We show that alpha5 integrin localises to adhesion complexes in the growth cone and neurites of preconditioned neurons, but not control neurons.

Objective: To describe the case of a woman exposed to angiotensin-II receptor blockers (ARBs) in the preconceptional period and to systematically review the literature on the safety of these drugs when used by pregnant women., Methods: The case was identified at the Korean Motherisk Program (Seoul). For the systematic review, we searched the PubMed for case reports, case series, and post-marketing surveys., Results: A hypertensive woman was exposed to irbesartan prior to conception. The embryo had delayed development of upper and lower extremities and decreased digital groove. A karyotype identified a 45,XO Turner syndrome. The patient had a spontaneous abortion. Including the case reported here, 64 published cases were identified in total; 57.8% had favorable and 42.2% had unfavorable outcomes. Duration of treatment during pregnancy among women who had adverse fetal outcomes was 26.3 +/- 10.5 weeks (mean +/- SD), compared with 17.3 +/- 11.6 weeks in those who had favorable outcomes (p = 0.04)., Conclusions: Exposure to ARBs for a period longer than the first trimester of pregnancy appears to be associated with a high risk for adverse fetal outcomes.

The congenital malformation gastroschisis has a genetic disposition in the inbred mouse strain HLG/Zte. It is increased after preconceptional irradiation of males or females. Radiation exposures during the meiotic stages are most efficient. This malformation can also be induced by ionising radiation when the exposure takes place during the preimplantation period especially during the zygote stage. This latter effect can be transmitted to the next mouse generation. Other macroscopically visible or skeletal malformations are not significantly induced under these experimental conditions. These latter malformations are increased by radiation exposures during major organogenesis. The mechanisms for the development of the effects are different. Radiation exposure of the mouse zygote (1 to 3 hours p.c.) also leads to the induction of genomic instability in skin fibroblasts of the fetus. This phenomenon also occurs in a mouse strain (C57BL/6J) which is not susceptible to radiation-induced gastroschisis during the preimplantation period. The genomic instability is transmitted to the next mouse generation. During genomic instability chromatide breaks are dominating as in non-exposed cells. With respect to "spontaneous" malformations gastroschisis is dominating in HLG/Zte mice. Late radiation effects seem to have similar patterns as observed in non-exposed subjects, however, the rates are increased after irradiation.

Neurodevelopmental models of schizophrenia that identify longitudinal precursors of illness have been of great heuristic importance focusing most etiologic research over the past two decades. These models have varied considerably with respect to specificity and timing of hypothesized genetic and environmental 'hits', but have largely focused on insults to prenatal brain development. With heritability around 80%, nongenetic factors impairing development must also be part of the model, and any model must also account for the wide range of age of onset. In recent years, longitudinal brain imaging studies of both early and adult (to distinguish from late ie elderly) onset populations indicate that progressive brain changes are more dynamic than previously thought, with gray matter volume loss particularly striking in adolescence and appearing to be an exaggeration of the normal developmental pattern. This supports an extended time period of abnormal neurodevelopment in schizophrenia in addition to earlier 'lesions'. Many subtle cognitive, motor, and behavioral deviations are seen years before illness onset, and these are more prominent in early onset cases. Moreover, schizophrenia susceptibility genes and chromosomal abnormalities, particularly as examined for early onset populations (ie GAD1, 22q11DS), are associated with premorbid neurodevelopmental abnormalities. Several candidate genes for schizophrenia (eg dysbindin) are associated with lower cognitive abilities in both schizophrenic and other pediatric populations more generally. Postmortem human brain and developmental animal studies document multiple and diverse effects of developmental genes (including schizophrenia susceptibility genes), at sequential stages of brain development. These may underlie the broad array of premorbid cognitive and behavioral abnormalities seen in schizophrenia, and neurodevelopmental disorders more generally. Increased specificity for the most relevant environmental risk factors such as exposure to prenatal infection, and their interaction with susceptibility genes and/or action through phase-specific altered gene expression now both strengthen and modify the neurodevelopmental theory of schizophrenia.

Alzheimer's disease (AD) is linked to certain common brain pathologies (e.g., ischemia, stroke, and trauma) believed to facilitate its development and progression. One of the logical approaches to this problem is to study the effects of ischemia and hypoxia on the metabolism of amyloid precursor protein, which plays one of the key roles in the pathogenesis of AD. This involves an analysis of (1) proteases, which participate in proteolysis of amyloid precursor protein either by the nonamyloidogenic route (alpha-secretase) or the amyloidogenic pathway and lead to formation of toxic beta-amyloid peptides (beta- and gamma-secretases) and (2) several metallopeptidases that might play a role in degradation of beta-amyloid peptide (Abeta). The study of the effects of prenatal hypoxia and acute hypoxia in adult animals allowed us to conclude that oxygen deprivation results not only in an increase of amyloid precursor protein expression in the brain but also in a decrease in the activity of alpha-secretase. In some brain structures involved in AD pathology (the cortex and striatum), we also observed a decrease in the expression of two of the Abeta degrading enzymes, neprilysin and endothelin-converting enzyme, after hypoxia. A decrease in expression of these metalloproteases was also observed in the model of four-vessel occlusion ischemia in rats with their restoration to the control levels after reperfusion. Preconditioning to mild hypoxia both in the prenatal period and in adults appeared to have a neuroprotective effect restoring, in particular, the levels of amyloid precursor protein, activity of alpha-secretase, and expression of neprilysin and endothelin-converting enzyme to their control values.

Background: It is well known that alcohol consumption during pregnancy can result in lower birth weight babies but many women stop consuming alcohol prior to conception as a part of pregnancy planning. The purpose of this study was to determine whether alcohol consumption prior to conception may also have an effect on fetal development., Methods: Male and female C57BL/6J mice at 4, 6, or 8 weeks of age received either a single administration of alcohol (3.0 g/kg) via intragastric gavage (IG) each day for at least 60 days, or an isovolumetric IG administration of sterile water. After 60 treatment days, males and females within each age and treatment group were mated overnight. Females continued to receive daily alcohol treatments until conception. Males continued to receive treatments until all females were successfully mated. At conception, females were isolated and left undisturbed. On embryonic day 14, fetus number, size, and weight was determined., Results: Maternal food consumption, body weight at conception, and delay to conception onset did not differ between the two treatment groups or among the three age groups. Fetal body weights did not differ among the three age groups. Fetuses from females treated with alcohol had lower body weights compared to those treated with water. Male treatments did not seem to affect fetal body weight., Conclusions: Fetal growth and development can be affected by alcohol consumption prior to the time of conception. Alcohol consumption prior to conception is a potential risk factor to fetal outcome and an important consideration for those females planning to have children.