Fetal alcohol spectrum disorder predisposes to metabolic abnormalities in adulthood

Weeks, Olivia; Bossé, Gabriel D.; Oderberg, Isaac M.; Akle, Sebastian; Houvras, Yariv; Wrighton, Paul J.; LaBella, Kyle A.; Iversen, Isabelle; Tavakoli, Sahar; Adatto, Isaac; Schwartz, Arkadi; Kloosterman, Daan J.; Tsomides, Allison; Charness, Michael E.; Peterson, Randall T.; Steinhauser, Matthew L.; Fazeli, Pouneh K.; Goessling, Wolfram

doi:10.1172/jci132139

Cited by 35 publications

(35 citation statements)

References 92 publications

(98 reference statements)

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“…Different studies have found in rodents that these effects are maintained later in life, leading to an altered glucose metabolism with high gluconeogenesis, an altered lipid profile, impairments in insulin signaling (since insulin levels are increased) and GLUT4 expression, an increase in resistin serum levels without affecting leptin levels, an imbalance in the plasma lipid profile, which induces liver steatosis, and to an enhanced susceptibility to IR due to the hypothalamic generation of OS, which affects HPA axis-associated neuroendocrine metabolism [ 169 , 170 , 171 , 172 , 173 ]. Similar results have been found in humans [ 174 , 175 ]. Some of these effects have also been confirmed when pups were exposed to EtOH only during the lactation period [ 170 ].…”

Section: Oxidative Stress-programming Pathologies and Sesupporting

confidence: 91%

Fetal Programming Is Deeply Related to Maternal Selenium Status and Oxidative Balance; Experimental Offspring Health Repercussions

et al. 2021

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Nutrients consumed by mothers during pregnancy and lactation can exert permanent effects upon infant developing tissues, which could represent an important risk factor for diseases during adulthood. One of the important nutrients that contributes to regulating the cell cycle and tissue development and functionality is the trace element selenium (Se). Maternal Se requirements increase during gestation and lactation. Se performs its biological action by forming part of 25 selenoproteins, most of which have antioxidant properties, such as glutathione peroxidases (GPxs) and selenoprotein P (SELENOP). These are also related to endocrine regulation, appetite, growth and energy homeostasis. In experimental studies, it has been found that low dietary maternal Se supply leads to an important oxidative disruption in dams and in their progeny. This oxidative stress deeply affects gestational parameters, and leads to intrauterine growth retardation and abnormal development of tissues, which is related to endocrine metabolic imbalance. Childhood pathologies related to oxidative stress during pregnancy and/or lactation, leading to metabolic programing disorders like fetal alcohol spectrum disorders (FASD), have been associated with a low maternal Se status and intrauterine growth retardation. In this context, Se supplementation therapy to alcoholic dams avoids growth retardation, hepatic oxidation and improves gestational and breastfeeding parameters in FASD pups. This review is focused on the important role that Se plays during intrauterine and breastfeeding development, in order to highlight it as a marker and/or a nutritional strategy to avoid diverse fetal programming disorders related to oxidative stress.

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Section: Oxidative Stress-programming Pathologies and Sesupporting

confidence: 91%

Fetal Programming Is Deeply Related to Maternal Selenium Status and Oxidative Balance; Experimental Offspring Health Repercussions

et al. 2021

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“…However, FASD is increasingly being recognized as a ‘whole-body’ disorder, rather than simply a brain-based disorder. Studies in both animal models and human populations have documented cardiovascular ( Walton et al, 2019 ), renal ( Gray et al, 2010 ), pulmonary ( Gauthier and Brown, 2017 ) and metabolic dysfunction ( Weeks et al, 2020 ) including impaired glucose tolerance ( Gardebjer et al, 2015 ), with insulin insensitivity ( Nguyen et al, 2019 , Weeks et al, 2020 ). PAE has also been shown to alter the endocrine function within the hypothalamic–pituitaryadrenal axis ( Weinberg, 1993 , Weinberg et al, 2008 ) and to disrupt the developing immune system ( Ahluwalia et al, 2000 , Bodnar et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Prenatal alcohol-induced sex differences in immune, metabolic and neurobehavioral outcomes in adult rats

Bake

Pinson

Pandey

et al. 2021

Brain, Behavior, and Immunity

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Prenatal alcohol exposure (PAE) can result in neurobehavioral anomalies, that may be exacerbated by co-occurring metabolic and immune system deficits. To test the hypothesis that the peripheral inflammation in adult PAE offspring is linked to poor glucose metabolism and neurocognitive deficits, pregnant Sprague-Dawley rats were exposed to ethanol vapor or ambient air during the latter half of gestation. We assessed, in adult offspring of both sexes, performance on a battery of neurocognitive behaviors, glucose tolerance, circulating and splenic immune cells by flow-cytometry, and circulating and tissue (liver, mesenteric adipose, and spleen) cytokines by multiplexed assays. PAE reduced both the ratio of spleen to body weight and splenic regulatory T-cell (Treg) numbers. PAE males, but not females exhibited an increase in circulating monocytes. Overall, PAE males exhibited a suppression of cytokine levels, while PAE females exhibited elevated cytokines in mesenteric adipose tissue (IL-6 and IL1α) and liver (IFN-γ, IL-1β, IL-13, IL-18, IL-12p70, and MCP-1), along with increased glucose intolerance. Behavioral analysis also showed sex-dependent PAE effects. PAE-males exhibited increased anxiety-like behavior while PAE-females showed decreased social interaction. PAE offspring of both sexes exhibited impaired recognition of novel objects. Multilinear regression modeling to predict the association between peripheral immune status, glucose intolerance and behavioral outcomes, showed that in PAE offspring, higher levels of adipose leptin and liver TNF- α predicted higher circulating glucose levels. Lower liver IL-1 α and higher plasma fractalkine predicted more time spent in the center of an open-field with sex being an additional predictor. Higher circulating and splenic Tregs predicted better social interaction in the PAE-offspring. Collectively, our data show that peripheral immune status is a persistent, sex-dependent predictor of glucose intolerance and neurobehavioral function in adult PAE offspring.

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“…Sex differences and sex by PAE interactions were not able to be assessed in this analysis due to the limited number of subjects. Previous research has indicated that sex may alter the impact of PAE on metabolic functioning with females having evidence of increased vulnerability (Weeks et al, 2020). Although the distribution of individual subject data in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The impact of PAE on adipose tissue may also be an important area of investigation as it plays a role in insulin resistance through adipokines, which influence glucose metabolism (Leal Vde and Mafra, 2013). In a zebrafish model, PAE was found to alter visceral adipose tissue (Weeks et al, 2020), leading to abdominal obesity.…”

Section: Discussionmentioning

confidence: 99%

“…A survey of 300 adults with FASD found increased rates of autoimmune disorders, cardiovascular disease, diabetes, thyroid disorders, digestive disorders, and mental health problems (Himmelreich et al, 2016). In another study, an archival review of medical records found that adult individuals diagnosed with an FASD were more likely to be diagnosed with type II diabetes mellitus after controlling for body mass index (BMI) but only in males (Weeks et al, 2020). Although these reports are suggestive of a link between PAE and adult‐disease onset, consistent with the developmental origins health and disease model (DOHaD) (Barker, 1990), prospective exposure cohorts of prenatal alcohol followed beyond their 20s are limited (Das et al, 2019), making it difficult to understand the nature, range, and mechanisms by which these vulnerabilities interact and play out over the course of the individual’s lifespan.…”

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confidence: 99%

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Alterations in Insulin Levels in Adults with Prenatal Alcohol Exposure

Kable

Mehta

Coles

2021

Alcoholism Clin & Exp Res

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Objective Evidence suggests that prenatal alcohol exposure (PAE) may adversely impact insulin production and signaling but there is limited information on the range of these effects and their future health consequences. Method A prospective cohort of predominantly African‐American individuals identified while in utero and followed into adulthood were used to evaluate differences in various indicators of diabetes, including fasting plasma glucose, hemoglobin A1c (HbA1c), and insulin levels. The homeostatic model assessment of insulin resistance (HOMA‐IR) was also computed. Body mass index (BMI) was calculated and normal defined as < 25 kg/m2. Participants were categorized as having PAE (n = 39) if their mothers drank at least 1 ounce of absolute alcohol per week or more during the 1st trimester of pregnancy and as Controls (n = 22) if their mothers reported abstaining from alcohol consumption during pregnancy. Results Mean age of the sample was 36.0 ± 1.5 years. Indices of glucose metabolism, including fasting plasma glucose and hemoglobin A1c levels, did not vary by group status but insulin levels and HOMA‐IR values varied by group status and BMI level. PAE individuals with a normal BMI had lower insulin levels than Controls. However, in PAE subjects, there was a steeper increase in insulin levels relative to their BMI than in Control subjects. A cluster of 5 PAE cases had low levels of insulin and 4 of the 5 had severe cognitive impairment. Conclusions The bidirectional effects on insulin level and insulin resistance associated with PAE may indicate differential rates of diabetes disease impact or differential PAE impact in the brain and peripheral areas involved in insulin production and signaling. These alterations may contribute to the metabolic disease risk associated with PAE.

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Fetal alcohol spectrum disorder predisposes to metabolic abnormalities in adulthood

Cited by 35 publications

References 92 publications

Fetal Programming Is Deeply Related to Maternal Selenium Status and Oxidative Balance; Experimental Offspring Health Repercussions

Fetal Programming Is Deeply Related to Maternal Selenium Status and Oxidative Balance; Experimental Offspring Health Repercussions

Prenatal alcohol-induced sex differences in immune, metabolic and neurobehavioral outcomes in adult rats

Alterations in Insulin Levels in Adults with Prenatal Alcohol Exposure

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