Alcohol abuse is a global problem, currently shows an upward trend in both the amount and rate of alcohol consumption per capita worldwide [1]. Almost any level of alcohol consumption is considered harmful, however, it is almost impossible to achieve this global goal of reducing alcohol consumption [1, 2]. More strikingly, the global rate of alcohol consumption among women during pregnancy is also increasing, and has hitherto reached 9.8% [3]. Accordingly, prenatal alcohol exposure (PAE) is also the most common cause of fetal origin disease [4].

Fetal Alcohol Spectrum Disorder (FASD) is a general term for multiple manifestations of fetal defects that is likely caused by PAE [5, 6]. Once aggravated with permanent neurological and birth defects, FASD will develop into FAS [5, 6]. Due to direct, lasting, multisystemic and irreversible damage to the embryo, the global prevalence of FASD is approximately 7.7 per 1000 population (95% CI, 4.9–11.7 per 1000 population), and varies by different regions [7, 8]. For instance, the developed regions such as Europe have the highest prevalence (19.8 per 1,000) and the Mediterranean region has the lowest prevalence (0.1 per 1,000) [8]. In a survey of mainstream elementary school in Manchester, UK, the crude prevalence of FASD reached an alarming 1.8% (95% CI: 1.0%, 3.4%) [9]. Based on a systematic review of 23,470 studies from Svetlana Popova, approximately 15% women who drink during pregnancy will give birth to children with Fetal Alcohol Syndrome (FAS) [3].

Although there are a variety of prenatal exposures which could cause embryonic neurodevelopmental disorders, in terms of exposure risk and degree of nerve damage, alcohol is more severe than other risky substances like tobacco and marijuana [10]. PAE often affects the neurological development of the embryo, resulting in FASD and even FAS, which is indicative of the most typical features, such as morphological changes, cognitive impairment, and behavioral deficit. Regarding abnormalities of these aspects, a study done by Amanda Facciol showed the aforementioned abnormalities in a zebrafish model with different alcohol gradients [11]. Notably, PAE remarkably affected genotypes, displaying a significant increase in anxiety-like behavior [11]. In addition, a systematic evaluation and comprehensive analysis of patients has demonstrated a causal relationship between PAE and fetal cognitive, learning, and memory deficits [12]. This implied that alcohol has a significant negative impact on neurodevelopment, which is proportional to the severity of PAE [13]. Concurrently, the complicated medical and social obstacles associated with FAS in children severely compromise their physical and mental development. A meta-analysis from Canada indicated that 428 comorbidities co-occur with FASD, which includes genetic, homeostatic, behavioral disorders and so on [14, 15]. Additionally, social issues such as dating, schooling, and maintaining stable employment will follow [16]. Given that the onset of FASD is mostly silent and undetectable and the underlying mechanism is still unknown, it is challenging to reduce the harmful use of alcohol for decrease of frequency of occurrence or presence of FASD. Presently, it has been shown that maternal alcohol consumption during pregnancy causes FASD, and chronic alcohol consumption by the father also causes FASD (This mainly ascribes to the effect of alcohol on the embryo through the father’s spermatogenesis) [17, 18]. Therefore, a better understanding of the molecular mechanisms underlying FASD is very important to prevent and treat FASD. Furthermore, it is imperative to explore effective treatment strategies for FASD and give patients with FASD some special cares at the societal level to reduce stigma, improve quality of life and prevent the occurrence of FASD in future generations [1, 14, 16, 19]. The multiple hazards brought by the aforementioned PAE and the challenge for treatment of FASD all imply an urgent need for immediate and efficient action to resolve this serious issue [20].

Owing to a serious disruption of PAE in embryo's brain development and the complexity of the pathogenesis, diagnosis and treatment FASD, a further understand the pathophysiology and pathogenesis of FASD is vital to develop optimal strategies to prevent, diagnose, and achieve breakthroughs of treatment of FASD. This review will focus mainly on the molecular mechanism of FASD pathogenesis, treatment, prevention and future research breakthroughs.

The search of cited research was conducted in electronic databases from dates April 2023: PubMed, MEDLINE, Embase, Web of Science Core Collection, Cochrane Database of Systematic Reviews. Title and abstract screening were performed in two stages by one reviewer, supported by a second reviewer. Full‐text screening, data extraction, and quality appraisal were performed by two reviewers independently. The papers selected were English language only.

Among a host of embryonic diseases, prenatal alcohol exposure (PAE) is the most frequent cause of a variety of non-genetic factors resulting in fetal neurodevelopmental or fetal neuro-related behavioral abnormalities. Alcohol could directly or indirectly impair development of embryos in utero in a multi-systemic, multi-faceted, and multi-level manner, leading to the development of FASD in the fetus after birth, or further developing into FAS [4]. The main mechanism of FASD is closely related with alcohol-induced neuroinflammation and oxidative stress, by which potentially result in neural cell apoptosis in the developing embryonic brain, thus impeding the development of the embryonic brain [7, 21]. Ethanol neurotoxicity is another major mechanism by which ethanol causes FASD by direct damage to various signaling pathways [7, 22]. Through several signal transduction pathways, including G protein-coupled receptor, tyrosine kinase receptor and insulin receptor, ethanol can subtly interfere with the normal development of the embryonic nervous system [23, 24]. In addition, through epigenetic mechanisms like aberrant DNA methylation and gene expression (transcription, translation, etc.), excessive alcohol use also impedes the neurological system development [7, 25, 26]. Although ethanol can cause extensive damage to normal tissues and cells, the exact mechanisms of alcohol neurotoxicity remain unknown. Therefore, more research needed to be further investigated.

In spite of alcohol consumed by the mother, the main composition of alcohol (ethanol and its metabolite acetaldehyde) has the ability to cross the placental barrier and directly harm an embryo's developing nervous system. The alcohol-Induced damage to the developing nervous system is associated with ethanol-induced oxidative stress and neurotoxicity which elicit varying degrees of neural cell apoptosis, degeneration or necrosis, eventually resulting in neurodevelopmental abnormalities and functional deficits [21, 22, 27]. Regarding this point, more PAE animal models and studies of children with FASD both demonstrate this standpoint [28, 29]. In short, ethanol could affect the development of nerve cells through various signaling pathways, eventually leading to a decrease of total numbers of neurons in the embryonic nervous system and the resultant neural dysfunction and neurodevelopmental defects in children.

The pathogenesis of FASD is mainly attributed to the autophagy of growing neurons following the inflammatory response caused by ethanol in the fetal body through oxidative stress, which is directly linked to the raise in reactive oxygen species (ROS) in the embryo after ethanol ingestion [21, 22]. It is reported that apart from reactive oxygen and nitrogen species, ROS includes at least one oxygen atom and one or more unpaired electrons, can live independently in the human body [30]. The group is generally composed of oxygen radicals, including hydroxyl, singlet oxygen, hydrogen peroxide, free nitrogen, and superoxide anion radicals. Consequently, ROS are the generic term for a group of substances [31]. Previously, ROS were considered as toxic byproducts of the body's oxygen metabolism, which could damage DNA directly or indirectly before causing cell death [32, 33]. However, with in-depth understanding of ROS, a growing number of studies showed that a particular biological level of ROS is constantly generated in the human body. As a signal molecule in numerous regular physiological processes of the human body, ROS are primarily produced by mitochondria and NADPH oxidase (NOX) in cells [30, 34, 35]. Each ROS has distinct biochemical properties and participates in various bodily physiological processes [31, 34, 35]. Once ROS level reaches physiological threshold concentration, it can function as anti-microbial effectors and signal molecules, and interacts with the protein complex nuclear transcription factor-kappa β (NF-β), which controls DNA transcription [34]. Notably, the body regular metabolism is mainly due to the balance between generation and removal of free radicals, which is conducive to natural selection through regulation of physiological differentiation and death of healthy cells [30, 31, 35]. However, once the equilibrium between antioxidant and oxidative factors or the generation and removal of ROS are disturbed, it will cause oxidative stress to harm the human body [36]. For instance, a long-term alcohol abuser’s body usually has a variety of oxidation/anti-oxidation imbalances [37]. In the research of PAE mice, the increased expression of different NOX subunits was found to result in excessive ROS production [38]. In addition, reduced expression of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase and catalase were identified [39]. This is likely to due to an imbalance ROS in the developing embryo resulting in oxidative damage. Based on these reports, we speculate the ROS in the embryo and uterus are more likely to be elevated as maternal alcohol abuse during pregnancy through the placental barrier, and the increased ROS breaks the equilibrium [21, 40]. As a result, the embryo development of different system including the nervous system are usually attacked [21, 40, 41]. In general, the numerous systems that are affected by oxidative stress produce an imbalance of ROS, resulting in cell death, vascular sclerosis, an increase in autoimmune illnesses, and others [41]. As a result, damage to the developing nerve system in the womb causes FASD [21, 40]. The damage to DNA and the damage triggered by associated inflammatory factors serve as the primary pathogenesis of the process of ROS-induced oxidative stress leading to FASD [41]. This mechanism of damage is thus called as embryonic pathological neurogenesis.

The damage caused by oxidative stress cascade serves as the primary pathogenesis of the process of ROS-induced oxidative insult leading to FASD. In studies on C57BL/6 mice with PAE, both Jian Dong and Liya Qin found that the mRNA expression of the catalytic and regulatory subunit of NADPH oxidase (NOX) was significantly increased; however, after treatment with NOX enzyme inhibitor, ROS production and oxidative DNA damage in mice were significantly reduced. In addition, the incidence of embryonic cell was also significantly reduced [42, 43]. Consistently, another study by Mara José Pérez, Roco Loyola, et al. also found that ethanol-induced oxidative stress, mitochondrial dysfunction, and damage to synaptic vesicle activity were all considerably reduced in the mice after treated with apocytin, a NADPH inhibitor [44]. These results demonstrate that exogenous ROS produced by the metabolism of NOX in cells, can result in cell DNA damage, apoptosis, and other damages, are increased by ethanol consumption (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

PAE also induces the generation of ROS. Concomitantly, ROS can result in oxidative stress, leading to DNA damage of cells and cognitive impairments in embryo. In the cell nucleus, chromatin DNA can be attacked by ROS, including DNA damage from direct attack and indirectly induced lipid peroxidation to produce lipid peroxyl radicals (LOO•) to further form multiple DNA adducts and thus cause cell damage [32, 33]. It was reported by Zhen Luo et al., that exogenous ROS were capable to eliciting the trophoblastic ectoderm cell cycle arrest in the S phase and G2/M phase, and increased the autophagic protein expression in the endoplasmic reticulum and the rate of ectoderm cell apoptosis [22, 45]. Nevertheless, the limitation of this study is not to precisely elucidate how ROS result in DNA damage. Subsequently, this question was addressed through a series of studies by Lutfiya Miller-Pinsler et al. They found that the most common exogenous ROS were verified as main source of the DNA damage, and the cognitive and behavioral deficits of the offspring of the CD-1 mouse model of PAE pretreatment with phenyl-N-tert-butyl nitrone (PBN; 40 mg/kg), a free radio spin trap which can reduce ROS, were dramatically reduced as compared to those of regular PAE animals [46]. Especially, PBN pretreatment decreased postnatal learning deficit (p < 0.01) and EtOH-induced DNA oxidation in the brains of children (p < 0.05) [46]. For substantiating the view, the oxyguanine glycosylase 1 (Ogg1) gene involved in DNA repair, was later knocked out. Encouragingly, the pathogenicity and level of 8-oxo-2'- deoxyguanosine (8-oxodGuo), a marker of DNA double-strand break, which is a major product of DNA oxidation and belongs to premutagenic damage, were both increased, indicating that serious DNA damage does exist in PAE mice [40, 47]. Based on the results, ROS arising from embryonic ethanol exposure will produce severe DNA damage of cells and cognitive impairments in children [40,