An overview of current advances in perinatal alcohol exposure and pathogenesis of fetal alcohol spectrum disorders

Abstract

The adverse use of alcohol is a serious global public health problem. Maternal alcohol consumption during pregnancy usually causes prenatal alcohol exposure (PAE) in the developing fetus, leading to a spectrum of disorders known as fetal alcohol spectrum disorders (FASD) and even fetal alcohol syndrome (FAS) throughout the lifelong sufferers. The prevalence of FASD is approximately 7.7 per 1,000 worldwide, and is even higher in developed regions. Generally, Ethanol in alcoholic beverages can impair embryonic neurological development through multiple pathways leading to FASD. Among them, the leading mechanism of FASDs is attributed to ethanol-induced neuroinflammatory damage to the central nervous system (CNS). Although the underlying molecular mechanisms remain unclear, the remaining multiple pathological mechanisms is likely due to the neurotoxic damage of ethanol and the resultant neuronal loss. Regardless of the molecular pathway, the ultimate outcome of the developing CNS exposed to ethanol is almost always the destruction and apoptosis of neurons, which leads to the reduction of neurons and further the development of FASD. In this review, we systematically summarize the current research progress on the pathogenesis of FASD, which hopefully provides new insights into differential early diagnosis, treatment and prevention for patents with FASD.

Keywords: Alcohol spectrum disorder; Fetal alcohol syndrome; Neuroinflammation; Neurotoxicity; Pathogenesis; Prenatal alcohol exposure.

Fig. 1

The damage of ROS from ethanol metabolism to neuronal development through multiple pathways. a Ethanol decreases the level of antioxidant enzymes in the embryo; b Ethanol is metabolized by NADPH oxidase in mitochondria to produce excessive by-products of ROS; c Overabundant ROS can enter the nuclei and directly attack dsDNA causing diverse types of DNA damage; d Overabundant ROS can catch H chain from lipids and peroxidize them to produce LOO; e The LOO ·produced bind to DNA to generate DNA adducts that indirectly damage dsDNA; f Overabundant ROS activates microglia via PRRs on the microglia membrane

Fig. 2

The FASD pathways of Ethanol-mediated neurotoxicity. a Ethanol causes an increase in the phosphorylation level of S1152, resulting in the structural domain ECD sensitive to ethanol more bound; b Ethanol binding ECD Ig-4 impairs the biofunction of NCAM; c Ethanol directly drives DNA methylation transferase to increase the methylation of genes; d Ethanol directly attacks DNA and its histones, causing cell cycle arrest and DNA breakage; e Ethanol causes a decrease in NF-κB through the cAMP/PKA pathway by targeting the promoter EGR1,miR-145, etc.; f Ethanol can hypersensitize the HPAA axis and consequently increase GABAergic interneuron; g Ethanol inhibits the IGF-IGFBP pathway and decreases the levels of NGF, BDNF, resulting in neuronal undernutrition and dysplasia

Fig. 3

Ethanol causes migration and ectopia of inhibitory neurons. a Ethanol breaks blood–brain barrier to enter embryonic brain; b Ethanol hypersensitizes the HPAA axis and causes the generation of GABA interneurons and ectopic to the frontal cortex

Fig. 4

Ethanol elicits neuronal apoptosis through regulating calcium mobilization and G protein-coupled receptor driving cascades. a Calcium mobilization promotes cellular recruitment of extracellular Ca2 + ; b CaMKII hyperphosphorylation and activation leads to phosphorylated β-linked proteins, reducing their stability