Influence of Prenatal Drug Exposure, Maternal Inflammation, and Parental Aging on the Development of Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) affects reciprocal social interaction and produces abnormal repetitive, restrictive behaviors and interests. The diverse causes of ASD are divided into genetic alterations and environmental risks. The prevalence of ASD has been rising for several decades, which might be related to environmental risks as it is difficult to consider that the prevalence of genetic disorders related to ASD would increase suddenly. The latter includes (1) exposure to medications, such as valproic acid (VPA) and selective serotonin reuptake inhibitors (SSRIs) (2), maternal complications during pregnancy, including infection and hypertensive disorders of pregnancy, and (3) high parental age. Epidemiological studies have indicated a pathogenetic role of prenatal exposure to VPA and maternal inflammation in the development of ASD. VPA is considered to exert its deleterious effects on the fetal brain through several distinct mechanisms, such as alterations of γ-aminobutyric acid signaling, the inhibition of histone deacetylase, the disruption of folic acid metabolism, and the activation of mammalian target of rapamycin. Maternal inflammation that is caused by different stimuli converges on a higher load of proinflammatory cytokines in the fetal brain. Rodent models of maternal exposure to SSRIs generate ASD-like behavior in offspring, but clinical correlations with these preclinical findings are inconclusive. Hypertensive disorders of pregnancy and advanced parental age increase the risk of ASD in humans, but the mechanisms have been poorly investigated in animal models. Evidence of the mechanisms by which environmental factors are related to ASD is discussed, which may contribute to the development of preventive and therapeutic interventions for ASD.

Neuroinflammation and Oxidative Stress in the Pathogenesis of Autism Spectrum Disorder

“…Lipopolysaccharide (LPS) is a molecule composed of lipids and carbohydrates found on the cell wall surface of Gram-negative bacteria such as Escherichia coli , and mimics bacterial infection to induce inflammation [ 54 ]. LPS is also used a reagent for making animal models of MIA [ 55 ], and it regulates inflammation and immunity by activating downstream signals through toll-like receptor 4 (TLR4) [ 39 , 54 ]. Administration of either LPS or poly(I:C) are commonly used methods to induce MIA, and the phenotype of ASD model animals obtained by both is similar [ 56 ].…”

“…In the preclinical studies of ASD, antioxidant effects have been reported using ASD model animals ( Table 2 ). Valproic acid (VPA) exposure during pregnancy increases the risk of ASD in offspring (VPA mice or rats), which has been widely used as a method for producing ASD model animals [ 10 , 55 ]. In VPA-induced ASD model mice, HRW administration improved ASD-like behaviors such as social behavior and pain sensation as well as anxiety-like behavior and memory impairment and IL-6 and TNF-α inflammatory cytokines [ 183 ].…”

Recent Developments in Autism Genetic Research: A Scientometric Review from 2018 to 2022

“…The major citing documents for Clusters #4 and #6 are authored by St. Clair and Johnstone [ 108 ] (coverage = 22; GCS = 13) and Lord et al [ 109 ] (coverage = 23; GCS = 211), respectively. While Clusters #4 and #6 were originally labelled “Valproic Acid” and “Brain Organoid”, respectively, a more representative label for both clusters may be “Stem Cell Technology”, as papers in the two clusters focus on the exposure of stem cells to various molecules, including valproic acid (a molecule that is associated with higher likelihood of developing ASD [ 110 ]), to investigate the development of ASD-like phenotypes [ 108 , 111 , 112 , 113 , 114 ]. Papers in Cluster #4 use stem cells to mimic the prenatal development processes in order to trace the pathogeneses of ASD.…”

mTOR Signaling Disruption and Its Association with the Development of Autism Spectrum Disorder

“…The various non-genetic elements mediating ASD risk comprise of parental age, maternal nutritional status, infections during pregnancy, and exposure to certain toxins, heavy metals, or drugs [ 30 ]. Clinical investigations reveal an imbalance in the microbiota of ASD individuals [ 31 ].…”