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The Plausibility of Maternal Nutritional Status Being a Contributing Factor to the Risk for Fetal Alcohol Spectrum Disorders: The Potential Influence of Zinc Status as an Example
Abstract
There is increasing evidence that human pregnancy outcome can be significantly compromised by suboptimal maternal nutritional status. Poor diet results in a maternal-fetal environment in which the teratogenicity of other insults such as alcohol might be amplified. As an example, there is evidence that zinc (Zn) can interact with maternal alcohol exposure to influence the risk for fetal alcohol spectrum disorders (FASD). Studies with experimental animals have shown that the teratogenicity of alcohol is increased under conditions of Zn deficiency, whereas its teratogenicity is lessened when animals are given Zn-supplemented diets or Zn injections before the alcohol exposure. Alcohol can precipitate an acute-phase response, resulting in a subsequent increase in maternal liver metallothionein, which can sequester Zn and lead to decreased Zn transfer to the fetus. Importantly, the teratogenicity of acute alcohol exposure is reduced in metallothionein knockout mice, which can have improved Zn transfer to the conceptus relative to wild-type mice. Consistent with the above, Zn status has been reported to be low in alcoholic women at delivery. Preliminary data from two basic science and clinical nutritional studies that are ongoing as part of the international Collaborative Initiative on Fetal Alcohol Spectrum Disorders support the potential role of Zn, among other nutritional factors, relative to risk for FASD. Importantly, the nutrient levels being examined in these studies are relevant to general clinical populations and represent suboptimal levels rather than severe deficiencies. These data suggest that moderate deficiencies in single nutrients can act as permissive factors for FASD, and that adequate nutritional status or intervention through supplementation may provide protection from some of the adverse effects of prenatal alcohol exposure.
... These include the appropriate amount and proportion of nutrients necessary for the proper functioning of the mother's body and, consequently, the development of the fetus. The number of kilocalories provided in the diet and the mother's lifelong and current nutrition (body weight, fat content, and BMI) have a substantial impact on the relative risk for FASD [23,24] including its more severe FAS syndrome [4,25]. ...
... The risk of FASD-related central damage and clinical effects in children of mothers with mental disabilities and h-PAE alcohol intoxication is believed to be higher. This is partly due to choline deficiency in the diet of this group of women [23,43]. Because an undernourished mother has a limited supply of nutrients for the fetus, low postnatal nutrition can exacerbate the effects of malnutrition, resulting in growth retardation and impaired cognitive functions such as IQ and language development [6]. ...
... Because an undernourished mother has a limited supply of nutrients for the fetus, low postnatal nutrition can exacerbate the effects of malnutrition, resulting in growth retardation and impaired cognitive functions such as IQ and language development [6]. Therefore, the administration of choline early in pregnancy should be a preventive measure [23,43]. As a result, heavy prenatal alcohol exposure's adverse effects on postnatal growth and cognitive functions, including nonverbal intelligence, visual-spatial skills, working memory ability, verbal memory, and fewer behavioral symptoms of attention deficit hyperactivity in human infants, may be mitigated [23,43]. ...
Prenatal alcohol exposure (PAE), which refers to alcohol consumption by pregnant women, is associated with the risk of numerous severe complications during fetal development. The State Agency for Alcohol Problem Solving reports that the incidence of fetal alcohol spectrum disorder (FASD) in Poland’s general population is over 1.7%, and the incidence of fetal alcohol syndrome (FAS) is estimated at more than 0.5%. This study aimed to evaluate the significance of alcohol exposure and focused on the pattern of alcohol intoxication exhibited by the mother during pregnancy and other environmental factors of the maternal environment contributing to the development of FASD. The study covered 554 subjects, including 251 mothers and 303 children (213 girls and 90 boys). The mother’s drinking problem was determined based on the information obtained from the case history. All children qualified for the study fulfilled the h-PAE (high alcohol exposure) criteria during their fetal life. The clinical diagnosis of FAS and pFAS (occurrence of morphological symptoms of fetal alcohol syndrome) was made using a four-digit diagnostic questionnaire validated in the Polish version of the Washington Questionnaire for the assessment of the spectrum of alcohol-related neurodevelopmental disorders or alcohol-related cognitive impairment (ARND/C). Statistical analysis of the obtained research results was developed using statistical software–STATISTICA PL, version 13.1 (StatSoft, Inc., Szczecin, Poland 2016, STATISTICA–data analysis software system, version 13.1). The most destructive drinking behaviors are compulsive intoxication (BD, binge drinking) during the first 6 weeks of pregnancy and chronic addiction throughout its duration (CHD, chronic drinking). Chronic alcohol intoxication (CHD) leads to a poorer nutritional status in mothers, which is reflected in a lower body mass index (BMI) (<18 kg/m2).
... Alcohol exposure in animal models also allows variables known to be associated with FASD to be tested. These variables include: genetic and epigenetic factors (Kaminen-Ahola et al., 2010;Kleiber et al., 2014), maternal and fetal stress (Glavas, Ellis, Yu, & Weinberg, 2007;Raineki et al., 2014;Uban, Comeau, Ellis, Galea, & Weinberg, 2013), nutritional status (Keen et al., 2010;Weinberg, 1985;Young, Giesbrecht, Eskin, Aliani, & Suh, 2014) (Keen et al., 2010;Weinberg, 1985;Young et al., 2014), and the ability of the mother or the fetus to metabolize alcohol (Ramchandani, Bosron, & Li, 2001;Riley, Infante, & Warren, 2011;Yelin et al., 2007). These variables can be tested in conjunction with alcohol exposure to determine which variables can further exacerbate the alcohol-induced phenotypes and which treatments or manipulations can rescue or prevent the malformations, such as vitamin A, retinoic acid, or folate (Ballard et al., 2012;Marrs et al., 2010;Serrano et al., 2010;Twal & Zile, 1997;Yelin et al., 2005). ...
... Alcohol exposure in animal models also allows variables known to be associated with FASD to be tested. These variables include: genetic and epigenetic factors (Kaminen-Ahola et al., 2010;Kleiber et al., 2014), maternal and fetal stress (Glavas, Ellis, Yu, & Weinberg, 2007;Raineki et al., 2014;Uban, Comeau, Ellis, Galea, & Weinberg, 2013), nutritional status (Keen et al., 2010;Weinberg, 1985;Young, Giesbrecht, Eskin, Aliani, & Suh, 2014) (Keen et al., 2010;Weinberg, 1985;Young et al., 2014), and the ability of the mother or the fetus to metabolize alcohol (Ramchandani, Bosron, & Li, 2001;Riley, Infante, & Warren, 2011;Yelin et al., 2007). These variables can be tested in conjunction with alcohol exposure to determine which variables can further exacerbate the alcohol-induced phenotypes and which treatments or manipulations can rescue or prevent the malformations, such as vitamin A, retinoic acid, or folate (Ballard et al., 2012;Marrs et al., 2010;Serrano et al., 2010;Twal & Zile, 1997;Yelin et al., 2005). ...
Fetal Alcohol Spectrum Disorder (FASD) is a set of neurodevelopmental malformations caused by maternal consumption of alcohol during pregnancy. FASD sentinel facial features are unique to the disorder and microcephaly is common in severe forms of FASD. Retinoic acid deficiency has been shown to cause craniofacial malformations and microcephaly in animal models reminiscent of those caused by prenatal alcohol exposure. Alcohol exposure affects the migration and survival of cranial neural crest cells, which are required for proper frontonasal prominence and pharyngeal arch development. Defects in craniofacial development are further amplified by the many downstream pathways that are transcriptionally controlled retinoic acid target genes, including Shh signaling. Recent evidence shows that alcohol exposure itself is sufficient to induce retinoic acid deficiency in the embryo. These data suggest that retinoic acid deficiency is an important underlying etiology of FASD. In disorders like Vitamin A Deficiency, FASD, DiGeorge, CHARGE, Smith‐Magenis, Matthew‐Wood and Congenital Zika Syndromes, evidence is accumulating to link reduced retinoic acid signaling with developmental defects like craniofacial malformations and microcephaly. Research focus on characterizing the effects of retinoic acid deficiency during early development and on understanding the downstream signaling pathways involved in aberrant head and craniofacial development will reveal underlying etiologies of these disorders.
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... A population-based study the Western Cape Province of South Africa showed that mothers with FASD children had major nutritional deficiencies, with significantly lower intake of vitamins A, C, D, E, B 2 , calcium, omega-3 fatty acids and choline compared to nondrinking mothers (May et al. 2014). Another study with pregnant women in Ukraine and Russia showed that the mothers that consumed alcohol during pregnancy had lower levels of plasma zinc that non-drinking mothers (Keen et al. 2010). Some researches tried to treat women with choline, minerals and ...
... antioxidants in order to reverse nutritional deficiencies commonly seen in FAS mothers (Cohen-Kerem and Koren 2003;Keen et al. 2010;Kable et al. 2015). ...
Ethanol is the most important teratogen agent in humans. Prenatal alcohol exposure can lead to a wide range of adverse effects, which are broadly termed as fetal alcohol spectrum disorder (FASD). The most severe consequence of maternal alcohol abuse is the development of fetal alcohol syndrome, defined by growth retardation, facial malformations, and central nervous system impairment expressed as microcephaly and neurodevelopment abnormalities. These alterations generate a broad range of cognitive abnormalities such as learning disabilities and hyperactivity and behavioural problems. Socioeconomic status, ethnicity, differences in genetic susceptibility related to ethanol metabolism, alcohol consumption patterns, obstetric problems, and environmental influences like maternal nutrition, stress, and other co-administered drugs are all factors that may influence FASD manifestations. Recently, much attention has been paid to the role of nutrition as a protective factor against alcohol teratogenicity. There are a great number of papers related to nutritional treatment of nutritional deficits due to several factors associated with maternal consumption of alcohol and with eating and social disorders in FASD children. Although research showed the clinical benefits of nutritional interventions, most of work was in animal models, in a preclinical phase, or in the prenatal period. However, a minimum number of studies refer to postnatal nutrition treatment of neurodevelopmental deficits. Nutritional supplementation in children with FASD has a dual objective: to overcome nutritional deficiencies and to reverse or improve the cognitive deleterious effects of prenatal alcohol exposure. Further research is necessary to confirm positive results, to determine optimal amounts of nutrients needed in supplementation, and to investigate the collective effects of simultaneous multiple-nutrient supplementation.
... Prenatal alcohol consumption is known to affect postnatal intestinal absorption of zinc [83]. Women with a history of alcohol abuse are at risk of zinc deficiency [84,85]. As the nutritional status of the biological mothers of the patients in our cohort is unknown, we can speculate that patients with increased serum zinc concentration could have experienced zinc deficiency during pregnancy. ...
Background/Objectives: Malnutrition is a significant concern in paediatric populations, particularly among children with neurodevelopmental disorders such as foetal alcohol spectrum disorder (FASD). This study aimed to examine macronutrient and micronutrient imbalances and assess the nutritional status of a group of patients with FASD. Methods: This study involved an analysis of the serum levels of key nutrients in a group of children diagnosed with FASD. Macronutrients and micronutrients were measured to identify any imbalances, including vitamin D, B12, E, A, albumin, and serum protein, among others. Results: The study found a high prevalence of vitamin D deficiency among the patients. Additionally, elevated serum concentrations of micronutrients such as vitamin B12, E, and A were observed in 8%, 7%, and 19% of patients, respectively. Macronutrient imbalances were noted, including high levels of albumin and serum protein, indicating a possible metabolic disturbance. Unexpectedly, high rates of hypercholesterolemia were observed, raising concerns about an increased risk of metabolic syndrome in this population. Conclusions: These findings suggest that the principal issue among patients with FASD is an altered metabolism rather than nutritional deficiencies. Potential causes of these abnormalities could include oxidative stress and changes in body composition. The results underline the need for further research to better understand the unique nutritional challenges in children with FASD and to guide the development of targeted therapeutic strategies.
... It is also important to consider the general pattern of alcohol consumption before pregnancy diagnosis, the most common drinking pattern is that women who drink alcohol about three months before pregnancy diagnosis continue consuming to the first trimester of pregnancy [27]. Additionally, some women are also smokers, which also affects the abnormal development of the fetus [32,33]. Confirmation of alcohol consumption by a pregnant woman should be an indication for education on the harmful effects of alcohol on the fetus. ...
Introduction and purpose Maternal alcohol consumption during pregnancy is a well-documented risk factor for adverse fetal outcomes, encompassing a spectrum of disorders known as Fetal Alcohol Spectrum Disorders (FASD). Fetal Alcohol Syndrome (FAS), the most severe form of FASD, manifests with craniofacial anomalies, growth retardation, neurological deficits, and cognitive impairments, imposing lifelong challenges on affected individuals. This article presents a case report of a 4-week-old female newborn with suspected Fetal Alcohol Syndrome, highlighting the clinical complexities and diagnostic challenges associated with FAS. The infant exhibited characteristic dysmorphic features and cardiac abnormalities, underscoring the diverse spectrum of health issues linked to maternal alcohol consumption. Conclusion A presented case report illustrating the clinical complexities of FAS underscores the importance of early recognition and multidisciplinary management. Early identification of FAS is imperative to mitigate long-term outcomes, emphasizing the importance of a multidisciplinary and holistic approach to clinical care. Strategies for addressing maternal alcohol consumption include targeted education, preconception counseling, and innovative therapeutic modalities. This case report underscores the need for ongoing research and collaborative efforts to reduce the prevalence and impact of FASD on affected individuals and society.
... As such, additional diagnostic tools are needed to identify FASD for early intervention and better outcomes. Due to the complex nature of the disorder, FASD has many contributing risk factors including alcohol dosage [4,5], duration of exposure and gestational timing [6-9], maternal nutrition, metabolism, socioeconomic factors, stress, and genetic variant composition [10][11][12][13][14]. ...
Fetal Alcohol Spectrum Disorder (FASD) is a common neurodevelopmental disorder that affects an estimated 2–5% of North Americans. FASD is induced by prenatal alcohol exposure (PAE) during pregnancy and while there is a clear genetic contribution, few genetic factors are currently identified or understood. In this study, using a candidate gene approach, we performed a genetic variant analysis of retinoic acid (RA) metabolic and developmental signaling pathway genes on whole exome sequencing data of 23 FASD-diagnosed individuals. We found risk and resilience alleles in ADH and ALDH genes known to normally be involved in alcohol detoxification at the expense of RA production, causing RA deficiency, following PAE. Risk and resilience variants were also identified in RA-regulated developmental pathway genes, especially in SHH and WNT pathways. Notably, we also identified significant variants in the causative genes of rare neurodevelopmental disorders sharing comorbidities with FASD, including STRA6 (Matthew–Wood), SOX9 (Campomelic Dysplasia), FDG1 (Aarskog), and 22q11.2 deletion syndrome (TBX1). Although this is a small exploratory study, the findings support PAE-induced RA deficiency as a major etiology underlying FASD and suggest risk and resilience variants may be suitable biomarkers to determine the risk of FASD outcomes following PAE.
... Multiple factors can lead to developmental abnormalities; however, there is a growing body of evidence suggesting that inadequate maternal nutrition plays a significant role in the occurrence of preventable birth defects and has a profound impact on the outcome of human pregnancies [72]. Hua Wang et al. (2015) proposed that maternal zinc (Zn) deficiency during pregnancy increases the likelihood of low birth weight (LBW) and small for gestational age (SGA) infants. ...
Introduction
Zinc is an essential trace element involved in different physiological functions. During pregnancy, it plays a crucial role in healthy embryogenesis. Abortion is the most severe problem associated with early pregnancy complications. This study aims to compare the levels of Zn in mothers with and without abortion.
Methods
This study is a systematic review and meta-analysis of studies published between 1980 and 2022 in PubMed, Science Direct, Pro Quest, Wiley, Web of Science, and Scopus databases. The search was conducted using both main and Mesh keywords, specifically targeting terms related to abortion, pregnancy loss, and zinc. Heterogeneity in the studies included in the meta-analysis was evaluated using statistical tests such as the chi-square test, I2, and forest plots. Publication bias was assessed using Begg's and Egger's tests. All analyses were conducted using Stata 15, and statistical significance was considered at p < 0.05.
Results
In general, nine studies were included in this analysis. Based on the results of the meta-analysis, the mean difference in the Zn level between mothers with and without abortion is equal to 193.18 (95 % CI; 107.11 to 279.25, P ≤ 0.001). In other words, the level of Zn in the group of mothers without abortion is 193 units higher than the group of mothers with abortion. The investigation into the comparison of Zn levels in mothers with and without abortion did not reveal any indication of publication bias according to both Begg's test (P-value = 0.858) and Egger's test (P-value = 0.270).
Conclusion
the study findings indicate a significant association between lower levels of Zn in mothers with abortion compared to mothers without abortion. This suggests that a higher level of Zn may have a preventive effect on the occurrence of abortion in pregnant women. The data also highlights the positive role of trace metals, particularly Zn, in influencing pregnancy outcomes and suggests that maintaining adequate levels of Zn may reduce the likelihood of abortion occurrence, along with other contributing factors. It is important to note that further research, including prospective cohort and experimental studies, is needed to provide more substantial evidence and strengthen these findings.
... The critical period of vulnerability is during pregnancy, particularly during the first trimester, when organ systems are rapidly developing [8]. The main risk factors for FASD are increased fetal exposure to alcohol and sustained alcohol intake during any trimester of pregnancy, genetic predisposition, maternal lower socioeconomic statuses and smoking, and paternal chronic alcohol use [9][10][11][12][13][14]. ...
Fetal alcohol spectrum disorders (FASD) represent a continuum of lifelong impairments resulting from prenatal exposure to alcohol, with significant global impact. The “spectrum” of disorders includes a continuum of physical, cognitive, behavioral, and developmental impairments which can have profound and lasting effects on individuals throughout their lives, impacting their health, social interactions, psychological well-being, and every aspect of their lives. This narrative paper explores the intricate relationship between oxidative stress and epigenetics in FASD pathogenesis and its therapeutic implications. Oxidative stress, induced by alcohol metabolism, disrupts cellular components, particularly in the vulnerable fetal brain, leading to aberrant development. Furthermore, oxidative stress is implicated in epigenetic changes, including alterations in DNA methylation, histone modifications, and microRNA expression, which influence gene regulation in FASD patients. Moreover, mitochondrial dysfunction and neuroinflammation contribute to epigenetic changes associated with FASD. Understanding these mechanisms holds promise for targeted therapeutic interventions. This includes antioxidant supplementation and lifestyle modifications to mitigate FASD-related impairments. While preclinical studies show promise, further clinical trials are needed to validate these interventions’ efficacy in improving clinical outcomes for individuals affected by FASD. This comprehensive understanding of the role of oxidative stress in epigenetics in FASD underscores the importance of multidisciplinary approaches for diagnosis, management, and prevention strategies. Continued research in this field is crucial for advancing our knowledge and developing effective interventions to address this significant public health concern.
... Moreover, maternal micronutrient deficiencies during pregnancy have been associated with poorer pregnancy and fetal outcomes [10][11][12][13][14]. The teratogenic effect of alcohol has also been shown to be increased when coupled with certain micronutrient deficiencies such as iron [15][16][17] and zinc [18]. Yet a randomized trial found that prenatal multivitamin supplementation with women who J o u r n a l P r e -p r o o f consumed alcohol during pregnancy had a protective effect resulting in better infant developmental outcomes [19]. ...
Maternal dietary intake is likely a contributing factor to fetal alcohol spectrum disorders (FASD). Two, 24-hour dietary recalls were completed by pregnant women (n=196) in South African communities with high rates of FASD. More than 50% of all women in this study were below the Estimated Average Requirement for pregnancy for vitamins A, C, D, E, riboflavin, vitamin B6, folate, calcium, magnesium, iron, and zinc. More than 90% of mothers were below the Recommended Dietary Allowance (RDA) or Adequate Intake (AI) for pregnancy on vitamin A, K, D, E, choline, calcium, magnesium, zinc, and potassium. More than 80% were below RDA/AI for pantothenic acid, vitamin B6, and folate. Women who consumed alcohol reported significantly lower intake of calcium and three saturated fatty acids and significantly higher intake of two monounsaturated fatty acids. On average, infants were <40th centile on length, weight, and head circumference at 6 weeks old, regardless of alcohol exposure. Twenty nutrients correlated with at least one measure of 1st trimester drinking (drinks per drinking day, number of drinking days per week, and total drinks per week). Nutrients included four saturated fatty acids, eight amino acids, calcium, B-complex vitamins, choline, and betaine. Calcium correlated with all three drinking measures. Further analyses revealed six nutrients were associated with infant length, weight, and/or head circumference among unexposed infants, and 12 nutrients were associated among infants with prenatal alcohol exposure. Inadequate maternal dietary intake, with alcohol exposure, may increase risk for poor infant growth and likelihood of FASD in this population.
... Alcohol-induced Zn deficiency may be associated with defective neurotransmission, severe cognitive and behavioral problems in infants. Decreased Zn in the cortex and elevated Zn in the cerebellum have been demonstrated after even short-term consumption of alcohol by female rats before conception (Keen et al., 2010). ...
... Because both prescription drug and nutrient exposure can influence pregnancy and child health outcomes, the interaction between maternal prescription drug exposure and nutritional status on maternal and child health outcomes is of special interest. While interactions between maternal opioid use and nutritional status have not been examined in the published literature, there is some evidence to suggest that maternal nutritional status may moderate the effects of prenatal alcohol exposure [23][24][25]. Thus, it is important to understand whether women taking prescription opioids represent a group at increased risk for poor nutritional status. ...
Prescription opioid use among pregnant women has increased in recent years. Prenatal exposure to opioids and poor nutrition can both negatively impact maternal–fetal outcomes. The objective of this study was to characterize the nutrition and health status of reproductive-age women taking prescription opioids, compared to women not taking opioids. Using NHANES 1999–2018 data, non-pregnant women aged 20–44 years were classified as taking a prescription opioid in the last 30 days (n = 404) or unexposed controls (n = 7234). Differences in anthropometric, cardiovascular, hematologic, and micronutrient status indicators between opioid-exposed and unexposed women were examined. Opioid-exposed women were older, had lower income and education, and were more likely to be non-Hispanic White, to smoke, and to have chronic health conditions compared to unexposed women. In unadjusted analyses, several nutrition and health markers were significantly different between opioid exposure groups. After controlling for covariates, women taking opioids had higher odds of Class II (OR = 1.6, 95% CI = 1.1–2.3) or III obesity (OR = 1.6, 95% CI = 1.1–2.5), and lower levels of serum folate, iron, and transferrin saturation. Reproductive-age women taking prescription opioids may be at risk for poorer nutritional and cardiometabolic health. Future research is needed to explore whether nutritional status impacts maternal–fetal outcomes for women exposed to opioids during pregnancy.
... Moreover, specialized, intensive home-visiting interventions for pregnant women at high risk improve maternal and child outcomes and are cost-effective in preventing new cases of FASD 227,228 . Improving maternal nutrition and reducing smoking and family violence may also improve child outcomes in current and future pregnancies 227,229,230 . ...
Alcohol readily crosses the placenta and may disrupt fetal development. Harm from prenatal alcohol exposure (PAE) is determined by the dose, pattern, timing and duration of exposure, fetal and maternal genetics, maternal nutrition, concurrent substance use, and epigenetic responses. A safe dose of alcohol use during pregnancy has not been established. PAE can cause fetal alcohol spectrum disorders (FASD), which are characterized by neurodevelopmental impairment with or without facial dysmorphology, congenital anomalies and poor growth. FASD are a leading preventable cause of birth defects and developmental disability. The prevalence of FASD in 76 countries is >1% and is high in individuals living in out-of-home care or engaged in justice and mental health systems. The social and economic effects of FASD are profound, but the diagnosis is often missed or delayed and receives little public recognition. Future research should be informed by people living with FASD and be guided by cultural context, seek consensus on diagnostic criteria and evidence-based treatments, and describe the pathophysiology and lifelong effects of FASD. Imperatives include reducing stigma, equitable access to services, improved quality of life for people with FASD and FASD prevention in future generations. Fetal alcohol spectrum disorders (FASD) are characterized by neurodevelopmental impairment with or without facial dysmorphology, congenital anomalies and poor growth. This Primer discusses the epidemiology, pathophysiology, diagnosis and treatment of FASD.
... Higher maternal age, gravidity, and parity are all associated with more severe FASD outcomes compared to women with similar drinking patterns [12]. Malnutrition or deficiencies in select micronutrients also increase the risk of FASD, especially in populations otherwise at high risk [13]. In that regard, the risk of conceiving a child with FAS is 15.8 times higher for women of lower socioeconomic status even when alcohol intake is comparable [14]. ...
Fetal alcohol spectrum disorder (FASD) encompasses the range of deleterious outcomes of prenatal alcohol exposure (PAE) in the affected offspring, including developmental delay, intellectual disability, attention deficits, and conduct disorders. Several factors contribute to the risk for and severity of FASD, including the timing, dose, and duration of PAE and maternal factors such as age and nutrition. Although poorly understood, genetic factors also contribute to the expression of FASD, with studies in both humans and animal models revealing genetic influences on susceptibility. In this article, we review the literature related to the genetics of FASD in humans, including twin studies, candidate gene studies in different populations, and genetic testing identifying copy number variants. Overall, these studies suggest different genetic factors, both in the mother and in the offspring, influence the phenotypic outcomes of PAE. While further work is needed, understanding how genetic factors influence FASD will provide insight into the mechanisms contributing to alcohol teratogenicity and FASD risk and ultimately may lead to means for early detection and intervention.
... The mixed-race ancestry ("Coloured") population in the Western Cape Province has both a high FASD prevalence and also experiences a broad range of nutrient insufficiencies [24,25]. Alcohol disrupts the metabolism of multiple nutrients including choline and other methyl donors [26] , iron [27][28][29], zinc [30], and docosahexaenoic acid (DHA) [31]. Such limitations in nutrient intake and utilization could have profoundly negative consequences for perinatal growth and development. ...
Prenatal alcohol exposure can produce offspring growth deficits and is a leading cause of neurodevelopmental disability. We used untargeted metabolomics to generate mechanistic insight into how alcohol impairs fetal development. In the Western Cape Province of South Africa, 52 women between gestational weeks 5–36 (mean 18.5 ± 6.5) were recruited, and they provided a finger-prick fasting bloodspot that underwent mass spectrometry. Metabolomic data were analyzed using partial least squares-discriminant analyses (PLS-DA) to identify metabolites that correlated with alcohol exposure and infant birth outcomes. Women who consumed alcohol in the past seven days were distinguished by a metabolite profile that included reduced sphingomyelins, cholesterol, and pregnenolones, and elevated fatty acids, acyl and amino acyl carnitines, and androsterones. Using PLS-DA, 25 of the top 30 metabolites differentiating maternal groups were reduced by alcohol with medium-chain free fatty acids and oxidized sugar derivatives having the greatest influence. A separate ortho-PLS-DA analysis identified a common set of 13 metabolites that were associated with infant length, weight, and head circumference. These included monoacylglycerols, glycerol-3-phosphate, and unidentified metabolites, and most of their associations were negative, implying they represent processes having adverse consequences for fetal development.
... Furthermore, PAE impairs placental nutrient transport and blood flow [10]. Animal models have identified an interaction between PAE and multiple nutrients: choline, copper, essential fatty acids, folate, iron, methionine, selenium, and zinc [11,12]. Pre-and post-natal micronutrient supplementation has been associated with improved aspects of memory and cognition [13,14]. ...
Prenatal alcohol exposure results in a spectrum of behavioral, cognitive, and morphological abnormalities collectively referred to as fetal alcohol spectrum disorder (FASD). FASD presents with significant phenotypic variability and may be modified by gestational variables such as maternal nutritional status. Iron serves a critical function in the development of and processes within central nervous system (CNS) structures. Gestational iron deficiency alters CNS development and may contribute to neurodevelopmental impairment in FASD. This review explores the relationship between iron deficiency and fetal alcohol spectrum disorder as described in small animal and human studies. Consideration is given to the pathophysiologic mechanisms linking iron homeostasis and prenatal alcohol exposure. Existing data suggest that iron deficiency contributes to the severity of FASD and provide a mechanistic explanation linking these two conditions.
... Although there are a few reports identifying nutrient intake of First Nations women at various stages of reproductive phases, at the present time, there are no reports identifying intakes for pregnant women at-risk either at the community, provincial, or federal level. A small number of international reports, which examine various dietary components with at-risk sub-analysis, have similarly smaller sample sizes ranging from 10 to 33 individuals in the at-risk group [53,54]. Therefore, this study provides the expected prevalence-a crucial variable in the calculation of the sample size for cross sectional designs. ...
The information on the nutrition status of women at-risk of carrying a child with fetal alcohol spectrum disorder (FASD) is scarce, particularly in the First Nations population living on reserve. This study examined and compared nutrition status, dietary intake, and lifestyle patterns of pregnant at-risk, defined as those who consume alcoholic drink during the current pregnancy, and non-at-risk women living in northern Manitoban community. Thirty-seven pregnant, First Nations women (at-risk n = 15; non-at-risk, n = 22) were recruited to participate in the study. A questionnaire, presented in paper and iPad formats, collected information on participants' demographics, dietary intake, lifestyle, pregnancy outcomes, and maternal health. A food frequency questionnaire and 24-h recall were used to determine nutrient intake. Nutrient values were assessed using Dietary Reference Intakes (DRI). At-risk and non-at-risk women were below the Canada Food Guide serving size recommended for Vegetable and Fruit, Grain, and Milk Products with 93%, 92%, and 93% of participants not meeting the recommendations, respectively. Women met the recommendations for vitamins A, B1, B12, C, niacin, choline, as well as calcium, and zinc. Sixty eight percentage (%) of participants did not meet the recommendations for folate and iron, and 97% for docosahexaenoic acid (DHA). Significant differences were observed between non-at-risk and at-risk women for mean % DRI intakes of vitamin C (313 ± 224 vs. 172 ± 81 mg/day), niacin (281 ± 123 vs. 198 ± 80 mg/day), folate (70 ± 38 vs. 10 ± 22 mcg/day), and iron (101 ± 74 vs. 74 ± 30 mg/day). The findings of this study lay a fundamental premise for the development of community nutrition programs, nutrition education, and nutrition intervention, such as community specific prenatal supplementation. These will assist in ensuring adequate maternal nutrient intake and benefit families and communities in Northern Manitoba with and without alcohol insult.
... Patients with eating disorders show adverse pregnancy outcomes such as miscarriage, preterm delivery, or fetal anomalies as poor fetal growth or malformations. Altered levels of many nutrients (i.e., vitamin B, folic acid, zinc) can increase the risk of developing fetal disorders [134,135]. ...
Epigenetics is the branch of genetics that studies the different mechanisms that influence gene expression without direct modification of the DNA sequence. An ever-increasing amount of evidence suggests that such regulatory processes may play a pivotal role both in the initiation of pregnancy and in the later processes of embryonic and fetal development, thus determining long-term effects even in adult life. In this narrative review, we summarize the current knowledge on the role of epigenetics in pregnancy, from its most studied and well-known mechanisms to the new frontiers of epigenetic regulation, such as the role of ncRNAs and the effects of the gestational environment on fetal brain development. Epigenetic mechanisms in pregnancy are a dynamic phenomenon that responds both to maternal–fetal and environmental factors, which can influence and modify the embryo-fetal development during the various gestational phases. Therefore, we also recapitulate the effects of the most notable environmental factors that can affect pregnancy and prenatal development, such as maternal nutrition, stress hormones, microbiome, and teratogens, focusing on their ability to cause epigenetic modifications in the gestational environment and ultimately in the fetus. Despite the promising advancements in the knowledge of epigenetics in pregnancy, more experience and data on this topic are still needed. A better understanding of epigenetic regulation in pregnancy could in fact prove valuable towards a better management of both physiological pregnancies and assisted reproduction treatments, other than allowing to better comprehend the origin of multifactorial pathological conditions such as neurodevelopmental disorders.
... While research on the relationship between alcohol use and food insecurity is limited, food security may be an important risk factor to address among women of childbearing age who consume alcohol. This is especially relevant for pregnant women who consume alcohol and experience food insecurity, since poor nutrition exacerbates the teratogenic effects of alcohol, which may contribute to the development of FAS (Keen et al., 2010). Further research is needed, but addressing food insecurity during pregnancy could play an important role in reducing the harms associated with prenatal alcohol use in low-income settings. ...
Objective
Reducing alcohol use during pregnancy is a pressing public health priority in Sub-Saharan Africa, but insight into the factors that influence prenatal drinking practices is lacking. This study investigated perceptions of, and motivations for, alcohol consumption during pregnancy and associated practices in a rural district of Lesotho.
Methods
A combination of purposive and snowball sampling methods were used to identify pregnant women and mothers with young children from the general community, as well as from alcohol-serving venues. Between September 2016 and March 2017, a trained data collector conducted in-depth interviews with 40 women on reasons why pregnant women drink, what they know about the risk of drinking alcohol during pregnancy, and perceptions of women who drink during pregnancy.
Results
Sixty-five percent of women (n = 26) reported that they consumed alcohol during pregnancy. Findings were clustered into four themes: 1) alcohol use in daily and cultural life; 2) alcohol as relief from stress and hunger; 3) alcohol's effect on the baby; and 4) access to information about alcohol consumption. Our data suggest that alcohol use was a prominent feature of daily life and a key part of traditional events and ceremonies. Other than potentially harming the baby through falling on their stomachs while inebriated, women did not mention other risks associated with prenatal alcohol use. Rather, there were prominent beliefs that drinking alcohol – home-brewed alcohol in particular – had cleansing or protective benefits for the baby. Experiences of food insecurity were prominent, and women reported that alcohol helped curb their hunger and allowed them to save food to give to their children.
Conclusions
Within this context of chronic poverty and food insecurity, alcohol use during pregnancy will continue to represent a valid, though tragic choice if the structural conditions and current social arrangements that facilitate prenatal alcohol use remain unchanged.
... Research studies show that many other risk factors can also influence development of FASD, which include a smaller body profile of mother (height, weight, and body mass index [BMI]), maternal age, low socioeconomic status and smoking [52], a poor nutritional status (deficit of riboflavin, calcium, and zinc; [70], genetic polymorphisms [71,72], and paternal alcohol consumption [73]. ...
Background:
Alcohol is a teratogen and prenatal exposure may adversely impact the developing fetus, increasing risk for negative outcomes, including Fetal Alcohol Spectrum Disorder (FASD). Global trends of increasing alcohol use among women of childbearing age due to economic development, changing gender roles, increased availability of alcohol, peer pressure and social acceptability of women's alcohol use may put an increasing number of pregnancies at risk for prenatal alcohol exposure (PAE). This risk has been exacerbated by the ongoing COVID-19 pandemic in some countries.
Method:
This literature review presents an overview on the epidemiology of alcohol use among childbearing age and pregnant women and FASD by World Health Organization regions; impact of PAE on fetal health, including FASD; associated comorbidities; and social outcomes.
Results/conclusion:
The impact of alcohol on fetal health and social outcomes later in life is enormous, placing a huge economic burden on countries. Prevention of prenatal alcohol exposure and early identification of affected individuals should be a global public health priority.
... Given that PTP1B dephosphorylates both JAK2 and STAT3 [40][41][42], this phosphatase emerges as a potential target for the adverse consequences of Zn deficiency on astrogliogenesis. In fact, indirect findings showed a possible connection between PTP1B and alcohol-associated Zn deficiency during pregnancy [43]. While prenatal alcohol exposure induces Zn deficiency and impairs Zn utilization by the offspring [44][45][46], PTP1B activity increased in the brain of rats exposed to alcohol during gestation [47]. ...
We previously showed that zinc (Zn) deficiency affects the STAT3 signaling pathway in part through redox-regulated mechanisms. Given that STAT3 is central to the process of astrogliogenesis, this study investigated the consequences of maternal marginal Zn deficiency on the developmental timing and key mechanisms of STAT3 activation, and its consequences on astrogliogenesis in the offspring. This work characterized the temporal profile of cortical STAT3 activation from the mid embryonic stage up to young adulthood in the offspring from dams fed a marginal Zn deficient diet (MZD) throughout gestation and until postnatal day (P) 2. All rats were fed a Zn sufficient diet (control) from P2 until P56. Maternal zinc deficiency disrupted cortical STAT3 activation at E19 and P2. This was accompanied by altered activation of JAK2 kinase due to changes in PTP1B phosphatase activity. The underlying mechanisms mediating the adverse impact of a decreased Zn availability on STAT3 activation in the offspring brain include: (i) impaired PTP1B degradation via the ubiquitin/proteasome pathway; (ii) tubulin oxidation, associated decreased interactions with STAT3 and consequent impaired nuclear translocation; and (iii) decreased nuclear STAT3 acetylation. Zn deficiency-associated decreased STAT3 activation adversely impacted astrogliogenesis, leading to a lower astrocyte number in the early postnatal and adult brain cortex. Thus, a decreased availability of Zn during early development can have a major and irreversible adverse effect on astrogliogenesis, in part via multistep alterations in the STAT3 pathway.
... There are both hyperglutamatergic (MacMaster et al. 2003) and hypoglutamatergic (Carlsson 2000(Carlsson , 2001O'Neill et al. 2013) models of ADHD which link the condition to cell energy metabolism (Russell et al. 2006;Todd and Botteron 2001), but it is not established whether putative glutamatergic abnormalities prevail in both ADHD+PAE and ADHD-PAE etiologies. Recent rodent (Ryan et al. 2008;Schneider and Thomas 2016;Thomas et al. 2000Thomas et al. , 2004Thomas et al. , 2007Thomas et al. , 2009Thomas et al. , 2012 and human (Coles et al. 2015;Kable et al. 2015;Keen et al. 2010;Nguyen et al. 2016;Wozniak et al. 2020) trials of prospective cholinotherapies for FASD have rekindled interest in choline. In a pilot study (O'Neill et al. 2019), we found lower choline in the anterior corona radiata in ADHD+PAE than ADHD-PAE. ...
Attention-deficit hyperactivity disorder (ADHD) is common in patients with (ADHD+PAE) and without (ADHD-PAE) prenatal alcohol exposure (PAE). Many patients diagnosed with idiopathic ADHD actually have covert PAE, a treatment-relevant distinction. To improve differential diagnosis, we sought to identify brain differences between ADHD+PAE and ADHD-PAE using neurobehavioral, magnetic resonance spectroscopy, and diffusion tensor imaging metrics that had shown promise in past research. Children 8–13 were recruited in three groups: 23 ADHD+PAE, 19 familial ADHD-PAE, and 28 typically developing controls (TD). Neurobehavioral instruments included the Conners 3 Parent Behavior Rating Scale and the Delis-Kaplan Executive Function System (D-KEFS). Two dimensional magnetic resonance spectroscopic imaging was acquired from supraventricular white matter to measure N-acetylaspartate compounds, glutamate, creatine + phosphocreatine (creatine), and choline-compounds (choline). Whole brain diffusion tensor imaging was acquired and used to to calculate fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity from the same superventricular white matter regions that produced magnetic resonance spectroscopy data. The Conners 3 Parent Hyperactivity/Impulsivity Score, glutamate, mean diffusivity, axial diffusivity, and radial diffusivity were all higher in ADHD+PAE than ADHD-PAE. Glutamate was lower in ADHD-PAE than TD. Within ADHD+PAE, inferior performance on the D-KEFS Tower Test correlated with higher neurometabolite levels. These findings suggest white matter differences between the PAE and familial etiologies of ADHD. Abnormalities detected by magnetic resonance spectroscopy and diffusion tensor imaging co-localize in supraventricular white matter and are relevant to executive function symptoms of ADHD.
... Some individuals with PAE have no readily observable impact of their exposure as indicated by the presence of alcohol-related dysmorphia, growth deficits, and alcohol-related neurodevelopmental deficits (Day and Richardson, 1991). The variability in impact may be linked to maternal and fetal genetics (Dodge et al., 2014;Fish et al., 2017), timing of exposure (Sulik, 2014), dosage and patterning of the exposure (Bandoli et al., 2019;Feldman et al., 2012), and various other co-occurring factors that may contribute to adverse fetal development (i.e., nutritional factors (Keen et al., 2010)). A biomarker is needed to identify those for whom intervention may be most beneficial, particularly during infancy when the brain is still going through rapid development (Fox et al., 2010). ...
Background
Prenatal alcohol exposure (PAE) has been identified as one of the leading preventable causes of developmental disabilities, but early identification of those impacted has been challenging. This study evaluated the use of infant cardiac orienting responses (CORs), which assess neurophysiological encoding of environmental events and are sensitive to the impact of PAE, to predict later fetal alcohol spectrum disorder (FASD) status.
Methods
Mother–infant dyads from Ukraine were recruited during pregnancy based on the mother’s use of alcohol. Participants (n = 120) were then seen at 6 and 12 months when CORs were collected and in the preschool period when they were categorized as having (i) fetal alcohol syndrome (FAS), (ii) partial FAS (pFAS), (iii) alcohol‐related neurodevelopmental disorder (ARND), (iv) PAE and no diagnosis, or (v) no PAE and no diagnosis. To assess CORs, stimuli (auditory tones and pictures) were presented using a fixed‐trial habituation/dishabituation paradigm. Heart rate (HR) responses were aggregated across the first 3 habituation and dishabituation trials and converted to z‐scores relative to the sample’s mean response at each second by stimuli. Z‐scores greater than 1 were then counted by condition (habituation or dishabituation) to compute a total risk index.
Results
Significant group differences were found on total deviation scores of the CORs elicited from visual but not auditory stimuli. Those categorized as pFAS/FAS had significantly higher total deviation scores than did those categorized as ARND or as having no alcohol‐related diagnosis with or without a history of PAE. Receiver operating characteristic curve analysis of the visual response yielded an area under the curve value of 0.765 for predicting to pFAS/FAS status.
Conclusions
A score reflecting total deviation from typical HR during CORs elicited using visual stimuli in infancy may be useful in identifying individuals who need early intervention as a result of their PAE.
... In developing countries, over half-a-million deaths of infants and small children are caused by a deficiency of zinc [9]. Special attention is paid to the influence of alcohol during pregnancy, which changes the metabolism of zinc and causes serious consequences for the foetus [10]. ...
Introduction. Interactions occur between concentrations of metals in the human body and the environment in various
geographic locations, which can be of importance for both the proper development and the course of pregnancy.
Objective. The aim of the study was to assess the concentrations of Zn, Cu and Cd and Zn:Cu and Zn:Cd molar ratios in the
placenta, umbilical cord and in the foetal membrane, and to examine the relationship between concentrations of these
elements and the place of residence.
Materials and method. The research material was obtained from 99 healthy women from north-western and central
Poland. Data for the study were collected from the medical history and documents of admission to the ward and documents
confirming the birth of the newborn. Concentrations of zinc (Zn), copper (Cu) and cadmium (Cd) were determined using
the ICP–AES method (spectrophotometry of atomic absorption) in inductively coupled argon plasma.
Results. The average concentration of Zn, Cu and Cd in afterbirths was ~ 0.01 mg/kg of dry weight (dw). In central Poland,
the results revealed a significant increase in zinc in the membrane (OR=1.098, p=0.002), cadmium in the placenta (OR=1.324,
p=0.006), Zn:Cu in the membrane (OR=1.012, p<0.001). In north-western Poland, an increase in copper in the membrane
(OR=1.239, p=0.025) was revealed.
Conclusions. The use biological materials, such as the placenta, foetal membrane and umbilical cord to assess exposure
to heavy metals and necessary elements is justified.
... Fetal alcohol spectrum disorders (FASD) encompass all alcohol-related birth defects including fetal alcohol syndrome and alcohol-related neurodevelopmental disorders. Since alcohol consumption can aggravate nutrient deficiencies, it has been suggested that maternal nutritional status plays a role in the risk for FASD (3)(4)(5). In addition, rates of cigarette smoking during pregnancy are often higher among women who consume alcohol creating additional consequences to nutritional status, as well as increasing odd ratios for preterm birth, low birth weight, and growth restriction beyond either alcohol or cigarette use alone (6)(7)(8)(9)(10)(11). ...
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.
... In lowand middle-income countries (LMICs), such as South Africa, the estimated prevalence of FASDs is as high as 111.1 per 1000 children in some communities (Olivier et al., 2016). The majority of previous studies exploring the impact of PAE on child development in the context of psychobiological and psychosocial factors have been performed in high-income countries, even though higher rates of PAE, poverty, post-traumatic stress disorder (PTSD) and depression exist in LMICs (May et al., 2008;Keen et al., 2010;Flak et al., 2014). The research taking into account contextual factors such as those cited above underscores the importance of examining the adverse effects of PAE in young children (May et al., 2008;Flak et al., 2014), within the broader context of psychosocial and environmental risk factors that may additionally influence not only early neurodevelopmental outcomes but also lifelong health trajectories. ...
Objective
To investigate the association of prenatal alcohol exposure (PAE) and early neurodevelopment in the first 2 years of life, adjusting for maternal sociodemographic and psychosocial factors, in the Drakenstein Child Health Study (DCHS), a South African birth cohort study.
Methods
The DCHS comprises a population-based birth cohort of 1143 children, of which, a subsample completed the Bayley Scales of Infant Development-III (BSID-III) at 6 (n = 260) and 24 months of age (n = 734). A subset of alcohol exposed, and unexposed children was included in this analysis at age 6 months (n = 52 exposed; n = 104 unexposed) and 24 months (n = 92 exposed; n=184 unexposed). Multiple hierarchical regression was used to explore the associations of PAE with motor and language development.
Results
PAE was significantly associated with decreased gross motor (OR = 0.16, 95%CI 0.06-0.44, p = 0.001) or fine motor (OR = 0.16, 95%CI 0.06-0.46, p = 0.001) functioning after adjusting for maternal sociodemographic and psychosocial factors at 6 months of age only. No significant effects were found in either receptive or expressive communication and cognitive outcomes at either time point.
Conclusion
PAE has potentially important consequences for motor development in the first 2 years of life, a period during which the most rapid growth and maturation occurs. These findings highlight the importance of identifying high-risk families in order to provide preventive interventions, particularly in antenatal clinics and early intervention services.
... Zinc is essential for proper immune system function of the fetus, and like smoking itself, zinc deficiency during pregnancy is linked to impaired fetal growth and development (Wellinghausen, 2001;Suzuki et al., 2014). Lack of zinc has also been linked to teratogenicity and neurodevelopmental abnormalities (Kuhnert et al., 1988;Chowanadisai et al., 2013) and in animal models, increasing the zinc supply to the fetus has thus been shown to ameliorate neurotoxicological effects such as the ones caused by prenatal alcohol exposures (Keen et al., 2010). ...
Study question:
Does maternal smoking in early pregnancy affect metallothionein 1 and 2 (MT1 and MT2) mRNA and protein expression in first trimester placenta or embryonic/fetal liver?
Summary answer:
In the first trimester, MT protein expression is seen only in liver, where smoking is associated with a significantly reduced expression.
What is known already:
Zinc homeostasis is altered by smoking. Smoking induces MT in the blood of smokers properly as a result of the cadmium binding capacities of MT. In term placenta MT is present and smoking induces gene and protein expression (MT2 in particular), but the MT presence and response to smoking have never been examined in first trimester placenta or embryonic/fetal tissues.
Study design, size, duration:
Cross sectional study where the presence of MT mRNA and protein was examined at the time of the abortion. The material was collected with informed consent after surgical intervention and frozen immediately. For protein expression analysis, liver tissue originating from smoking exposed n = 10 and unexposed n = 12 pregnancies was used. For mRNA expression analyses, placental tissue originating from smokers n = 19 and non-smokers n = 23 and fetal liver tissue from smoking exposed n = 16 and smoking unexposed pregnancies n = 13, respectively, were used.
Participants/materials, setting, methods:
Tissues were obtained from women who voluntarily and legally chose to terminate their pregnancy between gestational week 6 and 12. Western blot was used to determine the protein expression of MT, and real-time PCR was used to quantify the mRNA expression of MT2A and eight MT1 genes alongside the expression of key placental zinc transporters: zinc transporter protein-1 (ZNT1), Zrt-, Irt-related protein-8 and -14 (ZIP8 and ZIP14).
Main results and the role of chance:
A significant reduction in the protein expression of MT1/2 in liver tissue (P = 0.023) was found by western blot using antibodies detecting both MT forms. Overall, a similar tendency was observed on the mRNA level although not statistically significant. Protein expression was not present in placenta, but the mRNA regulation suggested a down regulation of MT as well. A suggested mechanism based on the known role of MT in zinc homeostasis could be that the findings reflect reduced levels of easily accessible zinc in the blood of pregnant smokers and hence a reduced MT response in smoking exposed fetal/embryonic tissues.
Limitations and reasons for caution:
Smoking was based on self-reports; however, our previous studies have shown high consistency regarding cotinine residues and smoking status. Passive smoking could interfere but was found mainly among smokers. The number of fetuses was limited, and other factors such as medication and alcohol might affect the findings. Information on alcohol was not consistently obtained, and we cannot exclude that it was more readily obtained from non-users. In the study, alcohol consumption was reported by a limited number (less than 1 out of 5) of women but with more smokers consuming alcohol. However, the alcohol consumption reported was typically limited to one or few times low doses. The interaction between alcohol and smoking is discussed in the paper. Notably we would have liked to measure zinc status to test our hypothesis, but maternal blood samples were not available.
Wider implications of the findings:
Zinc deficiency-in particular severe zinc deficiency-can affect pregnancy outcome and growth. Our findings indicate that zinc homeostasis is also affected in early pregnancy of smokers, and we know from pilot studies that even among women who want to keep their babies, the zinc status is low. Our findings support that zinc supplements should be considered in particular to women who smoke.
Study funding/competing interest(s):
We thank the Department of Biomedicine for providing laboratory facilities and laboratory technicians and the Lundbeck Foundation and Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis Legat for financial support. The authors have no competing interests to declare.
Trial registration number:
N/A.
... Maternal risk factors include being of an older age (Chiodo et al., 2010;Esper and Furtado, 2014;May et al., 2005May et al., , 2008Rubio et al., 2008;Skagerstrom et al., 2013), having a history of alcohol abuse in the family and/or maternal partner (Ceccanti et al., 2014;Esper and Furtado, 2014;May et al., 2008May et al., , 2014, and attending fewer prenatal appointments . Additionally, lower maternal body weight, height, and body mass index (May and Gossage, 2011;May et al., 2008May et al., , 2016, as well as poor nutrition (Keen et al., 2010;May et al., 2016), are associated with an increased risk of having a child with FASD. Several demographic factors have also been identified, including low maternal education, rural residence, (May et al., 2013;Rubio et al., 2008;Viljoen et al., 2002), and lower socioeconomic status (May et al., 2005. ...
In utero alcohol exposure can disrupt the development of the fetal brain and result in a wide range of neurobehavioral outcomes collectively known as fetal alcohol spectrum disorders (FASD). This paper provides a comprehensive review of the cognitive and behavioral outcomes of prenatal alcohol exposure, including domains of general intelligence, executive functioning, language development, learning and memory, adaptive functioning, academic performance, and concurrent psychopathology. In addition, the current status of the neurobehavioral profile of FASD and its potential as a diagnostic tool will be discussed.
... These associations may be due to latent factors such as tendencies towards healthy or unhealthy lifestyle behaviours (depicted as the 'risky behaviour' node in the DAG). Among children with PAE, lower calorific intake has been found to increase the risk of FASD, while evidence from animal studies suggests that specific nutrients (including vitamin A, docosahexaenoic acid, folate, zinc, choline, vitamin E, selenium, riboflavin, calcium, docosapentaenoic acid, zinc, B-vitamins, iron and protein) may reduce the risk of FASD-relevant outcomes including physical malformations, growth deficiency, behavioural regulation and memory [98,99,[103][104][105][106]. During pregnancy, mothers of children with FASD report a lower intake of key nutrients and report being hungry more often than controls [59,107]. ...
Foetal alcohol spectrum disorders (FASDs) are a leading cause of developmental disability. Prenatal alcohol use is the sole necessary cause of FASD, but it is not always sufficient. Multiple factors influence a child’s susceptibility to FASD following prenatal alcohol exposure. Much of the FASD risk factor literature has been limited to discussions of association, rather than causation. While knowledge of predictor variables is important for identifying who is most at risk of FASD and for targeting interventions, causal knowledge is important for identifying effective mechanisms for prevention and intervention programmes. We conducted a systematic search and narrative synthesis of the evidence and used this to create a causal diagram (directed acyclic graph; DAG) to describe the causal pathways to FASD. Our results show that the aetiology of FASD is multifaceted and complex. FASD risk is determined by a range of lifestyle, sociodemographic, maternal, social, gestational, and genetic factors. The causal diagram that we present in this review provides a comprehensive summary of causal risk factors for FASD and can be used as a tool to inform data collection and statistical modelling strategies to minimise bias in future studies of FASD.
... However, the onset of mental disorders can be influenced by moderator and mediator factors, which overlap with independent risk factors [12]. The complex interaction of genetic, metabolic, and nutritional factors [13,14] have generated uncertainties about the exact role of prenatal risk factors in the onset of mental disorders in childhood [15]. ...
The objective of the study was to investigate the association between alcohol use during pregnancy and mental disorders in childhood, controlling for confounding risk factors by a longitudinal study of pregnant women and their offspring. The initial cohort comprised pregnant women attending an obstetric service. From the initial sample of 449 pregnant women, 81 mother–child pairs agreed to participate. After 12 years, mother–child pairs were assessed through self-administered questionnaires and semi-structured interviews. The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime Version (K-SADS-PL) was used to assess the presence of any mental disorders in the children. The mothers were assessed by the Self-Reporting Questionnaire (SRQ) and the Alcohol Use Disorders Identification Test (AUDIT). Furthermore, data on the mother’s alcohol use collected during pregnancy were analysed. A logistic regression tested the influence of alcohol consumption in all trimesters and binge drinking on the occurrence of attention-deficit/hyperactivity disorder (ADHD), controlling for covariates. Binge drinking at any time during pregnancy or low–moderate alcohol consumption in all trimesters of pregnancy was associated with a fivefold increased odds of child ADHD. The combination of both patterns of alcohol use added an increase of 19% in the variance of ADHD’s occurrence. The episodic use of at least four drinks or the regular use of low–moderate alcohol doses during pregnancy was associated with significantly increased odds of subsequent child ADHD. Reducing binge drinking and regular alcohol use of pregnant women may lead to a significant decrease in their children developing ADHD.
... Some studies have examined nutrition profiles among children with neurodevelopmental disorders. They show that poor nutrition intake (according to the recommended dietary allowance and estimated average requirement guidelines) and multiple, rather than single, nutrient deficiencies are more common among these children and, in some cases, their mothers [14,15]. While not in and of itself proof of interactions among nutrient mixtures, this finding may be consistent with a nutrient mixture's effect on neurodevelopment. ...
Adequate nutrition is important for neurodevelopment. Although nutrients are ingested in combination, the impact of specific nutrients within the context of a nutrient mixture has not been studied with respect to health, such as neurodevelopment. Therefore, we examined the impact of prenatal and childhood nutrient mixtures on neurodevelopmental outcomes. Participants included mother–child pairs in the Programming Research in Obesity, Growth, Environment, and Social Stress (PROGRESS) prospective birth cohort in Mexico City. We assessed prenatal and child micro- and macronutrient profiles among 65 and 329 children, respectively, via food frequency questionnaires. Neurodevelopmental outcomes of 4–6-year-old children were measured using the McCarthy Scales of Children’s Abilities (MSCA). We conducted weighted quantile sum (WQS) regression analyses to calculate indices reflecting “good” and “poor” prenatal and childhood nutrition. After adjusting for maternal education, socioeconomic status, the Home Observation for Measurement of the Environment (HOME) score, and total caloric intake, the good prenatal and childhood nutrition indices predicted more favorable neurodevelopment, while both poor nutrition indices predicted poorer neurodevelopment. These associations were stronger in prenatal than childhood models. Monounsaturated fats predicted various neurodevelopmental abilities relatively strongly in both models. Prenatal and childhood consumption of combinations of beneficial nutrients may contribute to more favorable neurodevelopment.
... A recent study analysed plasma levels of zinc (Zn) and Copper (Cu) in heavy drinking pregnant women in Ukraine and Russia, showing that mothers who consumed alcohol during pregnancy had lower levels of these minerals than non-drinking mothers [42]. Alcohol decreases serum levels of zinc because it causes a low intake of intestinal absorption and increases urinary excretion. ...
The consumption of alcohol and drugs of abuse among pregnant women has experienced a significant increase in the last decades. Suitable maternal nutritional status is crucial to maintain the optimal environment for fetal development but if consumption of alcohol or drugs of abuse disrupt the intake of nutrients, the potential teratogenic effects of these substances increase. Despite evidence of the importance of nutrition in addicted pregnant women, there is a lack of information on the effects of alcohol and drugs of abuse on maternal nutritional status; so, the focus of this review was to provide an overview on the nutritional status of addicted mothers and fetuses. Alcohol and drugs consumption can interfere with the absorption of nutrients, impairing the quality and quantity of proper nutrient and energy intake, resulting in malnutrition especially of micronutrients (vitamins, omega–3, folic acid, zinc, choline, iron, copper, selenium). When maternal nutritional status is compromised by alcohol and drugs of abuse the supply of essential nutrients are not available for the fetus; this can result in fetal abnormalities like Intrauterine Growth Restriction (IUGR) or Fetal Alcohol Spectrum Disorder (FASD). It is critical to find a strategy to reduce fetal physical and neurological impairment as a result of prenatal alcohol and drugs of abuse exposure combined with poor maternal nutrition. Prenatal nutrition interventions and target therapy are required that may reverse the development of such abnormalities.
... Therefore, it is important to understand the variables that may increase or decrease the probability that PAE will produce deleterious effects on fetal development. These factors include the gestational timing, duration, and dose of alcohol (Astley et al. 1999), amount consumed per drinking session (Khoale et al. 2004), genetic and epigenetic factors (Kaminen-Ahola et al. 2010a;Kleiber et al. 2014;Lussier et al. 2015), maternal and fetal stress (Glavas et al. 2007;Uban et al. 2013;Raineki et al. 2014), nutritional status (Weinberg 1984(Weinberg , 1985Keen et al. 2010), and the mother's ability to metabolize alcohol, which are all known to be critically involved in alcohol teratogenicity (Ramchandani et al. 2001;Riley et al. 2011). ...
The potential impact of prenatal alcohol exposure (PAE) varies considerably among exposed individuals, with some displaying serious alcohol-related effects and many others showing few or no overt signs of fetal alcohol spectrum disorder (FASD). In animal models, variables such as nutrition, genetic background, health, other drugs, and stress, as well as dosage, duration, and gestational timing of exposure to alcohol can all be controlled in a way that is not possible in a clinical situation. In this review we examine mouse models of PAE and focus on those with demonstrated craniofacial malformations, abnormal brain development, or behavioral phenotypes that may be considered FASD-like outcomes. Analysis of these data should provide a valuable tool for researchers wishing to choose the PAE model best suited to their research questions or to investigate established PAE models for FASD comorbidities. It should also allow recognition of patterns linking gestational timing, dosage, and duration of PAE, such as recognizing that binge alcohol exposure(s) during early gestation can lead to severe FASD outcomes. Identified patterns could be particularly insightful and lead to a better understanding of the molecular mechanisms underlying FASD.
... Значний вплив алкоголю протягом першого триместру пов'язаний з розвитком у плода структурних аномалій, включаючи аномалії головного мозку; вживання алкоголю в другому триместрі підвищує ризик спонтанного аборту; а в третьому триместрі переважно впливає на вагу, довжину і зростання мозку [15]. Доведено, що нер-вові поведінкові ефекти можуть виникати навіть за відсутності лицевих або структурних аномалій головного мозку [7,12,13]. ...
... Populationbased studies propose an association between poor maternal nutrition and increased FASD risk (May et al. 2014;May et al. 2016). Research predominantly in animal models has identified individual nutrients that may interact with PAE, such as zinc, choline, iron, copper, selenium, methionine, folate, and essential fatty acids (Keen et al. 2010;Young et al. 2014;Zeisel 2013). Alcohol abuse may exacerbate nutrient deficiencies because the alcohol calories displace nutrient-dense foods and because alcohol may impair nutrient absorption and utilization, in part by disrupting liver and gut function (Bishehsari et al. 2017), but also by increasing intestinal bleeding and nutrient losses in stool. ...
Alcohol consumption during pregnancy places the fetus at risk for permanent physical, cognitive, and behavioral impairments, collectively termed fetal alcohol spectrum disorder (FASD). However, prenatal alcohol exposure (PAE) outcomes vary widely, and growing evidence suggests that maternal nutrition is a modifying factor. Certain nutrients, such as iron, may modulate FASD outcomes. Untreated gestational iron deficiency (ID) causes persistent neurodevelopmental deficits in the offspring that affect many of the same domains damaged by PAE. Although chronic alcohol consumption enhances iron uptake and elevates liver iron stores in adult alcoholics, alcohol-abusing premenopausal women often have low iron reserves due to menstruation, childbirth, and poor diet. Recent investigations show that low iron reserves during pregnancy are strongly associated with a worsening of several hallmark features in FASD including reduced growth and impaired associative learning. This review discusses recent clinical and animal model findings that maternal ID worsens fetal outcomes in response to PAE. It also discusses underlying mechanisms by which PAE disrupts maternal and fetal iron homeostasis. We suggest that alcohol-exposed ID pregnancies contribute to the severe end of the FASD spectrum.
A congenital malformation is an anatomical or structural abnormality present at birth. Congenital malformations may be caused by genetic factors or environmental insults or a combination of the two that occur during prenatal development. Most common congenital malformations demonstrate multifactorial inheritance with a threshold effect and are determined by a combination of genetic and environmental factors. During the first two weeks of gestation, teratogenic agents usually kill the embryo rather than cause congenital malformations. Major malformations are more common in early embryos than in newborns; Derna University Journal of Medical Sciences, 2(1): 1-8, 2024 Sana et al., 2024 2 however, most severely affected embryos are spontaneously aborted during the first six to eight weeks of gestation. Teratology is the science that investigates the congenital malformations and their causes. Intrauterine exposure to a toxicant, particularly in early pregnancy, induces embryonic and fetal changes ranging from none up to malformations and stillbirths. The teratogenic agents include some viral, spirochetal and protozoal infections, physical agents as ionizing radiations and excessive heat, pharmacological drugs as thalidomide, excessive vitamin A, corticosteroids, antiepileptic, antimalarial, anti leishmaniasis and antihypertensive agents, industrial pollutants as toluene and cadmium, alcohol and smoking abuse, and narcotics. Maternal health problems as diabetes mellitus, multiple sclerosis and rheumatoid arthritis may also add to the etiology list of teratogenesis. The prevalence of the congenital birth defects ranges from 2 to 5% throughout the first year of postnatal life in this study, about 170 cases were collected from the questionnaire in an attempt to study the factors causing the birth of a teratogenic child and the diseases and deformities that result from it. It was found that many medications and chemicals that the mother is exposed to during pregnancy cause the birth of a teratogenic child
Fetal Alcohol Spectrum Disorders (FASD) represent a continuum of lifelong impairments resulting from prenatal exposure to alcohol, with significant global impact. The “spectrum” of disorders includes a continuum of physical, cognitive, behavioral, and developmental impairments, which can have profound and lasting effects on individuals throughout their lives impacting their health, social interactions, psychological well-being and every aspect of their lives. This narrative paper explores the intricate relationship between oxidative stress and epigenetics in FASD pathogenesis and its therapeutic implications. Oxidative stress, induced by alcohol metabolism, disrupts cellular components, particularly in the vulnerable fetal brain, leading to aberrant development. Furthermore, oxidative stress is implicated in epigenetic changes, including alterations in DNA methylation, histone modifications, and microRNA expression, which influence gene regulation in FASD patients. Moreover, mitochondrial dysfunction and neuroinflammation contribute to epigenetic changes associated with FASD. Understanding these mechanisms holds promise for targeted therapeutic interventions. This includes antioxidant supplementation and lifestyle modifications to mitigate FASD-related impairments. While preclinical studies show promise, further clinical trials are needed to validate these interventions' efficacy in improving clinical outcomes for individuals affected by FASD. This comprehensive understanding of the role of oxidative stress on epigenetics in FASD underscores the importance of multidisciplinary approaches for diagnosis, management, and prevention strategies. Continued research in this field is crucial for advancing our knowledge and developing effective interventions to address this significant public health concern.
Fetal Alcohol Spectrum Disorder (FASD) arises from maternal consumption of alcohol during pregnancy affecting 2%–5% of the Western population. In Xenopus laevis studies, we showed that alcohol exposure during early gastrulation reduces retinoic acid (RA) levels at this critical embryonic stage inducing craniofacial malformations associated with Fetal Alcohol Syndrome. A genetic mouse model that induces a transient RA deficiency in the node during gastrulation is described. These mice recapitulate the phenotypes characteristic of prenatal alcohol exposure (PAE) suggesting a molecular etiology for the craniofacial malformations seen in children with FASD. Gsc +/Cyp26A1 mouse embryos have a reduced RA domain and expression in the developing frontonasal prominence region and delayed HoxA1 and HoxB1 expression at E8.5. These embryos also show aberrant neurofilament expression during cranial nerve formation at E10.5 and have significant FASD sentinel-like craniofacial phenotypes at E18.5. Gsc +/Cyp26A1 mice develop severe maxillary malocclusions in adulthood. Phenocopying the PAE-induced developmental malformations with a genetic model inducing RA deficiency during early gastrulation strongly supports the alcohol/vitamin A competition model as a major molecular etiology for the neurodevelopmental defects and craniofacial malformations seen in children with FASD.
Objective:
This paper aims to explore the available literature to understand how risks regarding prenatal alcohol exposure are perceived.
Methods:
A systematic review (PROSPERO; CRD 42020212887) was undertaken. PubMed, Embase, PsycINFO, and CINAHL were searched for relevant quantitative and qualitative studies. A thematic analysis of the studies was performed.
Results:
Fifteen articles-nine quantitative and six qualitative studies met the inclusion criteria. Three dimensions of risk perceptions were identified-perceived susceptibility, perceived severity, and affective risk perception. Three influencing factors of these dimensions were also identified: information (i.e., consistency, confirmation bias, strength of the evidence, and perceived relevance), sociocultural (i.e., social inclusivity, cultural context, and risk interpretation), and individual (i.e., risks versus benefits, controllability, and experience). These dimensions and influencing factors were brought together to create the proposed novel Pregnancy Alcohol Risk Perception (PARP) conceptual model.
Conclusions:
The novel PARP conceptual model developed from the current literature provides a framework to guide understanding of risk perceptions, which includes a wide range of potential influencing factors.
Implications for public health:
The novel PARP conceptual model provides the groundwork for further refinement with stakeholders, which could in turn be used to inform the design of interventions and health promotional materials to support harm reduction approaches and prevention of prenatal alcohol exposure.
The focus of this chapter is on behavioral and mental health disorders (BMHDs). The disorders represent an amalgamation of challenging behaviors, emotional and behavioral consequence of brain dysfunction associated with medical and neurological disorders, and equally complex, primary psychiatric disorders. The emphasis is on autism spectrum disorders (ASD), attention-deficit hyperactivity disorder (ADHD), cerebral palsy (CP), and fetal alcohol spectrum disorder (FASD). As discrete entities, there are many differences between their underlying pathophysiology and phenotypic expression. Genome-wide association scans suggest some shared predisposition and sensitivities to negative environmental and psychosocial experiences. These concepts are elaborations of the biopsychosocial model. This model rests on the multi-direction interrelationships between life experiences (psychosocial forces) such as temperament, attachment and adverse experiences, and the complex of predisposing factors noted above. The primary challenge for the authors is dealing with the breadth of this subject. There are dozens of behavioral and psychiatric disorders to consider. Narrowing the focus to those listed above requires condensing the explosive growth of new information from genetics, epigenetics, translational neurosciences, neurophysiology, and functional neuroimaging of pediatric neurodevelopmental disorders into a single chapter. Two issues dominate (1) the transactional nature of gene environment interactions on emerging phenotypes, and (2) the growing realization that many of these phenotypes represent spectrum disorders that suggest final common pathways. From a biopsychosocial perspective, the neurodevelopmental disorders reviewed in this chapter differ in terms of pathophysiology, but are not mutually exclusive disorders. For example, ADHD is common in children with CP, FAS, and ASD. This realization reinforces the idea that many neurodevelopmental/psychiatric disorders are not discrete entities with firm boundaries. They are in fact products of many biological and psychosocial influences. From a behavioral health perspective, the negative consequences of adverse childhood experiences on these disorders are not a linear or deterministic process. Resilience and other protective factors and timely interventions can attenuate or prevent some of the negative outcomes discussed in this chapter.
Some historical clues suggest an ancient understanding that alcohol should be avoided during pregnancy, but these may have been overstated. Further evidence appears during times of widespread alcohol use in the middle ages, but the current understanding of prenatal alcohol exposure and FASD has its source in the latter half of the 20th century. This chapter describes the history of FASD, from Aristotle and the Old Testament up to modern neuroscience and genetics. After bringing the reader back to the present day, there follows a review of the mechanisms of alcohol-related harm to the foetus, and factors that mediate that harm.
Neurobehavioral disorder associated with prenatal alcohol exposure (ND_PAE) was proposed to capture the full range of mental health problems found in individuals who have been adversely impacted by their prenatal alcohol exposure (PAE). The disorder can be used with individuals who both have and do not have the physical symptoms of PAE. Specific symptoms of the disorder are described and the psychometric characteristics of the disorder are reviewed. Although there is substantial evidence to support the validity of the symptoms in individuals with a history of PAE, the unique formulation of these symptoms as currently proposed in the American Psychiatric Diagnostic and Statistical Manual, fifth edition (DSM-5), may need modification.
Increased regurgitant blood flow has been linked to endocardial cushion defects and resultant congenital heart diseases (CHDs). Prenatal alcohol exposure (PAE) has been shown to alter early blood flow resulting in abnormal endocardial cushions and CHDs. Compounds, including folic acid (FA), mitigate PAE effects and prevent CHDs, but few studies have assessed their effects on blood flow. We modeled binge drinking in quail embryos at gastrulation. Embryos were exposed to ethanol alone, FA (3.2 μg/egg) alone, and the two simultaneously. We quantified in cardiac looping stages (equivalent to 4 weeks of human gestation) regurgitant blood flow with Doppler optical coherence tomography (OCT) and endocardial cushion volumes using OCT imaging. Incidences of abnormal body curvature and heart rates were also measured. Embryos exposed to ethanol showed significantly increased regurgitant blood flow compared to controls, while embryos given FA with ethanol had significantly reduced regurgitant blood flow but did not return to control levels. Ethanol exposure led to significantly smaller, abnormal endocardial cushions and the addition of FA improved their size, but they remained smaller than controls. Abnormal body curvatures after PAE were reduced in incidence but not fully prevented by FA. FA supplementation partially alleviated PAE induced abnormal cardiovascular function and morphology. Normal blood flow and endocardial cushions are both required to produce a healthy four-chambered heart. These findings support that FA supplementation should begin early in pregnancy to prevent heart as well as neural tube defects. Investigations into the efficacy of combinations of compounds to prevent PAE-induced defects is warranted.
Pregnant women are at risk of developing trace elements deficiency. This is attributed to deficient dietary sources, physiological changes during pregnancy, and genetic factors. Adequate trace elements are essential for the health of the mother and her fetus. Many deleterious effects are associated with trace elements deficiency, which can be extended even after delivery and contribute to maternal and fetal morbidity and mortality. Trace elements deficiency can lead to congenital malformations, e.g., neural tube defects, aortic aneurysm, and valvular lesions. Clinical trials demonstrated that supplementation of trace elements has beneficial effects.
This chapter highlights the molecular mechanism by which select trace elements are implicated in the pathogenicity of selected clinical conditions such as gestational diabetes, preeclampsia, low birth weight, and teratogenicity.
Compute population prevalence rates of neural tube defects and microcephaly as well as levels of incorporated Cs137 by pregnant women in two areas of the Rivne Province of Ukraine, a northern half (Polissia) polluted by Chornobyl radiation and not‐Polissia areas. Monitoring of congenital malformations was conducted with adherence to methods adopted by a European surveillance network (EUROCAT). Incorporated Cs137 (Bq/kg) by pregnant women residing in the Polissia and not‐Polissia areas were obtained concurrently with prenatal ultrasound examinations. In Polissia, the incorporated Cs137 levels by pregnant women as well as the prevalence rates of neural tube defects and microcephaly are significantly higher than in not‐Polissia. In Polissia, the prevalence rates of neural tube defects and microcephaly are among the highest in Europe. The debate concerning the teratogenic impact of chronic exposures to low levels of ionizing radiation was re‐ignited by our 2010 report. Health agencies uphold the notion that exposure to Chornobyl radiation levels are too low to be teratogenic, which is inconsistent with our observations. Further investigations in Rivne by international teams can, we believe, contribute facts to the ongoing debate. Our monitoring system, experience and data can facilitate concurrent investigations of teratogenic risks from exposures to other sources of ionizing radiation, alcohol, folate and zinc deficiencies, among other risk factors. Study of genomic impacts can likewise be undertaken.
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Objective
To investigate associations between alcohol consumption patterns and diet quality, nutrient intakes and biochemical profile of women of childbearing age.
Design
Nutrient intake data from 24 h diet recalls, alcohol consumption data and diet quality from the Dietary Habits Questionnaire, and biochemical analyses from the cross-sectional 2008/09 Adult Nutrition Survey in New Zealand.
Setting
New Zealand households.
Participants
New Zealand women aged 18–45 years ( n 1124).
Results
All analyses were completed using Stata and survey weights were used to allow for the complex survey design to produce population estimates. Multinomial logistic regression models were used to examine the associations between drinking patterns and the variables of interest, with ‘infrequent moderate/light’ drinkers being the reference category. The findings indicate that alcohol-consuming women of childbearing age tend to replace food energy with alcohol energy ( P = 0·022). ‘More frequent heavy’ and ‘more frequent moderate/light’ drinkers had higher intakes of total, mono- and polyunsaturated fats with the latter group also consuming higher levels of saturated fats ( P < 0·05). Women who were ‘infrequent moderate/light’ drinkers had relatively better diet quality, nutrient intakes and adequate biochemical status in comparison to other drinkers and abstainers. ‘Infrequent heavy’ drinkers, who were predominantly younger in age, had lower serum vitamin B 12 levels ( P = 0·01) with a higher proportion of women in this category having below-recommended levels of serum folate ( P < 0·05).
Conclusions
Alcohol consumption, especially heavy drinking patterns, may compromise nutritional status of women of childbearing age.
Human infertility has become a serious medical and social issue worldwide, especially in developed countries. Numerous assisted reproductive technologies (ARTs) (e.g., artificial insemination [AI], in vitro fertilization [IVF], and intracytoplasmic sperm injection [ICSI]) are widely used to treat infertility, but when embryos produced using these techniques are transferred, the pregnancy outcome is only approx. 20–50%, necessitating further improvement in ARTs. Many factors (including zinc) affect successful fertilization, further embryonic development, and the establishment and maintenance of pregnancy. Zinc signaling has many physiological functions in various types of cells, and it is thus speculated that zinc signaling has an important role in the abovementioned reproductive events, even in germ cells and reproductive tissues. Prior studies demonstrated that zinc deficiency results in a number of anomalies in the formation and maturation of spermatozoa, ovulation, and fertilization. During pregnancy, zinc deficiency causes spontaneous abortion, pregnancy-related toxemia, extended pregnancy or preterm birth, malformations, and retarded growth. The molecular mechanisms underlying zinc signaling in reproduction are not yet clear. In this chapter, we summarize the current knowledge about zinc signaling in reproduction—mainly in mammals—and we discuss recent advances in this field.
Background:
We previously reported that maternal alcohol use significantly increases the risk of sepsis in premature and term newborns. In the mouse, fetal ethanol exposure results in an immunosuppressed phenotype for the alveolar macrophage (AM) and decreases bacterial phagocytosis. In pregnant mice, ethanol decreased AM zinc homeostasis, which contributed to immunosuppression and impaired AM phagocytosis. In this study, we explored whether ethanol-induced zinc insufficiency extended to the pup AMs and contributed to immunosuppression and exacerbated viral lung infections.
Methods:
C57BL/6 female mice were fed a liquid diet with 25% ethanol-derived calories or pair-fed a control diet with 25% of calories as maltose-dextrin. Some pup AMs were treated in vitro with zinc acetate before measuring zinc pools or transporter expression and bacteria phagocytosis. Some dams were fed additional zinc supplements in the ethanol or control diets, and then we assessed pup AM zinc pools, zinc transporters, and the immunosuppressant TGFβ1. On postnatal day 10, some pups were given intranasal saline or respiratory syncytial virus (RSV), and then AM RSV phagocytosis and the RSV burden in the airway lining fluid were assessed.
Results:
Fetal ethanol exposure decreased pup AM zinc pools, zinc transporter expression, and bacterial clearance, but in vitro zinc treatments reversed these alterations. In addition, the expected ethanol-induced increase in TGFβ1 and immunosuppression were associated with decreased RSV phagocytosis and exacerbated RSV infections. However, additional maternal zinc supplements blocked the ethanol-induced perturbations in the pup AM zinc homeostasis and TGFβ1 immunosuppression, thereby improving RSV phagocytosis and attenuating the RSV burden in the lung.
Conclusion:
These studies suggest that, despite normal maternal dietary zinc intake, in utero alcohol exposure results in zinc insufficiency, which contributes to compromised neonatal AM immune functions, thereby increasing the risk of bacterial and viral infections.
The consumption of alcohol and drugs of abuse among pregnant women has experienced a significant increase in the last decades. Optimal maternal nutritional status is of great importance for proper fetal development, yet is often altered with alcohol or drugs consumption. There is a lack of information on the effects of alcohol and drugs on maternal nutritional status, so the focus of this review was to provide an overview on nutrional status of mother and fetus in abusers pregnant women. Alcohol and drugs consumption can adversely affect the quality and quantity of proper nutrient supply and energy intake, resulting in malnutrition especially of micronutrients (vitamins, omega-3, folic acid, zinc, choline, iron, copper, selenium). When maternal nutritional status is compromised by alcohol and drugs essential nutrients are not available for the fetus, this can result in suboptimal outcomes like Intrauterine Growth Restriction (IUGR) or Fetal Alcohol Spectrum Disorder (FASD). It is critical to determine a means to resolve and reduce the physical and neurological malformations that develop in the fetus as a result of prenatal alcohol and drugs exposure combined with poor maternal nutrition. Prenatal nutrition interventions are required that may prevent or alleviate the development of such abnormalities.
Objective:
To review data on the role of ethanol-induced alteration of Zn homeostasis in mediation of adverse effects of alcohol abuse.
Methods:
The scholarly published articles on the association between Zn metabolism and alcohol-associated disorders (liver, brain, lung, gut dysfunction, and fetal alcohol syndrome) have been reviewed.
Results:
It is demonstrated that alcohol-induced modulation of zinc transporters results in decreased Zn levels in lungs, liver, gut, and brain. Zn deficiency in the gut results in increased gut permeability, ultimately leading to endotoxemia and systemic inflammation. Similarly, Zn deficiency in lung epithelia and alveolar macrophages decreases lung barrier function resulting in respiratory distress syndrome. In turn, increased endotoxemia significantly contributes to proinflammatory state in alcoholic liver disease. Finally, impaired gut and liver functions may play a significant role in alcoholic brain damage, being associated with both increased proinflammatory signaling and accumulation of neurotoxic metabolites. It is also hypothesized that ethanol-induced Zn deficiency may interfere with neurotransmission. Similar changes may take place in the fetus as a result of impaired placental zinc transfer, maternal zinc deficiency, or maternal Zn sequestration, resulting in fetal alcoholic syndrome. Therefore, alcoholic Zn deficiency not only mediates the adverse effects of ethanol exposure, but also provides an additional link between different alcohol-induced disorders.
Conclusions:
Generally, current findings suggest that assessment of Zn status could be used as a diagnostic marker of metabolic disturbances in alcohol abuse, whereas modulation of Zn metabolism may be a potential tool in the treatment of alcohol-associated disorders.
Periconceptional folate and folic acid intake prevents orofacial clefts (OFC) in the offspring. It has been suggested that other nutrients also play a role. We investigated the preconceptional intake of macronutrients (protein, fat, carbohydrate, fiber, and cholesterol), vitamins (vitamin A, retinol, beta-carotene, ascorbic acid, and alpha-tocopherol), minerals (calcium, phosphorus, iron, magnesium, and zinc) and food groups in mothers of OFC children and controls. At approximately 14 mo after the index pregnancy, 206 mothers of a child with a nonsyndromic OFC and 203 control mothers completed a FFQ on current food intake and a general questionnaire. After exclusion of pregnant and lactating mothers, mothers who reported a change in diet compared with the preconceptional period, and those for whom periconceptional folic acid supplement use was unclear, 182 OFC mothers and 173 control mothers were evaluated. Macronutrient, vitamin, mineral, and food group intakes were compared. After adjustment for energy, quintiles of dietary nutrient intake and odds ratios with 95% CI were calculated. The preconceptional intake of all macronutrients, vitamins, minerals, and food groups with the exception of milk (products), potatoes, pies/cookies were lower in OFC mothers than in controls. The energy-adjusted intakes of vegetable protein, fiber, beta-carotene, ascorbic acid, alpha-tocopherol, iron, and magnesium were significantly lower in cases compared with controls. Increasing intakes of vegetable protein, fiber, ascorbic acid, iron, and magnesium decreased OFC risk. In conclusion, a higher preconceptional intake of nutrients predominantly present in fruits and vegetables reduces the risk of offspring affected by OFC.
The insulin-like growth factor (IGF) axis, a key regulator of embryonic growth and development, is exquisitely sensitive to the nutrient status of the animal. In addition to macronutrient deficiencies, zinc deficiency can impact the IGF axis. Gestational zinc deficiency is teratogenic, resulting in intrauterine growth retardation and structural abnormalities. The aim of this study was to investigate the effects of gestational zinc deficiency on the fetal IGF axis in a rat model. From gestation day (GD) 0.5, dams consumed zinc-deficient (ZD, 0.3 mg zinc/kg) or control (25 mg zinc/kg) diet ad libitum, while a third group of dams consumed the control diet in amounts equivalent to the food intake of the ZD dams (Paired group). On GD 19.5 fetal tissue, blood and amniotic fluid were collected. Fetal growth was significantly reduced by zinc deficiency compared with the Paired and Control groups. Fetuses from the Paired group were smaller compared with the Control, but only ZD fetuses had structural malformations. Amniotic fluid IGF-1 concentrations were significantly lower in the Paired group than in the ZD and Control groups. Plasma of ZD fetuses contained lower levels of IGF binding protein-1 when compared with fetuses in the Paired and Control groups. Fetal liver IGF-1 mRNA levels were lower in the ZD fetuses than in the Paired and Control fetuses. These observations suggest that differences in the fetal IGF axis between ZD and Paired groups contribute to the poor pregnancy outcome and enhanced fetal growth retardation observed with zinc deficiency.
Early life nutritional exposures, combined with changes in lifestyle in adult life, can result in increased risk of chronic diseases. Although much of the focus on the developmental origins of disease has been on birth size and growth in postnatal life and the availability of energy and protein during these critical developmental periods, micronutrient deficiencies may also play an important role in fetal growth and development. Micronutrient status in fetal and early life may alter metabolism, vasculature, and organ growth and function, leading to increased risk of cardiometabolic disorders, adiposity, altered kidney function, and, ultimately, to type 2 diabetes and cardiovascular diseases. This review elucidates pathways through which micronutrient deficiencies lead to developmental impairment and describes the research to date on the evidence that micronutrient deficiencies in utero influence the development of chronic disease risk. Animal studies, observational human studies examining maternal diet or micronutrient status, and limited data from intervention studies are reviewed. Where data are lacking, plausible mechanisms and pathways of action have been derived from the existing animal and in vitro models. This review fills a critical gap in the literature related to the seminal role of micronutrients in early life and extends the discussion on the developmental origins of health and disease beyond birth size and energy and protein deficiency.
Although iron and zinc deficiencies are known to occur together and also appear to be high in Ghana, a few supplementation studies addressed this concurrently in pregnancy. In a double-blind, randomized controlled trial, 600 pregnant women in Ghana were randomly assigned to receive either a combined supplement of 40 mg of zinc as zinc gluconate and 40 mg of iron as ferrous sulphate or 40 mg of elemental iron as ferrous sulphate. Overall, there was no detectable difference in the mean birthweight between the study groups, although the effect of iron-zinc supplementation on the mean birthweight was masked by a strong interaction between the type of supplement and the iron status of participants [F (1,179) = 5.614, p = 0.019]. Prenatal iron-zinc supplementation was effective in increasing the mean birthweight among anaemic and iron-deficient women but not among women with elevated iron stores in early pregnancy.
Although a requirement of zinc (Zn) for normal brain development is well documented, the extent to which Zn can modulate neuronal proliferation and apoptosis is not clear. Thus, we investigated the role of Zn in the regulation of these two critical events. A low Zn availability leads to decreased cell viability in human neuroblastoma IMR-32 cells and primary cultures of rat cortical neurons. This occurs in part as a consequence of decreased cell proliferation and increased apoptotic cell death. In IMR-32 cells, Zn deficiency led to the inhibition of cell proliferation through the arrest of the cell cycle at the G0/G1 phase. Zn deficiency induced apoptosis in both proliferating and quiescent neuronal cells via the intrinsic apoptotic pathway. Reductions in cellular Zn triggered a translocation of the pro-apoptotic protein Bad to the mitochondria, cytochrome c release, and caspase-3 activation. Apoptosis is the resultant of the inhibition of the prosurvival extracellular-signal-regulated kinase, the inhibition of nuclear factor-kappa B, and associated decreased expression of antiapoptotic proteins, and to a direct activation of caspase-3. A deficit of Zn during critical developmental periods can have persistent effects on brain function secondary to a deregulation of neuronal proliferation and apoptosis.
"Barker's hypothesis" emerged almost 25 years ago from epidemiological studies of birth and death records that revealed a high geographic correlation between rates of infant mortality and certain classes of later adult deaths as well as an association between birthweight and rates of adult death from ischemic heart disease. These observations led to a theory that undernutrition during gestation was an important early origin of adult cardiac and metabolic disorders due to fetal programming that permanently shaped the body's structure, function, and metabolism and contributed to adult disease. This theory stimulated interest in the fetal origins of adult disorders, which expanded and coalesced approximately 5 years ago with the formation of an international society for developmental origins of health and disease (DOHaD). Here we review a few examples of the many emergent themes of the DOHaD approach, including theoretical advances related to predictive adaptive responses of the fetus to a broad range of environmental cues, empirical observations of effects of overnutrition and stress during pregnancy on outcomes in childhood and adulthood, and potential epigenetic mechanisms that may underlie these observations and theory. Next, we discuss the relevance of the DOHaD approach to reproductive medicine. Finally, we consider the next steps that might be taken to apply, evaluate, and extend the DOHaD approach.
Deprivation is associated with poor pregnancy outcome but the role of nutrition as a mediating factor is not well understood. We carried out a prospective cohort study of 1461 singleton pregnancies in Aberdeen, UK during 2000-6. We measured nutrient intake and supplement use, B vitamin and homocysteine status, birth weight, gestational age, neonatal treatment and socio-economic deprivation status. Women in the most deprived deciles were approximately 6 years younger and half as likely to take folic acid supplements periconceptually as the least deprived mothers. Deprivation was associated with low blood folate, high homocysteine and diets low in protein, fibre and many of the vitamins and minerals. The diets of the more deprived women were also characterised by low intakes of fruit, vegetables and oily fish and higher intakes of processed meat, fried potatoes, crisps and snacks. Deprivation was related to preterm birth (OR 1.14 (95 % CI 1.03, 1.25); P = 0.009) and whether the baby required neonatal treatment (OR 1.07 (95 % CI 1.01, 1.14); P = 0.028). Low birth weight was more common in women consuming diets low in vitamin C (OR 0.79 (95 % CI 0.64, 0.97); P = 0.028), riboflavin (OR 0.77 (95 % CI 0.63, 0.93); P = 0.008), pantothenic acid (OR 0.79 (95 % CI 0.65, 0.97); P = 0.023) and sugars (OR 0.78 (95 % CI 0.64, 0.96); P = 0.017) even after adjustment for deprivation index, smoking, marital status and parity. Deprivation in pregnancy is associated with diets poor in specific nutrients and poor diet appears to contribute to inequalities in pregnancy outcome. Improving the nutrient intake of disadvantaged women of childbearing age may potentially improve pregnancy outcome.
The aim of this study was to assess the effect of high dose zinc (Zn) supplement during pregnancy in pregnancy outcome in healthy pregnant women with a previous preterm delivery in Isfahan, Iran.
A double-blind placebo-controlled randomized clinical trial was conducted between January 2007 and June 2008. Eighty-four pregnant women with a previous preterm delivery age 19 to 35 years were randomly allocated to receive either 50 mg/day Zn as Zn sulfate or placebo from 12 to 16 weeks of gestation till delivery. Pregnancy outcome was assessed in term of incidence of intrauterine growth retardation (IUGR), birth weight, crown-heel length, head circumference, Apgar score, and gestational age at delivery.
The mean birth head circumference was higher in Zn supplemented group than in the placebo group (35.0 cm vs. 33.7 cm, P < 0.05). Although gestational age at delivery (37.1 week vs. 36.7 week) and birth weight (2960.6 g vs. 2819.0 g) of babies born in Zn supplemented group was slightly higher than placebo group, it was not statistically significant. No significant differences were seen for infant length, Apgar score, and IUGR.
Adding Zn supplementation during pregnancy to routine care of women with a previous preterm delivery had no significant effect on the gestational age at delivery and birth weight but increased the birth head circumference.
Previous studies have shown a high rate of neural tube defects (NTD) in Gorgan, northern (tub efcs (NTD) in Gorgan, northern Islamic Republic of Iran. This case-control study during 2003-04 compared serum zinc levels and other variables in 23 mothers of neonates affected with NTD and 36 mothers with normal healthy neonates in Dezyani hospital in Gorgan. Mean serum zinc levels in the case and control groups were 13.43 micromol/L (SD 6.3) and 11.41 micromol/L (SD 6.3) respectively. Zinc deficiency was found in 13 (36.5%) of the cases and 7 (19.4%) of the controls. Logistic regression analysis showed an association between the presence of NTD and zinc deficiency (OR 5.06; 95% CI: 1.51-16.94).
Zinc deficiency increases the risk and severity of a variety of infections, restricts physical growth, and affects specific outcomes of pregnancy. Global recognition of the importance of zinc nutrition in public health has expanded dramatically in recent years, and more experience has accumulated on the design and implementation of zinc intervention programs. Therefore, the Steering Committee of the International Zinc Nutrition Consultative Group (IZiNCG) completed a second IZiNCG technical document that reexamines the latest information on the intervention strategies that have been developed to enhance zinc nutrition and control zinc deficiency. In particular, the document reviews the current evidence regarding preventive zinc supplementation and the role of zinc as adjunctive therapy for selected infections, zinc fortification, and dietary diversification or modification strategies, including the promotion and protection of breastfeeding and biofortification.
The purposes of this introductory paper are to summarize new guidelines on the assessment of population zinc status, as recommended by the World Health Organization (WHO), the United Nations Children's Fund (UNICEF), the International Atomic Energy Agency (IAEA), and IZiNCG, and to provide an overview on several new advances in zinc metabolism. The following papers will then review the intervention strategies individually.
Adolescents are more likely than adults to consume energy-dense, micronutrient-poor diets and to experience adverse pregnancy outcomes.
The objectives were to assess micronutrient intake and blood biomarkers prospectively in pregnant adolescents recruited to the About Teenage Eating (ATE) Study and to determine associations with pregnancy outcome.
Pregnant adolescents (n = 500) were recruited from 2 UK inner city populations. Dietary intake was assessed with three 24-h dietary recalls, and micronutrient status was assessed by measurement of third trimester blood biomarkers. Pregnancy outcomes included small-for-gestational age (SGA) birth and preterm delivery.
Median iron and folate intakes were lower than UK and US recommended amounts. Folate and vitamin B-12 status were lower in smokers, despite no differences in dietary intake. Serum folate was <7.0 nmol/L in 12% of subjects, and serum total homocysteine (tHcy) was elevated (>10 micromol/L) in 20% of subjects. Fifty-two percent of the subjects had iron deficiency anemia, and 30% had serum 25-hydroxyvitamin D concentrations <25 nmol/L. The incidence of SGA birth was higher in subjects with poorer folate status (red blood cell folate, P = 0.003; serum folate, P = 0.02; tHcy, P = 0.01; simple regression) and those with low folate intakes, regardless of the inclusion (P = 0.021) or exclusion (P = 0.049) of intake from supplements (simple regression). Adjustment for confounding variables confirmed the independence of these associations. The risk of SGA birth was also higher in subjects with low food iron intake (P = 0.049), but not when intake included iron from supplements (P = 0.21). The risk of SGA birth was lower in subjects with iron deficiency anemia (P = 0.002).
Poor micronutrient intake and status increase the risk of SGA births in pregnant adolescents.
Chronic alcohol abuse impairs both alveolar epithelial and macrophage function, and renders individuals susceptible to acute lung injury, pneumonia, and other serious lung diseases. Zinc deficiency, which is known to impact both epithelial and immune cell functions, is also associated with alcohol abuse. In this study, chronic alcohol ingestion (6 wk) in rats altered expression of key zinc transporters and storage proteins in the small intestine and the lung, and decreased zinc levels in the alveolar compartment. Zinc supplementation of alveolar epithelial monolayers derived from alcohol-fed rats in vitro, or of the diets of alcohol-fed rats in vivo, restored alveolar epithelial barrier function, and these improvements were associated with salutary changes in tight junction protein expression and membrane localization. In parallel, dietary zinc supplementation increased intracellular zinc levels, GM-CSF receptor expression, and bacterial phagocytic capacity in the alveolar macrophages of alcohol-fed rats. Together, these studies implicate zinc deficiency as a novel mechanism mediating alcohol-induced alveolar epithelial and macrophage dysfunction. Importantly, these findings argue that dietary supplementation can overcome alcohol-induced zinc deficiency and restore alveolar epithelial and macrophage function, and therefore could be an effective treatment for the susceptible alcoholic lung phenotype.
Nutrient requirements increase during periods of growth and development such as pregnancy and lactation. In response, many clinicians recommend dietary supplements during these important periods of the life cycle. Although there exist some recommendations concerning the need for a limited number of nutrients in supplemental form (eg, iron, folic acid, and iodine), there is a relative paucity of data concerning the use of dietary supplements during pregnancy and lactation. Limited data suggest, however, that usage is dependent on demographic, sociologic, and economic factors. Thus, it is possible that the nation's most at-risk populations may be those who are least likely to comply with these recommendations. As researchers continue to study what is meant by "optimal nutrition" during pregnancy and lactation, it is likely that additional recommendations concerning dietary supplements will emerge. For example, it is possible that increased consumption of some of the long-chain polyunsaturated fatty acids during pregnancy or lactation may impart a benefit to infant health. Understanding better the population dynamics related to supplement use during these periods will be critical in implementation of campaigns designed to encourage appropriate use--and discourage inappropriate use--of dietary supplements during these important phases of human reproduction. The purpose of this article is to briefly review what is known about the use of dietary supplements in North America and, more specifically, in pregnant and lactating women. In addition, information concerning barriers to supplement use is discussed as are current recommendations for dietary supplement consumption during these periods of the life cycle.
During development, the fetus is entirely dependent on the mother for its nutrient requirements. Subsequently, it is a period when both are vulnerable to changes in dietary supply, especially of those nutrients that are marginal under normal circumstances. In developed countries, this applies mainly to micronutrients. Even now, iron deficiency is a common disorder, especially in pregnancy. Similarly, copper intake in the U.K. population is rarely above adequate levels. It is now becoming clear that nutrient deficiencies during pregnancy can result in problems for the offspring, in both the short- and long-term. Early studies showed that lambs born to mothers on copper-deficient pastures developed 'swayback', with neurological and muscular symptoms that could not be reversed by postnatal supplementation. Our own findings have shown that prenatal iron deficiency results in increased postnatal blood pressure, even though the offspring have normal dietary iron levels from birth. These observations emphasize the importance of iron and copper in growth and development. Complicating the situation further is the fact that copper and iron are known to interact with each other in many ways, including absorption and intracellular transport. However, their interactions during the pregnancy appear to be more complex than during the non-pregnant state. In the present review, we examine the importance of these metals and their interactions, the consequences, both short- and long-term, of deficiency and consider some possible mechanisms whereby these effects may be generated.
The SLC39A (solute carrier 39A) [ZIP (Zrt-Irt-like protein)] family consists of 14 members which are thought to control zinc uptake into the cytoplasm. Among these, ZIP4 is known to be particularly important for zinc homoeostasis. Mutations in this gene cause acrodermatitis enteropathica, a rare recessive-lethal human genetic disorder. In the present paper, our studies of the regulation and function of the mouse Zip4 gene are briefly reviewed. Mouse Zip4 is expressed at highest levels in tissues involved in absorption of dietary or maternal zinc, and the gene and protein are dynamically regulated by multiple post-transcriptional mechanisms in response to zinc availability. ZIP4 accumulates at the apical surface of enterocytes and endoderm cells when zinc is deficient, because of increased stability of the mRNA and stabilization of the protein. In contrast, when zinc is replenished, the mRNA is destabilized and the protein is internalized and degraded rapidly. The critical importance of ZIP4 in zinc homoeostasis is revealed in mice with targeted deletions of this gene. Homozygous Zip4-knockout embryos die during early morphogenesis and heterozygous offspring are significantly underrepresented and display an array of developmental defects, including exencephalia, anophthalmia and severe growth retardation. Mice heterozygous for Zip4-knockout are hypersensitive to zinc deficiency, which suggests that humans heterozygous for this gene may also be very sensitive to zinc deficiency.
Neural tube defects (NTDs) may be associated with syndromes, disorders and maternal risk factors. This article provides a comprehensive review of the syndromes, disorders and maternal risk factors associated with NTDs, including DK phocomelia syndrome (von Voss-Cherstvoy syndrome), Siegel-Bartlet syndrome, fetal warfarin syndrome, craniotelencephalic dysplasia, Czeizel-Losonci syndrome, maternal cocaine abuse, Weissenbacher- Zweymller syndrome, parietal foramina (cranium bifidum), Apert syndrome, craniomicromelic syndrome, XXagonadism with multiple dysraphic lesions including omphalocele and NTDs, Fryns microphthalmia syndrome, Gershoni-Baruch syndrome, PHAVER syndrome, periconceptional vitamin B6 deficiency, and autosomal dominant Dandy-Walker malformation with occipital cephalocele. NTDs associated with these syndromes, disorders and maternal risk factors are a rare but important cause of NTDs. The recurrence risk and the preventive effect of maternal folic acid intake in NTDs associated with syndromes, disorders and maternal risk factors may be different from those of nonsyndromic multifactorial NTDs. Perinatal diagnosis of NTDs should alert doctors to the syndromes, disorders and maternal risk factors associated with NTDs, and prompt thorough etiologic investigation and genetic counseling.
Zinc deficiency is a recognized reproductive hazard. The most common cause of embryonic zinc deficiency is low maternal plasma concentrations of the element, which can occur via numerous routes including the following: inadequate dietary zinc intake, genetic abnormalities in zinc metabolism, disease and drug-induced changes in zinc uptake and excretion, and cytokine-induced changes in zinc metabolism. Evidence is presented that tumor necrosis factor-α is a cytokine whose teratogenicity may be attributed, in part, to its effect on zinc metabolism. The concept that cytokine-induced changes in zinc metabolism represents a common mechanism underlying the developmental toxicity of several diverse toxicants is discussed.
Objective.
—To evaluate whether zinc supplementation during pregnancy is associated with an increase in birth weight.Design.
—A randomized double-blind placebo-controlled trial.Setting.
—Outpatient clinic and delivery service at the University of Alabama at Birmingham.Patients.
—Five hundred eighty medically indigent but otherwise healthy African-American pregnant women with plasma zinc levels below the median at enrollment in prenatal care, randomized at 19 weeks' gestational age. Women were subdivided by the population median body mass index of 26 kg/m2 into two groups for additional analyses.Intervention.
—Women who were taking a non—zinc-containing prenatal multivitamin/mineral tablet were randomized to receive either a daily dose of 25 mg of zinc or a placebo until delivery.Main Outcome Measures.
—Birth weight, gestational age at birth, and head circumference at birth.Results.
—In all women, infants in the zinc supplement group had a significantly greater birth weight (126 g, P=.03) and head circumference (0.4 cm, P=.02) than infants in the placebo group. In women with a body mass index less than 26 kg/m2, zinc supplementation was associated with a 248-g higher infant birth weight (P=.005) and a 0.7-cm larger infant head circumference (P=.007). Plasma zinc concentrations were significantly higher in the zinc supplement group.Conclusions.
—Daily zinc supplementation in women with relatively low plasma zinc concentrations in early pregnancy is associated with greater infant birth weights and head circumferences, with the effect occurring predominantly in women with a body mass index less than 26 kg/m2.(JAMA. 1995;274:463-468)
Studies were performed on adult and fetal rats receiving either a zinc-deficient (<0.5 ppm) diet and/or ethanol (20%) throughout pregnancy. Liver zinc levels were depressed in fetuses exposed toin utero zinc deficiency, but brain zinc levels were unchanged. Ethanol had no effect on the concentration of zinc in the several fetal and adult tissues studies. Lipid peroxidation, as measured by endogenous levels of malondialdehyde (MDA) increased following food restriction, zinc improverishment, and alcoholism in adult and fetal livers, but not in fetal brains. Generally, levels of MDA were highest when both zinc deficiency and the ingestion of alcohol occurred concurrently. Glutathione (GSH) was depressed by zinc restriction in several adult and fetal tissues, but not in the fetal brain. Ethanol alone had no effect on GSH levels. The activity of the enzyme glutathione peroxidase (GSH-Px) was not changed in either organism by alcohol or zinc deficiency.
Overall, the data point to increased lipid peroxidation in maternal and fetal rat tissues following zinc depletion and/or treatment with alcohol and draw attention to the apparent vulnerability of the fetal liver toin utero alcoholism. By contrast, the fetal brain seems to be especially resistant to alcohol and zinc-related lipoperoxidation. An association is suggested between the increased lipoperoxidation accompanying zinc deficiency and reduced levels of GSH, but this does not appear to relate to changes in the activity of GSH-Px. A similar relationship is not evident with respect to the increased levels of MDA in fetal and adult livers following chronic alcohol intoxication. A possible basis for the zinc-GSH interaction is discussed.
Fetal alcohol syndrome produces defects that parallel abnormalities associated with early iron deficiency. Hence, we examined the effects of prenatal exposure to ethanol on iron, transferrin, and ferritin concentrations. The subjects were the offspring of pregnant rats fed an ethanol-containing diet (Et), pair-fed an isocaloric control diet (Ct), or fed chow and water. The amounts of iron, transferrin, and ferritin were assessed in three CNS regions (cerebral cortex, subcortical forebrain, and brain-stem). In all three segments of the control rats, iron, transferrin, and ferritin levels decreased during the first 2 postnatal weeks, reached a minimum during week 3, and then rose to adult levels. This pattern was delayed by ethanol treatment, e.g., the minimal concentrations in iron, transferrin, and ferritin in the Et-treated rats were achieved later (3 days, 7 days, and 2 weeks, respectively) than they were in the Ct-treated rats. Ethanol-induced alterations in iron homeostasis persisted into adulthood; iron concentration was reduced, transferrin concentration was unaffected, and ferritin concentration was increased. The net result was that the timely delivery and bioavailability of iron were compromised by ethanol exposure. The defects in iron regulation are permanent and may underlie ethanol-induced abnormalities in iron-dependent growth processes such as myelination.
This study investigated the Interactive effects of alcohol and nutritional status of the pregnant female on fetal growth and development Three liquid diets were formulated ranging in protein content from suboptimal to supraoptimal: diet I provided 18% kcal as protein and 1.0 kcal/ml; diets II and III provided 25 and 32% kcal, respectively, as protein and 1.2 kcal/ml. In all cases, alcohol provided 36% of total calories. Both pair-fed and ad libitum fed control groups were included. We found that blood alcohol levels were consistently high in all three diet regimens throughout gestation. Alcohol intake suppressed weight gains and increased adrenal weights and placenta weights in pregnant females. Both body weights and brain weights were reduced in alcohol-exposed fetuses. However, relative brain weights were found to be increased in alcohol fetuses, indicating “brain sparing.” Maternal nutritional status had no major effect on developmental outcome. Thus, with alcohol administered as a high proportion of total dairy calories, increasing dietary protein levels did not attenuate the major adverse effects of alcohol on fetal development.
The objective of this paper was to compare the nutrient intakes of mothers of different ethnic origins after they had given birth to a low birth weight (LBW) baby (<2.5 kg). A total of 165 participants from East London, UK completed a prospective 7-day diet diary using household measures, between 8 and 12 weeks post-partum. The data were originally collected as baseline data prior to two separate nutrition intervention studies and were combined and re-interrogated for the purpose of this paper. Folate and iron intakes were low in all ethnic groups compared to the Reference Nutrient Intakes (RNI). Half did not meet the RNI for folate and 88% did not meet the RNI for iron. Nearly a quarter of the group did not achieve the Lower Reference Nutrient Intake (LRNI) for iron. The mean vitamin D and calcium intakes were significantly different between the ethnic groups (P = 0.007, P = 0.001, respectively). African women had the highest vitamin D intakes (4.72 µg d−1) and Caucasians and Asians the lowest (2.4 µg d−1). Caucasians had the highest calcium intakes (780 mg d−1) and Africans the lowest (565 mg d−1). Over two-thirds of African, Asian and African-Caribbean women did not meet the RNI for calcium. Thirty-one per cent of Africans did not meet the LRNI for calcium. Our data show a high prevalence of inadequate nutrition among women who deliver LBW babies with differences in nutrient intake between ethnic groups. This information can be used to target specific appropriate dietary advice to ethnic minorities for the prevention or repetition of LBW.
Background: Non-transferrin-bound iron, a low-molecular-weight iron complex capable of initiating free radical formation and lipid peroxidation, has been detected in the serum of animals experimentally fed with alcohol, but no data have been reported in alcohol abusers. The purpose of this study was to evaluate whether non-transferrin-bound iron is present in chronic alcohol abusers with liver involvement and whether alcohol plays any part in its appearance.
Methods: We measured non-transferrin-bound iron in a cohort of chronic alcohol abusers with and without liver cirrhosis at presentation, when 43 were active abusers and 33 were abstainers, and in a smaller group during a follow-up period.
Results: At presentation, non-transferrin-bound iron was detectable in 83.7% of active abusers but only in 21.2% of abstainers, and within the group of abusers, patients with cirrhosis had significantly higher non-transferrin-bound iron than patients without. Non-transferrin-bound iron was present not only in patients with transferrin saturation >45% but also in those with transferrin saturation ≤45%. Multiple regression analyses revealed that only alcohol intake and total bilirubin were associated independently with non-transferrin-bound iron values. Longitudinal study confirmed the data of the cross-sectional study.
Conclusions: Non-transferrin-bound iron could have a role in initiating or promoting alcohol-induced liver damage.
Ethanol profoundly affects fetal development, and this is proposed to be due primarily to a transient fetal zinc (Zn) deficiency that arises from the binding of Zn by metallothionein (MT) in the maternal liver. Zn homeostasis and fetal outcome were investigated in normal (MT+/+) and metallothionein-null (MT-/-) mice in response to ethanol exposure.
Mice were treated with saline or ethanol (0.015 ml/g intraperitoneally at 0 and 4 hr) on day 8 of gestation (Gd8), and the degree of fetal dysmorphology was assessed on Gd18. The incidence of external abnormalities was significantly increased in offspring from MT+/+ dams exposed to ethanol, where 27.4% of fetuses were affected. MT-/- ethanol-, MT+/+ saline-, and MT-/- saline-treated dams had fetuses in which the frequencies of abnormalities were 2.2, 6.4, and 6.9%, respectively. To investigate Zn homeostasis, nonpregnant mice were killed at intervals over 16 hr after ethanol injection. Liver MT concentrations in MT+/+ mice were increased 20-fold by 16 hr, with a significant elevation evident by 4 hr, whereas liver Zn levels were also significantly increased by 2 hr and maintained for 16 hr. In parallel with these changes, plasma Zn concentrations in MT+/+ mice decreased by 65%, with minimum levels of 4.5±0.3 μmol/liter at 8 hr. Conversely, MT-/- mice exhibited increased plasma Zn concentrations, with peak values of 20.8±0.3 observed at 4 hr.
These findings link the teratogenic effect of ethanol to the induction of maternal MT and the limitation of fetal Zn supply from the plasma.
The hypothesis that an acute-phase reaction in the pregnant animal causes a systemic redistribution of Zn, resulting in a transient but developmentally adverse Zn deficiency in the embryo, was tested by treating pregnant rats during organogenesis with α-hederin, an agent reported to induce substantial metallothionein (MT) synthesis in rat liver, and determining hepatic MT concentration, hepatic and plasma Zn concentration, and systemic distribution of a pulse of 65Zn after treatment. Developmental toxicity was assessed by evaluating morphologic development in term fetuses. A single dose of α-hederin, injected sc at dosages of 3 to 300 μmol/kg, caused an acute phase response, indicated by decreased Fe and Zn, and increases Cu, α1-acid glycoprotein, and ceruloplasmin concentration in plasma, along with a dosage-related increase in maternal hepatic MT concentration. The maximum induction of MT was 11 to 15-fold greater than control and occurred at dosages of 30 μmol/kg and higher, and MT concentration reached its peak 12 to 24 h after treatment. Zn concentration in liver and liver cytosol increased along with MT, reaching a maximum level at dosages of 30 μmol/kg and higher. Plasma Zn concentration decreased after α-hederin treatment to a level approximately 75% of control at a dosage of 30 μmol/kg and 50% of control at 300 μmol/kg. Therefore, hepatic MT induction was associated with most, but not all, of the decrease in plasma Zn concentration. Zn distribution was evaluated by giving an oral pulse of 65Zn 8 h after treatment with 0, 30, or 300 μmol/kg α-hederin on gestation day 11, and measuring 65Zn levels 18 h after treatment. The fraction of 65Zn distributed to the liver of treated rats (either dosage) was twice that of control, but distribution of 65Zn to other maternal tissues was decreased. 65Zn accumulation by conceptuses was significantly decreased, attributable to decreased accumulation in decidua, but not in visceral yolk sacs or embryos; however, at this stage of development the decidua accounts for a greater quantity of Zn than either of the other products of conception and may serve as the Zn-storing tissue for the conceptus. Both 30 and 300 μmol/kg increased resorption incidence, and 300 μmol/kg also decreased fetal weight and increased the incidence of abnormal fetuses. Serum collected from rats two hours after α-hederin treatment (i.e., before the onset of MT synthesis) supported rat embryo development in vitro, whereas serum collected 18 h after treatment did not. Adding Zn to this serum restored normal embryonic development. These data are consistent with the hypothesis that systemic changes in Zn status, brought about by a hepatic acute phase response, including a substantial induction of hepatic MT, may be a mechanism for maternally mediated abnormal development.
Free zinc ions are potent effectors of proteins. Their tightly controlled fluctuations ("zinc signals") in the picomolar range of concentrations modulate cellular signaling pathways. Sulfur (cysteine) donors generate redox-active coordination environments in proteins for the redox-inert zinc ion and make it possible for redox signals to induce zinc signals. Amplitudes of zinc signals are determined by the cellular zinc buffering capacity, which itself is redox-sensitive. In part by interfering with zinc and redox buffering, reactive species, drugs, toxins, and metal ions can elicit zinc signals that initiate physiological and pathobiochemical changes or lead to cellular injury when free zinc ions are sustained at higher concentrations. These interactions establish redox-inert zinc as an important factor in redox signaling. At the center of zinc/redox signaling are the zinc/thiolate clusters of metallothionein. They can transduce zinc and redox signals and thereby attenuate or amplify these signals.
Background : Alcohol increases body iron stores. Alcohol and iron may increase oxidative stress and the risk of alcohol-related liver disease. The relationship between low or “safe” levels of alcohol use and indices of body iron stores, and the factors that affect the alcohol-iron relationship, have not been fully characterized. Other aspects of the biological response to alcohol use have been reported to depend on iron status.
Methods: We have measured serum iron, transferrin, and ferritin as indices of iron stores in 3375 adult twin subjects recruited through the Australian Twin Registry. Information on alcohol use and dependence and smoking was obtained from questionnaires and interviews.
Results: Serum iron and ferritin increased progressively across classes of alcohol intake. The effects of beer consumption were greater than those of wine or spirits. Ferritin concentration was significantly higher in subjects who had ever been alcohol dependent. There was no evidence of interactions between HFE genotype or body mass index and alcohol. Alcohol intake–adjusted carbohydrate-deficient transferrin was increased in women in the lowest quartile of ferritin results, whereas adjusted γ-glutamyltransferase, aspartate aminotransferase, and alanine aminotransferase values were increased in subjects with high ferritin.
Conclusions: Alcohol intake at low level increases ferritin and, by inference, body iron stores. This may be either beneficial or harmful, depending on circumstances. The response of biological markers of alcohol intake can be affected by body iron stores; this has implications for test sensitivity and specificity and for variation in biological responses to alcohol use.
To review zinc physiology and pathophysiology and the importance of zinc toxicity and deficiency in veterinary patients.
A review of human and veterinary medical literature.
There is a significant amount of original research in humans and animals on the role of zinc in multiple organ systems. There is also significant data available on human patients with zinc abnormalities.
Zinc deficiency has been studied in dogs with genetic disease and dietary deficiency leading to dermatological disease and immune deficiency. Zinc toxicity has been described after ingestion of metallic foreign bodies containing zinc.
Historically, the role of zinc in health and disease has been studied through patients with toxicity or severe deficiency with obvious clinical signs. As the ubiquitous contribution of zinc to structure and function in biological systems was discovered, clinically significant but subtle deficiency states have been revealed. In human medicine, mild zinc deficiencies are currently thought to cause chronic metabolic derangement leading to or exacerbating immune deficiency, gastrointestinal problems, endocrine disorders, neurologic dysfunction, cancer, accelerated aging, degenerative disease, and more. Determining the causal relationships between mild zinc deficiency and concurrent disease is complicated by the lack of sensitive or specific tests for zinc deficiency. The prevalence of zinc deficiency and its contribution to disease in veterinary patients is not well known. Continued research is warranted to develop more sensitive and specific tests to assess zinc status, to determine which patients are at risk for deficiency, and to optimize supplementation in health and disease.
Unlabelled:
Alcoholic steatosis is a fundamental metabolic disorder in the progression of alcoholic liver disease. Zinc deficiency is one of the most consistently observed biochemical/nutritional manifestations of alcoholic liver disease. The purpose of this study is to determine whether dietary zinc supplementation to mice previously exposed to alcohol could reverse alcoholic steatosis. Male 129S mice were pair-fed an alcohol or isocaloric maltose dextrin liquid diet for 16 weeks with or without dietary zinc supplementation for the last 4 weeks. Zinc supplementation significantly attenuated alcohol-mediated increases in hepatic triglyceride, cholesterol, and free fatty acids in association with accelerated hepatic fatty acid oxidation and very low density lipoproteins (VLDL) secretion. Hepatic genes related to fatty acid oxidation and VLDL secretion were up-regulated by zinc supplementation, which was accompanied by restoring activity of hepatocyte nuclear factor-4alpha (HNF-4alpha) and peroxisome proliferators activated receptor-alpha (PPAR-alpha). Zinc supplementation enhanced alcohol metabolism and attenuated oxidative stress and liver injury. Zinc supplementation also normalized alcohol-mediated increases in plasma triglycerides and partially reversed decrease in gonadal adipose depot mass. Studies in HepG2 cells showed that zinc deprivation significantly suppressed the DNA-binding activities of HNF-4alpha and PPAR-alpha, and reduced HNF-4alpha and PPAR-alpha target proteins. Consequently, zinc deprivation caused cellular accumulation of lipid droplets, triglycerides and free fatty acids in the HepG2 cells.
Conclusion:
Zinc supplementation reverses alcoholic steatosis, and reactivation of HNF-4alpha and PPAR-alpha by increasing zinc availability and inhibiting oxidative stress are potential mechanisms underlying these beneficial effects of zinc on hepatic lipid homeostasis.
Prenatal alcohol exposure can lead to a range of physical, neurological, and behavioral alterations referred to as fetal alcohol spectrum disorders (FASD). Variability in outcome observed among children with FASD is likely related to various pre- and postnatal factors, including nutritional variables. Choline is an essential nutrient that influences brain and behavioral development. Recent animal research indicates that prenatal choline supplementation leads to long-lasting cognitive enhancement, as well as changes in brain morphology, electrophysiology and neurochemistry. The present study examined whether choline supplementation during ethanol exposure effectively reduces fetal alcohol effects. Pregnant dams were exposed to 6.0g/kg/day ethanol via intubation from gestational days (GD) 5-20; pair-fed and lab chow controls were included. During treatment, subjects from each group received choline chloride (250mg/kg/day) or vehicle. Physical development and behavioral development (righting reflex, geotactic reflex, cliff avoidance, reflex suspension and hindlimb coordination) were examined. Subjects prenatally exposed to alcohol exhibited reduced birth weight and brain weight, delays in eye opening and incisor emergence, and alterations in the development of all behaviors. Choline supplementation significantly attenuated ethanol's effects on birth and brain weight, incisor emergence, and most behavioral measures. In fact, behavioral performance of ethanol-exposed subjects treated with choline did not differ from that of controls. Importantly, choline supplementation did not influence peak blood alcohol level or metabolism, indicating that choline's effects were not due to differential alcohol exposure. These data indicate early dietary supplements may reduce the severity of some fetal alcohol effects, findings with important implications for children of women who drink alcohol during pregnancy.
We investigated the relation between concentrations of maternal zinc and copper and the risk of an infant being born with an orofacial cleft. We did a case-control study using 116 mothers of children with isolated cleft lip with or without cleft palate (cleft group), and 64 mothers of unaffected children (control group). Mothers with a whole blood zinc concentration of 47.1 micromol/L or less had a risk 2.5 times higher of having a child with an orofacial cleft than those with a higher concentration (or level) (95% CI 1.03-6.23; p<0.05). A low zinc concentration combined with a high copper concentration was seen only in the cleft group. This evidence suggests an association between concentrations of maternal zinc and the risk of orofacial clefts in offspring.
Alcohol use by pregnant women is a significant public health issue despite well-described risks to the fetus including physical and intellectual growth retardation and malformations. Although clinical studies are limited, they suggest that in utero alcohol exposure also results in significant immune deficiencies in naive neonates. However, little is known about fetal alcohol exposure (FAE) effects on adult infections. Therefore, to determine the long-term effects of FAE on disease susceptibility and the adult immune system, we infected FAE adult mice with influenza virus. In this study, we demonstrate that mice exposed to ethanol during gestation and nursing exhibit enhanced disease severity as well as increased and sustained pulmonary viral titers following influenza virus infection. Secondary exposure to alcohol as an adult further exacerbates these effects. Moreover, we demonstrate that FAE mice have impaired adaptive immune responses, including decreased numbers of virus-specific pulmonary CD8 T cells, a decreased size and frequency of pulmonary B cell foci, and reduced production of influenza-specific Ab following influenza infection. Together, our results suggest that FAE induces significant and long-term defects in immunity and susceptibility to influenza virus infection and that FAE individuals could be at increased risk for severe and fatal respiratory infections.
Zinc is an essential trace element crucial for the function of more than 300 enzymes and it is important for cellular processes like cell division and apoptosis. Hence, the concentration of zinc in the human body is tightly regulated and disturbances of zinc homeostasis have been associated with several diseases including diabetes mellitus, a disease characterized by high blood glucose concentrations as a consequence of decreased secretion or action of insulin. Zinc supplementation of animals and humans has been shown to ameliorate glycemic control in type 1 and 2 diabetes, the two major forms of diabetes mellitus, but the underlying molecular mechanisms have only slowly been elucidated. Zinc seems to exert insulin-like effects by supporting the signal transduction of insulin and by reducing the production of cytokines, which lead to beta-cell death during the inflammatory process in the pancreas in the course of the disease. Furthermore, zinc might play a role in the development of diabetes, since genetic polymorphisms in the gene of zinc transporter 8 and in metallothionein (MT)-encoding genes could be demonstrated to be associated with type 2 diabetes mellitus. The fact that antibodies against this zinc transporter have been detected in type 1 diabetic patients offers new diagnostic possibilities. This article reviews the influence of zinc on the diabetic state including the molecular mechanisms, the role of the zinc transporter 8 and MT for diabetes development and the resulting diagnostic and therapeutic options.
Zinc has been reported to prevent and reverse liver fibrosis in vivo; however, the mechanisms of its action are poorly understood. We therefore aimed to determine the antifibrotic potential of zinc.
Assessed was the influence of preincubation of rat HSCs with 30 microM ZnCl2 on ethanol- (in the presence of 4-methyl pyrazole (4-MP)) or acetaldehyde-induced toxicity, apoptosis, migration, expression of smooth muscle alpha-actin (alpha-SMA) and procollagen I, release of reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-alpha), tumor growth factor-beta1 (TGF-beta1), metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinases (TIMPs) production. Intracellular signals such as nuclear factor-kappaB (NFkappaB), C-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) induced by ethanol and its metabolite were also assessed.
30 microM zinc protected HSCs against ethanol and acetaldehyde toxicity and inhibited their apoptosis. Zinc inhibited the production of ROS by HSCs treated with ethanol and acetaldehyde and inhibited their migration. Zinc also inhibited ethanol- and acetaldehyde-induced TGF-beta1 and TNF-alpha production. Zinc down-regulated ethanol- and acetaldehyde-induced production of TIMP-1 and TIMP-2 and decreased the activity of MMP-2. In ethanol- and acetaldehyde-induced HSCs, zinc inhibited the activation of the p38 MAPK as well as the JNK transduction pathways and phosphorylation of IkappaB and Smad 3.
The results indicated that zinc supplementation inhibited ethanol- and acetaldehyde-induced activation of HSCs on different levels, acting as an antioxidant and inhibitor of MAPK, TGF-beta and NFkappaB/IkappaB transduction signaling. The remarkable inhibition of several markers of HCS activation makes zinc a promising agent for antifibrotic combination therapies.
Fetal zinc (Zn) deficiency arising from ethanol-induction of the Zn-binding protein metallothionein (MT) in the mother's liver has been proposed as a mechanism of teratogenicity. Here, we determine the ontogeny of MT and Zn homeostasis in rats and mice and then examine the effect of acute ethanol exposure in early embryonic development on this relationship. The protective effect of Zn against ethanol-mediated fetal dysmorphology is also examined.
Study 1: Maternal liver MT and Zn homeostasis was determined in Sprague-Dawley rats and C57BL/6J mice throughout gestation. Study 2: Rats were administered ethanol (25% in saline, intraperitoneal 0.015 ml/g) or vehicle alone on gestational day (GD) 9. Maternal liver MT and Zn, and plasma Zn was determined over the ensuing 24 hours. Study 3: Pregnant rats were treated with ethanol and Zn (s.c. 2.5 microg Zn/g) on GD9 and fetal dysmorphology was assessed on GD 19.
Study 1: Maternal liver MT began to rise around GD 9 peaking on GD 15 before falling to nonpregnant levels around term. The pregnancy-related increase in MT was associated with a fall in plasma Zn which was significantly lower on GD 15 thereafter returning to nonpregnant levels by parturition. Study 2: Ethanol administered to pregnant rats on GD 9 resulted in a 10-fold induction of MT in the maternal liver and was associated with a 33% rise in liver Zn and a 30% fall in plasma Zn, 16 hours after treatment. Study 3: Ethanol treatment on GD 9 resulted in a significant increase in craniofacial malformations which were prevented by concurrent Zn treatment.
The findings indicate that maternal liver MT levels are lowest in early gestation (before GD 10) making this a sensitive period where ethanol-induction of MT can affect fetal Zn homeostasis and cause fetal dysmorphology. The study further provides evidence of a protective role for Zn against ethanol-mediated teratogenicity.
A variety of drugs, environmental chemicals, and physical agents induce a common limb malformation in the offspring of pregnant mice exposed on day 9 of gestation. This malformation, postaxial, right-sided forelimb ectrodactyly, is thought to arise via an alteration of hedgehog signaling.
We have studied two of these teratogens, acetazolamide and cadmium, using the technique of microarray analysis of limb bud ectoderm and mesoderm to search for changes in gene expression that could indicate a common pathway to postaxial limb reduction.
Results indicated a generalized up-regulation of gene expression after exposure to acetazolamide but a generalized down-regulation due to cadmium exposure. An intriguing observation was a cadmium-induced reduction of Mt1 and Mt2 expression in the limb bud mesoderm indicating a lowering of embryonic zinc.
We propose that these two teratogens and others (valproic acid and ethanol) lower sonic hedgehog signaling by perturbation of zinc function in the sonic hedgehog protein.
We have previously demonstrated that ethanol teratogenicity is associated with metallothionein-induced fetal zinc (Zn) deficiency, and that maternal subcutaneous Zn treatment given with ethanol in early pregnancy prevents fetal abnormalities and spatial memory impairments in mice. Here we investigated whether dietary Zn supplementation throughout pregnancy can also prevent ethanol-related dysmorphology.
Pregnant mice were injected with saline or 25% ethanol (0.015 ml/g intraperitoneally at 0 and 4 hours) on gestational day (GD) 8 and fed either a control (35 mg Zn/kg) or a Zn-supplemented diet (200 mg Zn/kg) from GD 0 to 18. Fetuses from the saline, saline + Zn, ethanol and ethanol + Zn groups were assessed for external birth abnormalities on GD 18. In a separate cohort of mice, postnatal growth and survival of offspring from these treatment groups were examined from birth until postnatal day 60.
Fetuses from dams treated with ethanol alone in early pregnancy had a significantly greater incidence of physical abnormalities (26%) compared to those from the saline (10%), saline + Zn (9%), or ethanol + Zn (12%) groups. The incidence of abnormalities in ethanol + Zn-supplemented fetuses was not different from saline-treated fetuses. While ethanol exposure did not affect the number of fetal resorptions or pre- or postnatal weight, there were more stillbirths with ethanol alone, and cumulative postnatal mortality was significantly higher in offspring exposed to ethanol alone (35% deaths) compared to all other treatment groups (13.5 to 20.5% deaths). Mice supplemented with Zn throughout pregnancy had higher plasma Zn concentrations than those in un-supplemented groups.
These findings demonstrate that dietary Zn supplementation throughout pregnancy ameliorates dysmorphology and postnatal mortality caused by ethanol exposure in early pregnancy.
Although specific maternal infections during pregnancy have been associated with birth defects and other adverse pregnancy outcomes, the prevalence of infections during pregnancy has not been well described.
We estimated the prevalence of self-reported infection among 4967 women with live-born infants without major birth defects. We assessed the prevalence of reported infections and fever by type of infection, specific illness, and maternal characteristics including race and age.
Overall, 63.6% of women reported at least one infection during pregnancy. Reports of infections were more common during pregnancy than in the 3 months before pregnancy. Nearly half (49.6%) of women reported a respiratory infection, 20.5% reported a fever, 17.1% reported a urinary tract infection, 4.2% reported a yeast infection, and 3.4% reported a sexually transmitted disease. A subanalysis of self-reported infection and preterm delivery was performed among primiparous mothers with singleton pregnancies, but no statistically significant differences in infection prevalence were found. Women younger than 35 years reported nonrespiratory infections more frequently than women aged 35 years or older (prevalence ratio [PR] 1.41; 95% confidence interval [CI]: 1.21-1.64). Prevalence of nonrespiratory infections was also higher among those who smoked than among those who did not (PR 1.33; 95% CI: 1.20-1.47).
Reported infections during pregnancy are common, implying that a small increase in risk for birth defects or other adverse pregnancy outcomes could have a significant public health effect and underscoring the importance of understanding the effects of prenatal infections.
One of the goals of birth defects research is to better understand risk or preventive factors for birth defects so that strategies for prevention can be developed. In this article, we have selected four areas of birth defects research that have led to the development of prevention strategies. These areas include rubella virus as a cause of congenital rubella syndrome, folic acid as a preventive factor for neural tube defects, cytomegalovirus infection as a cause of birth defects and developmental disabilities, and alcohol as a cause of fetal alcohol spectrum disorders. For each of these areas, we review key clinical and research findings that led to the identification of the risk or preventive factor, milestones in the development of prevention strategies, and the progress made thus far toward prevention.
Prenatal alcohol exposure can affect brain development, leading to behavioral problems, including overactivity, motor dysfunction and learning deficits. Despite warnings about the effects of drinking during pregnancy, rates of fetal alcohol syndrome remain unchanged and thus, there is an urgent need to identify interventions that reduce the severity of alcohol's teratogenic effects. Insulin-like growth factor-I (IGF-I) is neuroprotective against ethanol-related toxicity and promotes white matter production following a number of insults. Given that prenatal alcohol leads to cell death and white matter deficits, the present study examined whether IGF-I could reduce the severity of behavioral deficits associated with developmental alcohol exposure. Sprague-Dawley rat pups received ethanol intubations (5.25 g/kg/day) or sham intubations on postnatal days (PD) 4-9, a period of brain development equivalent to the third trimester. On PD 10-13, subjects from each treatment received 0 or 10 microg IGF-I intranasally each day. Subjects were then tested on a series of behavioral tasks including open field activity (PD 18-21), parallel bar motor coordination (PD 30-32) and Morris maze spatial learning (PD 45-52). Ethanol exposure produced overactivity, motor coordination impairments, and spatial learning deficits. IGF-I treatment significantly mitigated ethanol's effects on motor coordination, but not on the other two behavioral tasks. These data indicate that IGF-I may be a potential treatment for some of ethanol's damaging effects, a finding that has important implications for children of women who drink alcohol during pregnancy.
Serum zinc concentrations in 234 gravidae showed a gradual fall during the first and second trimesters. From the 25th week of gestation until delivery there is a levelling out of mean zinc values. No correlations between serum zinc, serum HCS, or urinary excretion of oestriol were found. Women with mature infants born by normal delivery showed significantly higher serum zinc during pregnancy than women with abnormal deliveries and/or abnormally developed infants (p less than 0.001). Eight infants showed congenital malformations. Five of the 8 mothers showed the lowest serum zinc concentrations recorded during respective week of pregnancy. A diabetic woman gave birth to an immature infant with multiple skeletal malformations. She showed the lowest serum zinc in the 21st week, and at the same time a very low alkaline phosphatase activity. Her serum proteins and serum HCS were normal. Women with dysmature infants showed significantly lower zinc values during pregnancy (p less than 0.02) than women with mature infants born by normal delivery. Data from studies on zinc metabolism show that there is a requirement of at least 375 mg of zinc during pregnancy in order to meet the demands of normal weight gain. Teenagers, women with multiple pregnancies, women with impaired intestinal absorption due to disease or drugs and in particular women with a low-protein, high-phytate diet seem to risk developing zinc deficiency during pregnancy.
The authors report a case of nutritional zinc deficiency in a young (18-year-old) Turkish woman, who previously delivered 2 anencephalic stillborn infants. The patient was supplemented with 22.5 mg oral zinc sulfate (100 mg ZnSO4.7H2O) for 5 months after her second delivery prior to her third pregnancy. Her blood (plasma and red blood cell) and hair zinc levels returned to normal following zinc supplementation. Good response to Zn supplementation was another criterion of Zn deficiency in this particular case. After an uneventful gestational period, she delivered an apparently normal full-term male child who has grown normally during the first 12 months.