Strain‐specific vulnerability to alcohol exposure in utero via hippocampal parent‐of‐origin expression of deiodinase‐III

Abstract

Prenatal exposure to alcohol is thought to be the most prevalent nongenetic cause of a wide range of neurodevelopmental deficits. Insufficient thyroid hormone levels are one mechanism that hampers development of the alcohol-exposed brain, and we hypothesized that altered dosage of the imprinted thyroid hormone-inactivating gene deiodinase-III (Dio3) is responsible. To follow parent-of-origin allelic expression of Dio3 in the fetal and adult offspring of alcohol-consuming and control dams, we reciprocally crossed 2 polymorphic rat strains. In the frontal cortex, prenatal alcohol exposure altered imprinting patterns and total expression of Dio3 in the fetus and produced a permanent hypothyroid milieu in the adult. In the hippocampus, alcohol affected the paternal and total expression of Dio3 in the fetus and in the adult male, where thyroid hormone levels were concomitantly increased. Hippocampus-dependent behavioral deficits were identified exclusively in males, suggesting they are dependent on aberrant allelic Dio3 expression. None of these effects were observed in offspring of the reciprocal cross. Thus, genetic background and sex modify vulnerability to prenatal alcohol via brain region-specific expression of Dio3. This finding implies that phenotypic heterogeneity in human fetal alcohol spectrum disorder can be linked to genetic vulnerability in affected brain regions.

Maternal Inheritance of an Inactive Type III Deiodinase Gene Allele Affects Mouse Pancreatic β-Cells and Disrupts Glucose Homeostasis

“…In fact, this was confirmed when different in vitro systems were used to assess the impact of increased thyroid hormone signaling in the ␤-cells. Exposing pancreatic explants (Figure 4, A and B), isolated pancreatic islets (Figure 4, C-G), or D3-expressing It is interesting that Dio3 is paternally imprinted in the mouse heart (10) and, in turn, maternally imprinted in the pancreatic ␤-cells, which is in agreement with reports that Dio3 expression is biallelic or maternally expressed in certain areas of the brain (23,24). In fact, the mechanisms involved in the allelic-specific Dio3 expression are complex.…”

“…The paternal allele contribution of Dio3 is 84% in embryonic mouse tissue, whereas in placenta it varies between 50% and 67% (22). At the same time, Dio3 expression has been reported to be biallelic or even maternally expressed in certain areas of the brain (23,24). These different imprinting patterns have led to the study of heterozygous (Htz)-D3KO animals, with the advantage that these animals exhibit normal thyroid economy (10).…”

Modeling Fetal Alcohol Spectrum Disorder: Validating an Ex Vivo Primary Hippocampal Cell Culture System

“…Additionally, impaired hippocampus-dependent spatial and social learning/memory is shown both in animal models of FASD (Wilcoxon et al, 2005, Sittig et al, 2011b, Weeber et al, 2001, Tunc-Ozcan et al, 2013) and FASD patients (Hamilton et al, 2003). It appears likely that many of the cognitive and behavioral deficits of FASD may involve the compromised neurodevelopment of the hippocampus.…”

Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain

“…Clinical (21, 30, 52) and preclinical (4, 23, 33, 35, 46) studies have reported that fetal programming by alcohol results in HPA dysregulation, including both hyperresponsiveness to stressors and deficits in recovery to basal levels. While mechanisms mediating these adverse effects of alcohol are starting to be elucidated (23,55,59,60,71), the molecular pathology underlying fetal alcohol effects on the HPA axis is not fully understood.Accumulating evidence suggests that the interplay between environmental factors and epigenetic processes, such as DNA methylation and chromatin modifications, could play a role in mediating the adverse effects of PAE, including its effects on HPA regulation (20,22,38). Alcohol-induced alterations in one-carbon metabolism provide one potential link between alcohol exposure and epigenetic processes.…”

“…Clinical (21,30,52) and preclinical (4,23,33,35,46) studies have reported that fetal programming by alcohol results in HPA dysregulation, including both hyperresponsiveness to stressors and deficits in recovery to basal levels. While mechanisms mediating these adverse effects of alcohol are starting to be elucidated (23,55,59,60,71), the molecular pathology underlying fetal alcohol effects on the HPA axis is not fully understood.…”