Abstract
Fetal alcohol spectrum disorder is the main preventable cause of intellectual disability in the Western world. Although binge drinking is the most studied prenatal alcohol exposure pattern, other types of exposure, such as the Mediterranean, are common in specific geographic areas. In this study, we analyze the effects of prenatal alcohol exposure in binge and Mediterranean human drinking patterns on placenta and brain development in C57BL/6J mice. We also assess the impact of prenatal treatment with the epigallocatechin-3-gallate antioxidant in both groups. Study experimental groups for Mediterranean or binge patterns: (1) control; (2) ethanol; (3) ethanol + epigallocatechin-3-gallate. Brain and placental tissue were collected on gestational Day 19. The molecular pathways studied were fetal and placental growth, placental angiogenesis (VEGF-A, PLGF, VEGF-R), oxidative stress (Nrf2), and neurodevelopmental processes including maturation (NeuN, DCX), differentiation (GFAP) and neural plasticity (BDNF). Prenatal alcohol exposure resulted in fetal growth restriction and produced imbalances of placental angiogenic factors. Moreover, prenatal alcohol exposure increased oxidative stress and caused significant alterations in neuronal maturation and astrocyte differentiation. Epigallocatechin-3-gallate therapy ameliorated fetal growth restriction, attenuated alcohol-induced changes in placental angiogenic factors, and partially rescued neuronal nuclear antigen (NeuN), (doublecortin) DCX, and (glial fibrillary acidic protein) GFAP levels. Any alcohol consumption (Mediterranean or binge) during pregnancy may generate a fetal alcohol spectrum disorder phenotype and the consequences may be partially attenuated by a prenatal treatment with epigallocatechin-3-gallate.
Highlights
The most commonly used teratogen, triggers many deleterious effects in the offspring when consumed during pregnancy, with the consequences falling under the umbrella of fetal alcohol spectrum disorder (FASD) [1], of which fetal alcohol syndrome (FAS) is the most severe form of prenatal alcohol exposure (PAE) impairment
Ethanol may alter the expression of a wide range of neural biomarkers, e.g., the neuronal nuclear antigen (NeuN) [13], doublecortin (DCX) [14], glial fibrillary acidic protein (GFAP) [15], and the brain-derived neurotrophic factor (BDNF) [16], as well as of the oxidative stress biomarkers, e.g., the nuclear factor erythroid 2-related factor 2 (Nrf2) [17]
EGCG ameliorates fetal growth restriction (FGR) produced by PAE and attenuates ethanol-related changes in vascular endothelial growth factor A (VEGF-A) and VEGF-R1 expression, partially restoring the imbalance produced by PAE
Summary
The most commonly used teratogen, triggers many deleterious effects in the offspring when consumed during pregnancy, with the consequences falling under the umbrella of fetal alcohol spectrum disorder (FASD) [1], of which fetal alcohol syndrome (FAS) is the most severe form of prenatal alcohol exposure (PAE) impairment. FASD in vitro and animal model studies have shown the detrimental effects of PAE on placental size, structure, and function [3] and alterations in the methylation pattern of placental genes affecting its growth and on fetal development [4,5,6]. PAE affects the central nervous system in all stages of brain development (neurulation, proliferation, migration, differentiation, synaptogenesis, gliogenesis, myelination, apoptosis, and plasticity) through a variety of mechanisms that include oxidative stress and the direct alteration of the epigenetic pattern in the neural lineages [11,12]. Ethanol may alter the expression of a wide range of neural biomarkers, e.g., the neuronal nuclear antigen (NeuN) [13], doublecortin (DCX) [14], glial fibrillary acidic protein (GFAP) [15], and the brain-derived neurotrophic factor (BDNF) [16], as well as of the oxidative stress biomarkers, e.g., the nuclear factor erythroid 2-related factor 2 (Nrf2) [17]
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