11 research outputs found
Teratology Primer-2nd Edition (7/9/2010)
Foreword:
What is Teratology?
“What a piece of work is an embryo!” as Hamlet might have said. “In form and moving how express and admirable! In complexity how infinite!” It starts as a single cell, which by repeated divisions gives rise to many genetically identical cells. These cells receive signals from their surroundings and from one another as to where they are in this ball of cells —front or back, right or left, headwards or tailwards, and what they are destined to become. Each cell commits itself to being one of many types; the cells migrate, combine into tissues, or get out of the way by dying at predetermined times and places. The tissues signal one another to take their own pathways; they bend, twist, and form organs. An organism emerges. This wondrous transformation from single celled simplicity to myriad-celled complexity is programmed by genes that, in the greatest mystery of all, are turned on and off at specified times and places to coordinate the process. It is a wonder that this marvelously emergent operation, where there are so many opportunities for mistakes, ever produces a well-formed and functional organism.
And sometimes it doesn’t. Mistakes occur. Defective genes may disturb development in ways that lead to death or to malformations. Extrinsic factors may do the same. “Teratogenic” refers to factors that cause malformations, whether they be genes or environmental agents. The word comes from the Greek “teras,” for “monster,” a term applied in ancient times to babies with severe malformations, which were considered portents or, in the Latin, “monstra.”
Malformations can happen in many ways. For example, when the neural plate rolls up to form the neural tube, it may not close completely, resulting in a neural tube defect—anencephaly if the opening is in the head region, or spina bifida if it is lower down. The embryonic processes that form the face may fail to fuse, resulting in a cleft lip. Later, the shelves that will form the palate may fail to move from the vertical to the horizontal, where they should meet in the midline and fuse, resulting in a cleft palate. Or they may meet, but fail to fuse, with the same result. The forebrain may fail to induce the overlying tissue to form the eye, so there is no eye (anophthalmia). The tissues between the toes may fail to break down as they should, and the toes remain webbed.
Experimental teratology flourished in the 19th century, and embryologists knew well that the development of bird and frog embryos could be deranged by environmental “insults,” such as lack of oxygen (hypoxia). But the mammalian uterus was thought to be an impregnable barrier that would protect the embryo from such threats. By exclusion, mammalian malformations must be genetic, it was thought.
In the early 1940s, several events changed this view. In Australia an astute ophthalmologist, Norman Gregg, established a connection between maternal rubella (German measles) and the triad of cataracts, heart malformations, and deafness. In Cincinnati Josef Warkany, an Austrian pediatrician showed that depriving female rats of vitamin B (riboflavin) could cause malformations in their offspring— one of the early experimental demonstrations of a teratogen. Warkany was trying to produce congenital cretinism by putting the rats on an iodine deficient diet. The diet did indeed cause malformations, but not because of the iodine deficiency; depleting the diet of iodine had also depleted it of riboflavin!
Several other teratogens were found in experimental animals, including nitrogen mustard (an anti cancer drug), trypan blue (a dye), and hypoxia (lack of oxygen). The pendulum was swinging back; it seemed that malformations were not genetically, but environmentally caused.
In Montreal, in the early 1950s, Clarke Fraser’s group wanted to bring genetics back into the picture. They had found that treating pregnant mice with cortisone caused cleft palate in the offspring, and showed that the frequency was high in some strains and low in others. The only difference was in the genes. So began “teratogenetics,” the study of how genes influence the embryo’s susceptibility to teratogens.
The McGill group went on to develop the idea that an embryo’s genetically determined, normal, pattern of development could influence its susceptibility to a teratogen— the multifactorial threshold concept. For instance, an embryo must move its palate shelves from vertical to horizontal before a certain critical point or they will not meet and fuse. A teratogen that causes cleft palate by delaying shelf movement beyond this point is more likely to do so in an embryo whose genes normally move its shelves late.
As studies of the basis for abnormal development progressed, patterns began to appear, and the principles of teratology were developed. These stated, in summary, that the probability of a malformation being produced by a teratogen depends on the dose of the agent, the stage at which the embryo is exposed, and the genotype of the embryo and mother.
The number of mammalian teratogens grew, and those who worked with them began to meet from time to time, to talk about what they were finding, leading, in 1960, to the formation of the Teratology Society. There were, of course, concerns about whether these experimental teratogens would be a threat to human embryos, but it was thought, by me at least, that they were all “sledgehammer blows,” that would be teratogenic in people only at doses far above those to which human embryos would be exposed. So not to worry, or so we thought.
Then came thalidomide, a totally unexpected catastrophe. The discovery that ordinary doses of this supposedly “harmless” sleeping pill and anti-nauseant could cause severe malformations in human babies galvanized this new field of teratology. Scientists who had been quietly working in their laboratories suddenly found themselves spending much of their time in conferences and workshops, sitting on advisory committees, acting as consultants for pharmaceutical companies, regulatory agencies, and lawyers, as well as redesigning their research plans.
The field of teratology and developmental toxicology expanded rapidly. The following pages will show how far we have come, and how many important questions still remain to be answered. A lot of effort has gone into developing ways to predict how much of a hazard a particular experimental teratogen would be to the human embryo (chapters 9–19). It was recognized that animal studies might not prove a drug was “safe” for the human embryo (in spite of great pressure from legislators and the public to do so), since species can vary in their responses to teratogenic exposures. A number of human teratogens have been identified, and some, suspected of teratogenicity, have been exonerated—at least of a detectable risk (chapters 21–32). Regulations for testing drugs before market release have greatly improved (chapter 14). Other chapters deal with how much such things as population studies (chapter 11), post-marketing surveillance (chapter 13), and systems biology (chapter 16) add to our understanding. And, in a major advance, the maternal role of folate in preventing neural tube defects and other birth defects is being exploited (chapter 32). Encouraging women to take folic acid supplements and adding folate to flour have produced dramatic falls in the frequency of neural tube defects in many parts of the world.
Progress has been made not only in the use of animal studies to predict human risks, but also to illumine how, and under what circumstances, teratogens act to produce malformations (chapters 2–8). These studies have contributed greatly to our knowledge of abnormal and also normal development. Now we are beginning to see exactly when and where the genes turn on and off in the embryo, to appreciate how they guide development and to gain exciting new insights into how genes and teratogens interact. The prospects for progress in the war on birth defects were never brighter.
F. Clarke Fraser McGill University (Emeritus) Montreal, Quebec, Canad
Vitamin D and Reproduction: From Gametes to Childhood
Vitamin D is well recognized for its essentiality in maintaining skeletal health. Recent research has suggested that vitamin D may exert a broad range of roles throughout the human life cycle starting from reproduction to adult chronic disease risk. Rates of vitamin D deficiency during pregnancy remain high worldwide. Vitamin D deficiency has been associated with an increased risk of fertility problems, preeclampsia, gestational diabetes, and allergic disease in the offspring. Vitamin D is found naturally in only a few foods thus supplementation can provide an accessible and effective way to raise vitamin D status when dietary intakes and sunlight exposure are low. However, the possibility of overconsumption and possible adverse effects is under debate. The effect of vitamin D supplementation during pregnancy and early life on maternal and infant outcomes will be of particular focus in this review
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Vitamin D Deficiency in Pregnant Ukrainian Women: Effects of Alcohol Consumption on Vitamin D Status.
ObjectiveHeavy alcohol consumption can alter vitamin D status; however, the relationships between alcohol consumption and vitamin D concentrations in pregnant women have not been well studied. The aim of this study was to investigate the vitamin D status in a population of alcohol-exposed (N = 180) and low/unexposed control (N = 179) Ukrainian pregnant women.MethodsWomen who attended prenatal care facilities in 2 regions of Ukraine (Rivne and Khmelnytsky) for a routine prenatal visit were screened for the study. At the time of enrollment (20.4 ± 7.0 weeks of gestation), blood samples and alcohol consumption data (during a typical week around conception and the most recent 2 weeks) were collected. Vitamin D status was assessed by 25-hydroxyvitamin D [25(OH)D] concentrations.ResultsA high prevalence of suboptimal vitamin D status in pregnant Ukrainian women was observed. Overall, 50.1% and 33.4% of the women were classified as vitamin D deficient [25(OH)D < 20 ng/mL] or insufficient [25(OH)D ≥ 20 ng/mL and ≤30 ng/mL], respectively, based on 2011 Endocrine Society guidelines. Alcohol-exposed women had significantly lower 25(OH)D concentrations than low/unexposed women in Spring (p = 0.006) and Winter (p = 0.022). When vitamin D concentrations were grouped into sunny season (Summer + Fall) compared to not sunny season (Winter + Spring), there was a significant ethanol by season interaction (p = 0.0028), with alcohol-drinking women having lower circulating vitamin D compared to low/unexposed women in seasons of low sun availability.ConclusionsThese data suggest that when vitamin D concentrations are generally low (e.g., during seasons of low sun availability), alcohol consumption during pregnancy has a negative impact on vitamin D status
Associations between maternal antioxidant intakes in pregnancy and infant allergic outcomes
Antioxidant intakes in pregnancy may influence fetal immune programming and the risk of allergic disease. We investigated associations between maternal intakes of β-carotene, vitamin C, vitamin E, copper and zinc, and infant allergic outcomes. Antioxidant intakes of pregnant women (n = 420) assessed prospectively by a food frequency questionnaire, were examined in relation to allergic outcomes at 1 year of age (n = 300). The main relationships with allergic outcomes were seen with dietary vitamin C and copper. Specifically, higher maternal dietary vitamin C intake was associated with a reduced risk of any diagnosed infant allergic disease and wheeze. After adjustment for potential confounders the relationship with wheeze remained statistically significant. There was also an inverse linear relationship between vitamin C and food allergy. Higher dietary copper intake was associated with reduced risk of eczema, wheeze and any allergic disease. The relationship with wheeze and any allergic disease remained statistically significant in multivariate analysis, and there was also an inverse linear relationship between copper and food allergy. However, these relationships were only seen for nutrients present in food. There were no relationships between β-carotene, vitamin E or zinc and any allergic outcomes. In summary, this study suggests that maternal diet of fresh foods rich in vitamin C is associated with reduced risk of infant wheeze, and that copper intake is associated with reduced risk of several allergic outcomes
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Altered Maternal Plasma Fatty Acid Composition by Alcohol Consumption and Smoking during Pregnancy and Associations with Fetal Alcohol Spectrum Disorders
Objective: Polyunsaturated fatty acids are vital for optimal fetal neuronal development. The relationship between maternal alcohol consumption and smoking with third trimester plasma fatty acids were examined and their association with Fetal Alcohol Spectrum Disorders (FASD).Methods: Moderate to heavy alcohol-using and low/unexposed comparison women were recruited during mid-pregnancy from two prenatal clinics in Ukraine. The participants' infants underwent physical and neurobehavioral exams prior to one-year of age and classified as having FASD by maternal alcohol consumption and neurobehavioral scores. A subset of mother-child pairs was selected representing three groups of cases and controls: Alcohol-Exposed with FASD (AE-FASD, n = 30), Alcohol-Exposed Normally Developing (AE-ND, n = 33), or Controls (n = 46). Third trimester maternal plasma samples were analyzed for fatty acids and levels were compared across groups.Results: The percent of C18:0 (p < 0.001), arachidonic acid (AA, C20:4n-6, p = 0.017) and C22:5n-6 (p = 0.001) were significantly higher in AE-FASD women than controls or AE-ND women. Alcohol-exposed women who smoked had lower C22:5n-3 (p = 0.029) and docosahexaenoic acid (DHA, C22:6n-3, p = 0.005) and higher C22:5n-6 (p = 0.013) than women consuming alcohol alone or abstainers.Conclusion: Alterations in fatty acid profiles were observed in moderate to heavy alcohol-consuming mothers with infants classified with FASD compared to alcohol-exposed normally developing infants or controls