Maternal influences on placental development

Epidemiological evidence suggests that size at birth may affect health in later life. The growth of the fetus may be adversely affected by a suboptimal maternal environment. Understanding placental development and function will help unravel the mechanisms controlling fetal growth. This article poses the problem: how does the maternal environment (uterine or systemic) influence placental development? Critical human placental functions include remodelling maternal uterine spiral arteries to increase the flow of blood to the maternofetal interface, and transferring oxygen and nutrients into the fetal vasculature, all processes involving trophoblast. Gene ablations that affect pregnancy outcome in mice lead to some interesting hypotheses.     

Effects of material methadone administration on ornithine decarboxylase in brain and heart of the offspring: Relationships of enzyme activity to dose and to growth impairment in the rat

Administration of 5 mg/kg of methadone daily to pregnant and nursing rats produced substantial retardation of body, brain and heart growth in the offspring; alterations in biochemical development also were present in the methadone-exposed pups, as evidenced by delays in the maturational declines of brain and heart ornithine decarboxylase (ODC) activity. Lowering the dose of methadone to levels which did not affect growth or brain ODC, still resulted in pro-found abnormalities in the developmental pattern of heart ODC. These studies indicate that downward adjustment of maternal methadone dosage to a point where birthweights and body and organ growth rates are normal, does not eliminate all of the biochemical alterations associated with the perinatal opiate syndrome.     

Identification of Grandchildless Loci Whose Products Are Required for Normal Germ-Line Development in the Nematode Caenorhabditis Elegans

To identify genes that encode maternal components required for development of the germ line in the nematode Caenorhabditis elegans, we have screened for mutations that confer a maternal-effect sterile or "grandchildless" phenotype: homozygous mutant hermaphrodites produced by heterozygous mothers are themselves fertile, but produce sterile progeny. Our screens have identified six loci, defined by 21 mutations. This paper presents genetic and phenotypic characterization of four of the loci. The majority of mutations, those in mes-2, mes-3 and mes-4, affect postembryonic germ-line development; the progeny of mutant mothers undergo apparently normal embryogenesis but develop into agametic adults with 10-1000-fold reductions in number of germ cells. In contrast, mutations in mes-1 cause defects in cytoplasmic partitioning during embryogenesis, and the resulting larvae lack germ-line progenitor cells. Mutations in all of the mes loci primarily affect the germ line, and none disrupt the structural integrity of germ granules. This is in contrast to grandchildless mutations in Drosophila melanogaster, all of which disrupt germ granules and affect abdominal as well as germ-line development.     

Arabidopsis haiku mutants reveal new controls of seed size by endosperm

In flowering plants, maternal seed integument encloses the embryo and the endosperm, which are both derived from double fertilization. Although the development of these three components must be coordinated, we have limited knowledge of mechanisms involved in such coordination. The endosperm may play a central role in these mechanisms as epigenetic modifications of endosperm development, via imbalance of dosage between maternal and paternal genomes, affecting both the embryo and the integument. To identify targets of such epigenetic controls, we designed a genetic screen in Arabidopsis for mutants that phenocopy the effects of dosage imbalance in the endosperm. The two mutants haiku 1 and haiku 2 produce seed of reduced size that resemble seed with maternal excess in the maternal/paternal dosage. Homozygous haiku seed develop into plants indistinguishable from wild type. Each mutation is sporophytic recessive, and double-mutant analysis suggests that both mutations affect the same genetic pathway. The endosperm of haiku mutants shows a premature arrest of increase in size that causes precocious cellularization of the syncytial endosperm. Reduction of seed size in haiku results from coordinated reduction of endosperm size, embryo proliferation, and cell elongation of the maternally derived integument. We present further evidence for a control of integument development mediated by endosperm-derived signals.     

Epidermal growth factor and parathyroid hormone-related peptide mRNA in the mammary gland and their concentrations in milk: effects of postpartum hypoxia in lactating rats.

The physiological adaptations of the neonatal rat to hypoxia from birth include changes in gastrointestinal function and intermediary metabolism. We hypothesized that the hypoxic lactating dam would exhibit alterations in mammary gland function leading to changes in the concentration of milk peptides that are important in neonatal gastrointestinal development. The present study assessed the effects of chronic hypoxia on peptides produced by the mammary glands and present in milk. Chronic hypoxia decreased the concentration of epidermal growth factor (EGF) in expressed milk and pup stomach contents and decreased maternal mammary gland EGF mRNA. The concentration of parathyroid hormone-related protein (PTHrp) was unchanged in milk and decreased in pup stomach contents; however, mammary PTHLH mRNA was increased by hypoxia. There was a significant increase in adiponectin concentrations in milk from hypoxic dams. Chronic hypoxia decreased maternal body weight, and pair feeding normoxic dams an amount of food equivalent to hypoxic dam food intake decreased body weight to an equivalent degree. Decreased food intake did not affect the expression of EGF, PTHLH, or LEP mRNA in mammary tissue. The results indicated that chronic hypoxia modulated mammary function independently of hypoxia-induced decreases in maternal food intake. Decreased EGF and increased adiponectin concentrations in milk from hypoxic dams likely affect the development of neonatal intestinal function.     

Glucose transport from mother to fetus—A theoretical study

The factors that affect and govern the glucose transfer from maternal blood to the fetus are not completely deciphered. We present a steady state, one dimensional mathematical simulation which integrates the main mechanisms that have been shown to exist: metabolic consumption of the placenta, simple and facilitated diffusion via the two membranes of the microvillous and simple diffusion within the placenta. The model uses all available physiologic data we could collect. Numerical results indicate that the most crucial factor in determining the fetal glucose concentration is the facilitated diffusion process at the basal membrane or, more specifically: the permeability of the basal membrane and the density of the transporter GLUT1 on its faces. The gradient between the maternal and the fetal glucose concentration is important as is the metabolic consumption of the placenta. The diffusion within the placenta and the conditions that prevail at the apical microvillous plasma membrane are much less significant. Intrasyncytial concentration of glucose is close to that of maternal blood. The adjustment of the fetal glucose concentration to abrupt changes of its surrounding is estimated to be quite rapid hence for all practical purposes this steady state model can serve as a reasonable approximation. Parameters that await experimental determination are identified.     

Effects of Antenatal Maternal Depression and Anxiety on Children’s Early Cognitive Development: A Prospective Cohort Study

Introduction

Studies have shown that depression or anxiety occur in 10–20% of pregnant women. These disorders are often undertreated and may affect mothers and children’s health. This study investigates the relation between antenatal maternal depression, anxiety and children’s early cognitive development among 1380 two-year-old children and 1227 three-year-old children.

Methods

In the French EDEN Mother-Child Cohort Study, language ability was assessed with the Communicative Development Inventory at 2 years of age and overall development with the Ages and Stages Questionnaire at 3 years of age. Multiple regressions and structural equation modeling were used to examine links between depression, anxiety during pregnancy and child cognitive development.

Results

We found strong significant associations between maternal antenatal anxiety and poorer children’s cognitive development at 2 and 3 years. Antenatal maternal depression was not associated with child development, except when antenatal maternal anxiety was also present. Both postnatal maternal depression and parental stimulation appeared to play mediating roles in the relation between antenatal maternal anxiety and children’s cognitive development. At 3 years, parental stimulation mediated 13.2% of the effect of antenatal maternal anxiety while postnatal maternal depression mediated 26.5%.

Discussion

The partial nature of these effects suggests that other mediators may play a role. Implications for theory and research on child development are discussed.     

Potential consequences of maternal hypothyroidism on the offspring: evidence and implications

The adequate functioning of both the maternal and fetal thyroid glands plays important roles to ensure that the fetal neuropsychointellectual development progresses normally. Three sets of clinical disorders ought to be envisaged, potentially leading to impaired brain development: defective glandular ontogenesis (leading to congenital hypothyroidism), maternal hypothyroidism (usually related to chronic autoimmune thyroiditis), and finally iodine deficiency (affecting both the maternal and fetal thyroid functions). The present review will be focused mainly on maternal hypothyroidism, where both the severity and temporal occurrence of maternal thyroid underfunction drive the resulting repercussions for an impaired fetal neuronal development: such clinical situations may take place during early gestation (in women with known but untreated hypothyroidism) or appear only during later gestational stages (in women with thyroid antibodies, who remain euthyroid during the first half of gestation). Recent available evidence and its implications are discussed, as well as our present concepts relating to the complexities of the fetomaternal thyroid relationships, and the potential impact of maternal thyroid function abnormalities on the ideal offspring's development.     

Sex Determination in Polyploids of Caenorhabditis Elegans

In Caenorhabditis elegans triploid animals with two X chromosomes (symbolized 3A;2X) are males. However, these triploid males can be feminized by making them mutant for recessive dosage compensation mutations, by adding X chromosome duplications or by microinjecting particular DNA sequences termed feminizing elements. None of these treatments affects diploid males. This study explores several aspects of these treatments in polyploids. The dosage compensation mutants exhibit a strong maternal effect, such that reduction of any of the dosage compensation gene functions in the mother leads to sex reversal of 3A;2X animals. Likewise, all X chromosome duplications tested cause both sex reversal and intersexual development of many 3A;2X animals. Microinjected feminizing element DNA does not cause extensive sex reversal, but does result in intersexual development in 3A;2X animals. Neither X chromosome duplications nor microinjected feminizing elements show the extreme maternal effect of the dosage compensation mutants, although there is indirect evidence for a maternal effect of the feminizing elements. In particular, very little feminizing element DNA needs to be microinjected in order to feminize triploid males, far less than what is needed for stable inheritance, implying that feminizing elements can work within the mother's gonad. However, even very high concentrations of microinjected feminizing elements do not affect sex determination in diploid males, suggesting that they are not part of the numerator of the X/A ratio. In addition, no pair of X chromosome duplications feminizes diploid males, suggesting that none of these duplications contains a numerator of the X/A ratio. Instead, I infer that an X-linked locus, as yet undefined, must be present in two copies for hermaphrodite development to ensue or that the two X chromosomes might interact.     

Murine maternal cell microchimerism: analysis using real-time PCR and in vivo imaging

In humans, maternal cells are present in the affected tissues of children with inflammatory myopathy, scleroderma, and neonatal lupus. It is unknown if maternal cell microchimerism (MCM) contributes to the pathology of disease. We sought to understand the factors that affect MCM to serve as a baseline for future mechanistic studies. Using a mouse model, we bred female mice transgenic for the luciferase (Luc) reporter gene to wild-type (WT) males. The WT offspring were sacrificed at various postnatal ages. DNA was extracted from multiple organs, and real-time PCR amplification was used to quantify Luc transgene as a marker for maternally derived cells. Sensitivity was one to two transgenic cells per 100,000 WT cells. MCM was noted in 85% of mice and 45% of tissues assayed. The average quantity of MCM was 158 maternal cells per 100,000 neonatal cells. The organs displaying the highest frequency and quantity of MCM were heart and lung (P < 0.001). Postnatal age up to 21 days did not appear to affect levels of MCM (P = 0.47), whereas increasing parity may increase levels of MCM. The data show that MCM is a common occurrence in healthy newborn mice, that it is present in their major organs, and that there are organ specific differences. This may represent differential migration of maternal cells or varying receptivity of specific fetal organs to microchimerism. Pregnancy history appears to play a role in maternal cell trafficking. The role of MCM in pregnancy and disease pathogenesis remains to be elucidated.     

Commentary on the Role of Maternal Toxicity on Developmental Toxicity

Maternal mammalian toxicity impacts prenatal development, with general systemic maternal toxicity, from reduced weight gain to morbidity, causative for reduced fetal weights/litter and increased fetal variations (especially skeletal)/litter, but not, in the author's opinion, for increased fetal malformations, reduced litter sizes or full litter losses. Increased fetal malformations are likely due to exposure to specific chemicals which alter specific maternal functions at critical point(s) in pregnancy, typically exaggerated effects from higher doses by drugs under development with known, desired pharmacological effects. Malformations can also be from genetic/epigenetic alterations, specific altered proteins, molecular pathways, etc. Full litter losses are triggered by the mother and are rare in rats. Information to inform maternal (and developmental) toxicity includes ovarian corpora lutea counts, uterine implantation profile, degree of litter reduction (if present), timing and extent of maternal toxicity relative to those of adverse embryofetal effects, etc. The view of maternal toxicity as confounding results in in vivo developmental toxicity studies, worldwide concerns about increased research animal usage, increasing time, labor, costs, and new software and hardware sophistication all drive the interest in development, validation, and performance of in vitro/in silico assays. These assays are fast, inexpensive, responsive to animal use concerns and amenable to mechanistic questions. The strength of these in vitro/in silico assays is considered by many to be the absence of the maternal organism/placenta. These assays inform mechanism and hazard, but NOT risk. The Environmental Protection Agency currently estimates that these new assays are approximately 70% accurate versus the whole animal tests.     

Size at birth and some sociodemographic factors in gypsies in Hungary

In 10,108 babies born to gypsy parents, birth weight, birth length and gestational age are compared with a national reference sample, taking into account maternal education, age, and birth interval. The gypsy babies tend consistently to be smaller, and this difference is attributable to the circumstances in which the gypsies live as well as the poorer maternal education. There appears to be a vicious circle--poor hygiene and living conditions adversely affect birth size, which in turn puts the child at a disadvantage in terms of survival, health and development.     

Ghrelin alters postnatal endocrine secretion and behavior in mouse offspring

Maternal bioactive substances, such as hormones and neuropeptides, are thought to be essential for fetal development. Recently, ghrelin, a gastrointestinal peptide, has been shown to pass through the rat placenta. The ghrelin receptor, growth hormone secretagogue receptor (GHS-R), has been shown to be expressed in the rat fetal central nervous system, and plasma ghrelin levels are related to birth weight in the rodent and human. In the present study, we report a role of maternal ghrelin in mouse fetal brain development. When ghrelin was administrated to pregnant mice, pups exhibited suppression of exploratory behavior in an open-field (OF) test. Control pups, however, remained for longer periods of time in the center area, correlating with exploratory behavior. Basal corticotropin-releasing hormone (CRH) plasma levels were greater in pups from ghrelin-treated dams, and did not change in response to acute restraint stress. Moreover, reduced growth hormone secretagogue receptor and neuropeptide Y mRNA expression was observed in the hypothalamus at postnatal day 3 and remained until 16 weeks of age. In addition, under physiological condition, increased maternal ghrelin plasma levels following repeated restraint stress to the dam had effect on the increase in fetal plasma acyl ghrelin levels. These results suggest that maternal ghrelin affect fetal plasma ghrelin levels and alters endocrine systems and behaviors of offspring.     

Behavior of structurally divergent alpha-tubulin isotypes during Drosophila embryogenesis: evidence for post-translational regulation of isotype abundance.

Two major alpha-tubulin isotypes are present during Drosophila embryogenesis: an evolutionarily divergent maternal isotype that is synthesized only in the ovary and deposited in the oocyte and a highly conserved constitutive isotype that is both maternally supplied and zygotically synthesized. A maternal isotype-specific antibody and a monoclonal antibody that recognizes both the maternal and constitutive isotypes were characterized and used to determine the distribution and abundance of alpha-tubulins during embryogenesis. Both isotypes are abundant and assemble into all classes of microtubules from the syncytial blastoderm stage until completion of germ band retraction. During subsequent development, however, the maternal isotype is retained only in the developing CNS, and later in a subset of connective fibers within the CNS. In contrast, total alpha-tubulin levels remain high in essentially all tissues throughout embryogenesis, indicating that most tissues selectively accumulate the constitutive isotype. To determine if selective accumulation of the constitutive isotype requires zygotic synthesis of this protein, mutant embryos that do not contain functional constitutive alpha-tubulin genes were examined. In these embryos, as in wild type, the maternal isotype decreases to background levels in tissues that retain high levels of the constitutive isotype. The constitutive isotype therefore appears to be more stable than the maternal isotype in most tissues. Differences in isotype stability may play an important role in determining the developmental pattern of isotype accumulation in Drosophila embryos.     

Milk Collection in the Rat Using Capillary Tubes and Estimation of Milk Fat Content by Creamatocrit

Milk, as the sole source of nutrition for the newborn mammal, provides the necessary nutrients and energy for offspring growth and development. It also contains a vast number of bioactive compounds that greatly affect the development of the neonate. The analysis of milk components will help elucidate key factors that link maternal metabolism and health with offspring growth and development. The laboratory rat represents a popular model organism for maternal studies, and rat milk can be used to examine the effect of various maternal physiological, nutritional, and pharmacological interventions on milk components, which may then impact offspring health. Here a simple method of manually collecting milk from the lactating rat that can be performed by a single investigator, does not require specialized vacuum or suction equipment, and provides sufficient milk for subsequent downstream analysis is described. A method for estimating the fat content of milk by measuring the percentage of cream within the milk sample, known as the creamatocrit, is also presented. These methods can ultimately be used to increase insight into maternal-child health and to elucidate maternal factors that are involved in proper growth and development of offspring.     

Prenatal Inflammation-Induced Hypoferremia Alters Dopamine Function in the Adult Offspring in Rat: Relevance for Schizophrenia

Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring''s dopamine function. Using a rat model of localized injury induced by turpentine, which triggers the innate immune response and inflammation, we investigated the effects of maternal iron supplementation on the offspring''s dopamine function by assessing behavioral responses to acute and repeated administration of the dopamine indirect agonist, amphetamine. In addition we measured protein levels of tyrosine hydroxylase, and tissue levels of dopamine and its metabolites, in ventral tegmental area, susbtantia nigra, nucleus accumbens, dorsal striatum and medial prefrontal cortex. Offspring of turpentine-treated mothers exhibited greater responses to a single amphetamine injection and enhanced behavioral sensitization following repeated exposure to this drug, when compared to control offspring. These behavioral changes were accompanied by increased baseline levels of tyrosine hydroxylase, dopamine and its metabolites, selectively in the nucleus accumbens. Both, the behavioral and neurochemical changes were prevented by maternal iron supplementation. Localized prenatal inflammation induced a deregulation in iron homeostasis, which resulted in fundamental alterations in dopamine function and behavioral alterations in the adult offspring. These changes are characteristic of schizophrenia symptoms in humans.     

EMBRYO GROWTH AND SEED SIZE IN RAPHANUS SATIVUS: MATERNAL AND PATERNAL EFFECTS IN VIVO AND IN VITRO

Theories on the evolution of the angiosperm seed disagree as to the effects of different plant tissues on embryo growth. To examine the relative contributions of maternal and paternal genes on embryo growth, we conducted controlled crosses in the greenhouse with wild radish plants (Raphanus sativus), looked for maternal, paternal, and interaction effects on embryo development, and compared the performance of embryos within fruits and in embryo culture. Maternal plant identity affected fruit set, seeds per fruit, embryo developmental stage, and mean seed weight. In embryo culture, maternal effects were found for cotyledon size and embryo weight. Paternal effects were fewer or smaller in magnitude than maternal effects. The identity of the pollen donor affected embryo developmental stage and mean seed weight. In culture, paternal effects were detected for cotyledon size and embryo weight. Our results demonstrate that both maternal and paternal elements affect embryo growth. The fact that maternal effects are greater than paternal effects on embryo development in culture may result from cytoplasmic elements or maternal nuclear genes. Embryo performance in vivo compared to that in vitro varied among maternal plants. The interaction between an embryo and its endosperm and maternal tissues may be either positive or negative, depending upon the maternal plant and the embryo's developmental stage.     

Behavioral profiles and stress-induced corticosteroid secretion in male Wistar rats subjected to short and prolonged periods of maternal separation

Early life experiences are important for the development of neurobiobehavioral mechanisms and subsequent establishment of mental functions. In experimental animals, early life experiences can be studied using the maternal separation model. Maternal separation has been described to induce neurobiological changes and thus affect brain function, mental state and behavior. We have established a protocol in order to study the effects of repeated short and prolonged periods of maternal separation during the postnatal period on adult neurochemistry, voluntary ethanol intake and behavior. In the present experiment, we focus on the long-term effects of maternal separation on exploration and risk assessment behavior as well corticosteroid secretion. Rat pups were assigned to 15 min (MS15) or 360 min (MS360) of daily maternal separation and normal animal facility rearing (AFR) during postnatal days 1-21. To establish the adult behavioral profile in male rats, three tests were used: the Concentric Square Field (CSF), the Open Field (OF) and the Elevated Plus-maze (EPM). No differences between the three experimental groups were found in the traditional OF and EPM tests. The CSF test indicated that the MS360 rats were more explorative and expressed an altered risk assessment and risk-taking profile. In response to a restraint stress, MS360 rats had a blunted corticosterone release in contrast to MS15 and AFR rats. In contrast to previous results, the outcome of the present investigation does not support the notion that a prolonged period of maternal separation results in an adult phenotype characterized by an increased emotional reactivity.     

Behavioral profiles and stress-induced corticosteroid secretion in male Wistar rats subjected to short and prolonged periods of maternal separation

Early life experiences are important for the development of neurobiobehavioral mechanisms and subsequent establishment of mental functions. In experimental animals, early life experiences can be studied using the maternal separation model. Maternal separation has been described to induce neurobiological changes and thus affect brain function, mental state and behavior. We have established a protocol in order to study the effects of repeated short and prolonged periods of maternal separation during the postnatal period on adult neurochemistry, voluntary ethanol intake and behavior. In the present experiment, we focus on the long-term effects of maternal separation on exploration and risk assessment behavior as well corticosteroid secretion. Rat pups were assigned to 15 min (MS15) or 360 min (MS360) of daily maternal separation and normal animal facility rearing (AFR) during postnatal days 1–21. To establish the adult behavioral profile in male rats, three tests were used: the Concentric Square Field (CSF), the Open Field (OF) and the Elevated Plus-maze (EPM). No differences between the three experimental groups were found in the traditional OF and EPM tests. The CSF test indicated that the MS360 rats were more explorative and expressed an altered risk assessment and risk-taking profile. In response to a restraint stress, MS360 rats had a blunted corticosterone release in contrast to MS15 and AFR rats. In contrast to previous results, the outcome of the present investigation does not support the notion that a prolonged period of maternal separation results in an adult phenotype characterized by an increased emotional reactivity.     

Intrauterine growth pattern and risk of childhood onset insulin dependent (type I) diabetes: population based case-control study.

OBJECTIVE: To investigate whether prenatal growth affects the risk of development of childhood onset insulin dependent (type I) diabetes mellitus. DESIGN: Population based case-control study. SETTING: Data from a nationwide childhood diabetes case register were linked with data from the nationwide Swedish Medical Birth Registry. SUBJECTS: Data from a total of 4584 diabetic children born after 1973 and diagnosed with diabetes from 1978 to 1992 were studied. For each child with insulin dependent diabetes three control children were randomly selected from among all infants born in the same year and at the same hospital as the proband. MAIN OUTCOME MEASURES: Birth weight, gestation, maternal age and parity, number of previous spontaneous abortions, and sex specific birth weight by gestational week expressed as multiples of the standard deviation (SD). RESULTS: There was a clear trend in the odds ratio for childhood onset diabetes according to SD of birth weight. The odds ratio (95% confidence interval) for small for gestational age after stratification for maternal age, parity, smoking habits, and maternal diabetes was 0.81 (0.65 to 0.99) and for large for gestational age after similar stratification was 1.20 (1.02 to 1.42). CONCLUSIONS: Intrauterine conditions that affect prenatal growth seem also to affect the risk of development of childhood diabetes in the way previously described for postnatal growth: a poor growth decreases and an excess growth increases the risk. The mechanism for this association is unclear.