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At least 19 recordsLinked to original sources
PubMed1996

[Delayed effects of prenatal exposure to phenobarbital on intelligence--Phenemal].

Two double-blind studies were conducted on two independent samples of adult men prenatally exposed to phenobarbital and matched control samples using two different measures of general intelligence (WAIS and a draft board test (BPP)). The two studies included 33 and 81 exposed adult men respectively, and the two control groups included 52 and 101 unexposed men matched on a wide spectrum of maternal variables recorded pre- and perinatally. Based on data from control subjects, regression models were built relating intelligence scores to relevant pre-exposure matching variables. Models generated predicted scores for each exposed subject. Men exposed prenatally to phenobarbital had significantly lower verbal intelligence scores than predicted. Lower socioeconomic status and being the offspring of an unwanted pregnancy increased the magnitude of the negative effects. Exposure which includes the last trimester was the most detrimental. Physicians are urged to use increased caution in prescribing such medications during pregnancy or to premature neonates.

Adult↗
PubMed2001

Delayed developmental effects following prenatal exposure to drugs.

Increasing evidence points to the possible risks of delayed effects upon prenatal exposure to chemicals; the evaluation of such effects may pose serious problems to clinicians, epidemiologists and toxicologists. In fact, several systems (e.g., nervous, excretory) show important developmental processes well after the organogenetic period, up to the postnatal phase; accordingly, these are also expected to be sensitive targets of developmental toxicants, resulting in impairment of the function and/or functional reserve. This review describes the effects of several groups of drugs on the functional maturation and histogenesis of the kidney (e.g., aminoglycosides, angiotensin-converting enzyme inhibitors, indomethacin) and brain (e.g., anticonvulsivants, antiretroviral compounds, benzodiazepines) upon exposure in utero of humans and laboratory animals. The available data stress the importance for risk assessment of an adequate knowledge of both developmental biology and mechanisms of toxicity. The design of developmental toxicity studies should allow an evaluation of targets most relevant for a given drug (or group of drugs); moreover, the analysis of functional development should receive the due attention within the safety assessment of chemicals.

Animals↗
PubMed1987

Delayed effects of prenatal or postnatal exposure to diethylstilbestrol in the adult female guinea pig.

Of 25 mature female guinea pigs exposed transplacentally to diethylstilbestrol (DES) for more than 20 days before term, 8 showed abnormal changes in the genital tract (stimulation of the epithelium and stroma, cystic glandular hyperplasia of the endometrial glands near the junction of the upper endocervix and endometrium) and 9 showed severe changes (cystic glandular hyperplasia of the endometrial glands throughout the corpus uteri and cornua, squamous metaplasia). Hyperkeratosis of the vulvar and nipple skin was also observed. No neoplastic changes were observed with one exception at 14 months in one ovary. Prenatal exposure to DES for less than 15 days before term or after birth for 3 days failed to result in abnormal changes in the adults. Prenatal exposure to estradiol for more than 20 days also was without effect in the adult, despite the higher tolerated doses given to the mothers. Cycling activity as judged by vaginal opening was abnormal in all experimental groups, suggesting a derangement of the pituitary-hypothalamic function not specifically related to DES exposure. It was concluded that there is a critical period of exposure of the Müllerian duct- and sinus-derived tissues with respect to the delayed effects of prenatal exposure to DES, which is estimated on the basis of embryological studies to range from the 28th to about the 45th day of gestation.

Animals↗
PubMed1999

Imprinting: perinatal exposures cause the development of diseases during the adult age.

Since the early reports linking the development of clear cell cervicovaginal adenocarcinoma in young women with diethylstilbestrol treatment of their mothers during pregnancy, it became clear that perinatal exposure to several substances may induce irreversible alterations, that can be detected later in life. Current evidence suggests that these substances induce, by the mechanism of imprinting, alterations of the differentiation of several cell-types, resulting in the development of disease during the adult age. The most known delayed effects to prenatal exposure to agents displaying hormone action, pollutants, food additives and natural food components, substances of abuse and stress by the mechanism of imprinting are described. Among them, estrogens, androgens, progestins, lead, benzopyrenes, ozone, dioxins, DDT, DDE, methoxychlor, chlordecone, parathion, malathion, polychlorobiphenyls, pyrethroids, paraquat, food additives, normal food constituents, tetrahydrocannabinol, cocaine and opiates. It is concluded that perinatal exposure to several agents causes irreversible changes that determine health conditions during adulthood. Several diseases developing during adulthood probably were determined during early stages of life, under the effect of exposure or preferential mother's diet during pregnancy. Regulations to avoid these early exposures may contribute to an important improvement of health conditions of humankind.

Environmental Pollutants↗
PubMed2005

Gestational programming: population survival effects of drought and famine during pregnancy.

The process whereby a stimulus or stress at a critical or sensitive period of development has long-term effects is termed "programming." Studies in humans and animals convincingly demonstrate that environmental perturbations in utero may permanently change organ structure and metabolism and/or alter homeostatic regulatory mechanisms among the offspring. These programmed changes may be the origins of adult diseases, including cardiovascular disease, obesity, and diabetes. Throughout evolution and development, humans and animals have been exposed to two common environmental stresses, drought and famine. Notably, drought-induced water deprivation is associated with dehydration anorexia and thus a concomitant potential nutrient stress. Our laboratory has performed studies among pregnant rat and sheep in which we simulate drought conditions via maternal dehydration and famine conditions via nutrient restriction. Maternal dehydration results in low-birth-weight offspring, which demonstrate gender-specific plasma hypernatremia and hypertonicity and arterial hypertension. Gestational nutrient restriction also resulted in low-birth-weight offspring. If permitted rapid catch-up growth by nutrient availability, these offspring demonstrate evidence of increased body weight and body fat, and leptin resistance as adults. Conversely, if the catch-up growth is delayed by nutrition restriction, the offspring exhibit normal body weight, body fat, and plasma leptin levels as adults. These studies indicate that osmoregulatory and cardiovascular homeostasis and phenotypic predisposition to obesity may be programmed in utero. Importantly, these results suggest that programming effects may be either potentiated or prevented by interventions during the neonatal period.

Animals↗
PubMed2004

Developmental immunotoxicity of lead in the rat: influence of maternal diet.

The effect of maternal dietary protein intake on lead-induced developmental immunotoxicity was studied in female Fischer 344 rats receiving lead acetate (250 ppm) or sodium acetate (control) in the drinking water during breeding and pregnancy until parturition. Dams were fed isocaloric diets (either 20% casein or 10% casein) from 2 wk prior to mating until the end of lactation. After weaning, dams and female offspring were given the 20% casein diet and regular water. Immune function was assessed in dams at 8 wk postpartum and in offspring at 13 wk of age. Dams showed no marked difference in any of the immune endpoints examined, regardless of diet or lead treatment. In contrast, lead exposure during early development produced a subsequent significant reduction of both the delayed-type hypersensitivity response and interferon gamma production in adult offspring independent of maternal diet. Lead-exposed offspring from the high-dietary-protein group had significantly elevated production of both interleukin-4 and tumor necrosis factor alpha(TNF-alpha) with increased relative spleen weight and a decreased body weight compared to offspring in the lead control group. In contrast, lead-exposed offspring from dams receiving the low-protein diet had no marked change in TNF-alpha levels, relative spleen weight, or body weight, while interleukin-4 levels were significantly reduced compared with the lead control group. In conclusion, maternal dietary protein intake can modulate the immunotoxic effects of lead exposure during early development. This occurred at levels of protein intake and doses of lead exposure that produced no detectable effect on the maternal immune system.

Animals↗
PubMedDate not supplied

Impact of diets and nutrients/drugs on early epigenetic programming.

Specific, often unbalanced diets are used to circumvent the metabolic defects of patients with monogenic inborn errors of metabolism. Human epidemiological studies and appropriately designed dietary interventions in animal models have provided considerable evidence to suggest that nutritional imbalance and metabolic disturbances, during critical time windows of developmental programming, may have a persistent effect on the health of the child and later in adulthood. Thus patients with monogenic inborn errors of metabolism may also suffer additional types of alterations due to the lack or excess of key nutrients. Interactions of nutrients with the epigenetic machinery lead to epigenetic changes associated with chromatin remodelling and regulation of gene expression that underlie the developmental programming of pathological consequences in adulthood. Today, with the explosion of new technologies, we can explore on a large scale the effects of nutrients on the level of expression of thousands of expressed genes (nutritional genomics and epigenomics), the corresponding protein products and their posttranslationally modified derivatives (proteomics), and the host of metabolites (metabolomics) generated from endogenous metabolic processes or exogenous dietary nutrients and can establish the relationship between these biological entities and diet, health or disease. The combination of these various lines of research on epigenetic programming processes should highlight new strategies for the prevention and treatment of inborn errors of metabolism.

Acetylation↗
PubMedDate not supplied

Fetal origins of developmental plasticity: are fetal cues reliable predictors of future nutritional environments?

Evidence that fetal nutrition triggers permanent adjustments in a wide range of systems and health outcomes is stimulating interest in the evolutionary significance of these responses. This review evaluates the postnatal adaptive significance of fetal developmental plasticity from the perspective of life history theory and evolutionary models of energy partitioning. Birthweight is positively related to multiple metabolically costly postnatal functions, suggesting that the fetus has the capacity to distribute the burden of energy insufficiency when faced with a nutritionally challenging environment. Lowering total requirements may reduce the risk of negative energy balance, which disproportionately impacts functions that are not essential for survival but that are crucial for reproductive success. The long-term benefit of these metabolic adjustments is contingent upon the fetus having access to a cue that is predictive of its future nutritional environment, a problem complicated in a long-lived species by short-term ecologic fluctuations like seasonality. Evidence is reviewed suggesting that the flow of nutrients reaching the fetus provides an integrated signal of nutrition as experienced by recent matrilineal ancestors, which effectively limits the responsiveness to short-term ecologic fluctuations during any given pregnancy. This capacity for fetal nutrition to minimize the growth response to transient ecologic fluctuations is defined here as intergenerational "phenotypic inertia," and is hypothesized to allow the fetus to cut through the "noise" of seasonal or other stochastic influences to read the "signal" of longer-term ecologic trends. As a mode of adaptation, phenotypic inertia may help the organism cope with ecologic trends too gradual to be tracked by conventional developmental plasticity, but too rapid to be tracked by natural selection. From an applied perspective, if a trait like fetal growth is designed to minimize the effects of short-term fluctuations by integrating information across generations, public health interventions may be most effective if focused not on the individual but on the matriline.

Adaptation, Physiological↗
PubMed2005

Experimental models for studying perinatal lipid metabolism. Long-term effects of perinatal undernutrition.

By using different experimental designs in the rat we have been able to answer several unanswered questions on the short- and long-term effects of alterations of lipid metabolism during the perinatal stage. The first was to demonstrate the importance of maternal body fat accumulation during the first half of pregnancy, since undernutrition in this critical period when fetal growth is slow, impedes fat depot accumulation and not only restrains intrauterine development but has long-term consequences, as shown by an impaired glucose tolerance when adults. Secondly, undernutrition during suckling has major long-term effect of decreasing body weight, even though food intake is kept normal from the weaning period. Our findings also show that a diet rich in n-3 fatty acids during pregnancy and lactation has adverse effects on offspring development, but cross fostered experiments showed that this effect was a consequence of the intake of these fatty acids during the lactation period rather than during pregnancy. Pups from dams that were fed a fish oil-rich diet during pregnancy and lactation were found to have altered glucose/insulin relationship at the age of 10 weeks. Since a n-3 fatty acid-rich diet decreases milk yield during lactation, additional experiments were carried out to determine whether decreased food intake or altered dietary fatty acid composition, or both, were responsible for the long-term effects on the glucose/insulin axis. Results show that the decreased food intake caused by a n-3 fatty acid-rich diet rather than the change in milk composition during suckling was responsible for the reduced pancreatic glucose responsiveness to insulin release at 16 weeks of age. In conclusion, present findings indicate that impaired maternal fat accumulation during early pregnancy and food intake during lactation, rather than a difference in dietary fatty acid composition, have major effects on postnatal development and affect glucose/insulin relationships in adult rats.

Adipose Tissue↗
PubMed2002

Effect of maternal feed restriction on blood pressure in the adult guinea pig.

Small size at birth has been associated with increased blood pressure in adult men and women. In rats, isocaloric protein restriction reduces fetal growth and increases systolic blood pressure in adult offspring. Balanced maternal undernutrition in the rat also increases adult blood pressure, but not consistently. The aim of this study was to determine the effect of moderate balanced maternal undernutrition (85% of ad libitum intake from 4 weeks before, and throughout pregnancy) on blood pressure of adult offspring in the guinea pig, a species that is relatively mature at birth. Blood pressure was measured in chronically catheterised offspring of ad libitum fed or feed-restricted mothers, at 3 months of age (young adult). Maternal feed restriction reduced birth weight (-17%) and increased systolic blood pressure (+9%, P < 0.03) in young adult male offspring. In offspring of ad libitum fed and feed-restricted mothers, combined data showed that systolic blood pressure and mean arterial pressure correlated negatively with head width at birth (P = 0.02 and P = 0.04, respectively, n = 28). Systolic blood pressure also correlated negatively with birth weight and the ratio birth weight/birth length, but only in offspring of ad libitum fed mothers (P = 0.04 and P = 0.03, respectively, n = 22). The effect of maternal feed restriction on systolic blood pressure in male offspring was not significant when adjusted for these measures of size at birth. Thus, moderate balanced undernutrition in the guinea pig increases systolic blood pressure in young adult male offspring; however, these effects may be mediated, at least in part, through effects on fetal growth.

Aging↗
PubMed2006

Morphometric analysis of brain lesions in rat fetuses prenatally exposed to low-level lead acetate: correlation with lipid peroxidation.

The effect of prenatal lead acetate exposure was studied microscopically together with the concentration of lead and lipid fluorescent products (LFP) in the brain of rat fetuses. Wistar rats were intoxicated with a lead solution containing either 160 or 320 ppm of lead acetate solution during 21 days through drinking water. The control group (ten rats) received deionized water for the same period. The rats were killed on gestation day 21 and fetuses were obtained; the placenta, umbilical cord and parietal cortex (Cx), striatum (St), thalamus (Th) and cerebellum (Ce) were collected for measuring tissue lead concentration, LFP as an index of lipid peroxidation and histopathologic examination. Lead contents were increased in placenta, umbilical cord, St, Th and Cx in both lead-exposed groups. Lead exposure increased (LFP) in placenta and umbilical cord, St, Th and Ce as compared to the control group. Histopathological examination showed severe vascular congestion in placenta, the Cx, St, Th and Ce with hyperchromatic and shrunken cells. Interstitial oedema was found in all regions studied of both lead exposed groups. The morphometric evaluation of the studied brain regions showed an absolute decrease in total cell number and increased number of damaged cells and interstitial oedema. Our results show that morphological changes in rat brain are correlated with increased lipid peroxidation, and the lead levels of the umbilical cord, however it is not clear whether oxidative stress is the cause or the consequence of these neurotoxic effects of lead.

Animals↗
PubMed2006

Effect of iron supplementation during pregnancy on the intelligence quotient and behavior of children at 4 y of age: long-term follow-up of a randomized controlled trial.

BACKGROUND: Iron supplements are often prescribed during pregnancy despite the lack of intervention trials that have assessed the effects of supplementation in pregnancy on childhood development. OBJECTIVE: The objective was to determine whether iron supplementation during pregnancy influences childhood intelligence quotient (IQ) in an industrialized country. DESIGN: Pregnant women (n = 430) were randomly allocated to receive iron (20 mg/d) or placebo from 20 wk gestation until delivery, and the women and their children were followed up over the long term (4 y). Seventy percent of these families participated in the follow-up. The proportion of women with iron deficiency anemia at the end of pregnancy was 1% (2 of 146) in the iron group and 11% (15 of 141) in the placebo group. The primary outcome was the IQ of the children at 4 y of age, as assessed by the Stanford-Binet Intelligence Scale. Secondary outcomes included child behavior and the general health of the mothers. RESULTS: The mean IQ was not significantly different (P = 0.980) between the children of the iron-supplemented mothers (109 +/- 11; n = 153) and the children of the mothers in the placebo group (109 +/- 11; n = 149). However, the percentage of children with an abnormal behavior score was higher in the iron group (24 of 151, or 16%) than in the placebo group (12 of 149, or 8%); the relative risk was 1.97 (95% CI: 1.03, 3.80; P = 0.037). There was no significant difference in the health of the mothers between groups, as assessed by the SF-36 Health Survey. CONCLUSIONS: Prenatal iron supplementation that reduces the incidence of iron deficiency anemia from 11% to 1% has no effect on the IQ of the offspring at 4 y of age.

Child Behavior↗
PubMed2005

A quantitative analysis of prenatal intake of n-3 polyunsaturated fatty acids and cognitive development.

Although a rich source of n-3 polyunsaturated fatty acids (PUFAs) that may confer multiple health benefits, some fish also contain methyl mercury (MeHg), which may harm the developing fetus. U.S. government recommendations for women of childbearing age are to modify consumption of high-MeHg fish to reduce MeHg exposure, while recommendations encourage fish consumption among the general population because of the nutritional benefits. The Harvard Center for Risk Analysis convened an expert panel (see acknowledgements) to quantify the net impact of resulting hypothetical changes in fish consumption across the population. This paper estimates the impact of prenatal n-3 intake on cognitive development. Other papers quantify the negative impact of prenatal exposure to MeHg on cognitive development, and the extent to which fish consumption protects against coronary heart disease mortality and stroke in adults. This paper aggregates eight randomized controlled trials (RCTs) comparing cognitive development in controls and in children who had received n-3 PUFA supplementation (seven studies of formula supplementation and one study of maternal dietary supplementation). Our analysis assigns study weights accounting for statistical precision, relevance of three endpoint domains (general intelligence, verbal ability, and motor skills) to prediction of IQ, and age at evaluation. The study estimates that increasing maternal docosahexaenoic acid (DHA) intake by 100 mg/day increases child IQ by 0.13 points. The paper notes that findings were inconsistent across the RCTs evaluated (although our findings were relatively robust to changes in the weighting scheme used). Also, for seven of the eight studies reviewed, effects are extrapolated from formula supplementation to maternal dietary intake.

Central Nervous System↗
PubMed2002

Increased systolic blood pressure in rats induced by a maternal low-protein diet is reversed by dietary supplementation with glycine.

When rat dams consume a diet low in protein during pregnancy, their offspring develop high blood pressure. On a low-protein diet, the endogenous formation of the amino acid glycine is thought to become constrained. Glycine may become conditionally essential, as its rate of endogenous formation is inadequate to meet metabolic needs, and may be limiting for the normal development of the fetus. In the present study, five groups of Wistar rats were provided during pregnancy with one of five diets: a control diet containing 18% (w/w) casein (CON), a low-protein diet containing 9% casein (MLP), or the low-protein diet supplemented with 3% glycine (MLPG), alanine (MLPA) or urea (MLPU). The offspring were weaned on to standard laboratory chow, and blood pressure was measured at 4 weeks of age. Blood pressure was significantly increased in the MLP, MLPA and MLPU groups compared with the CON group, but for the MLPG group blood pressure was not significantly different from CON. Compared with the CON group, body weight was significantly reduced for the MLP, MLPA and MLPG groups, but for the MLPU group body weight was not different from CON. These data show that different forms of non-essential dietary nitrogen, when consumed during pregnancy, exert different effects upon the growth and function of the offspring. The availability of glycine appears to be of critical importance for normal cardiovascular development.

Animals↗
PubMed2005

Fetal environment and schizophrenia.

Schizophrenia and related disorders are adult-onset illnesses with no definitively established risk factors. Several studies report that exposures to infection and nutritional deprivation during early development may elevate the risk of later developing schizophrenia, specifically during the prenatal period. Preliminary evidence implicates lead exposure as well, suggesting that chemical exposures during early development may constitute a new class of risk factors for schizophrenia that has not been adequately investigated. Exposure to lead is given as an example of a chemical agent for which some effects have been described throughout the life course on both general neurodevelopmental outcomes and now on a specific psychiatric diagnosis. Findings from prospectively collected birth cohorts are offered as examples of both innovations in methodology and opportunities for future generations of investigators.

Environmental Pollutants↗
PubMed2003

The influence of various physiological challenges on permanent changes to the cardiovascular system.

The concept of fetal programming provides an intellectual framework that links physiological adaptations that occur during development to permanent changes in postnatal regulatory systems. Recent research in the area of cardiovascular programming has highlighted the mechanisms by which these changes exert their effects. The aim of this review is to integrate some of the literature on nutritional changes, exposure to excess glucocorticoids and other challenges during development as they provide support for various mechanisms of programming of the cardiovascular system.

Animals↗
PubMed2006

Glucose tolerance at age 58 and the decline of glucose tolerance in comparison with age 50 in people prenatally exposed to the Dutch famine.

AIMS/HYPOTHESIS: People who were small at birth have an increased risk of type 2 diabetes in later life. People who were in utero during the Dutch famine had decreased glucose tolerance and raised insulin concentrations at age 50. We aimed to evaluate whether prenatal famine exposure leads to more rapid progression of impaired glucose/insulin homeostasis with increasing age. METHODS: We performed an OGTT in 702 men and women at age 50 and in 699 men and women at age 58, all born as term singletons immediately before, during or after the 1944-1945 Dutch famine. RESULTS: People who had been exposed to famine in utero had significantly higher 120-min glucose concentrations at age 58 compared with people who had not been exposed to famine (difference=0.4 mmol/l, 95% CI 0.1 to 0.7, adjusted for sex and BMI). Glucose tolerance deteriorated between the age of 50 and 58. The unadjusted 120-min glucose concentrations rose by 0.2 mmol/l (95% CI 0.0 to 0.4), while 120-min insulin concentrations had increased by 64 pmol/l (95% CI 48 to 82). There were no differences in the rates of glucose and insulin level increase between the famine-exposed group and the unexposed group (p=0.28 for the difference in increase in glucose concentrations and p=0.09 for insulin concentrations). CONCLUSIONS/INTERPRETATION: Although we confirmed that undernutrition during gestation is linked to decreased glucose tolerance, the effect does not seem to become more pronounced at age 58 as compared with age 50.

Adult↗