Physiological mediators of prenatal environmental influences in autism spectrum disorder

Frye, Richard E.; Cakir, Janet; Rose, Shannon; Palmer, Raymond F.; Austin, Christine; Curtin, Paul

doi:10.1002/bies.202000307

Cited by 17 publications

(11 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The prevalence of ASD has steadily increased for the last decades [ 111 , 112 ]. Prenatal and early postnatal exposure to negative environmental factors, such as pollutants, chemical agents, infections, immune activation, and epigenetics have been associated with ASD [ 113 , 114 , 115 ]. These environmental factors, e.g., exposure to pesticides [ 116 ], maternal cigarette smoking [ 117 ], infective agents [ 63 , 64 , 65 , 66 , 67 , 68 , 69 ], and immune stimulation [ 58 ], exhibit a significant impact on HERV expression.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Expression of Human Endogenous Retroviruses, TRIM28 and SETDB1 in Autism Spectrum Disorder

Tovo

Davico

Marcotulli

et al. 2022

IJMS

View full text Add to dashboard Cite

Human endogenous retroviruses (HERVs) are relics of ancestral infections and represent 8% of the human genome. They are no longer infectious, but their activation has been associated with several disorders, including neuropsychiatric conditions. Enhanced expression of HERV-K and HERV-H envelope genes has been found in the blood of autism spectrum disorder (ASD) patients, but no information is available on syncytin 1 (SYN1), SYN2, and multiple sclerosis-associated retrovirus (MSRV), which are thought to be implicated in brain development and immune responses. HERV activation is regulated by TRIM28 and SETDB1, which are part of the epigenetic mechanisms that organize the chromatin architecture in response to external stimuli and are involved in neural cell differentiation and brain inflammation. We assessed, through a PCR realtime Taqman amplification assay, the transcription levels of pol genes of HERV-H, -K, and -W families, of env genes of SYN1, SYN2, and MSRV, as well as of TRIM28 and SETDB1 in the blood of 33 ASD children (28 males, median 3.8 years, 25–75% interquartile range 3.0–6.0 y) and healthy controls (HC). Significantly higher expressions of TRIM28 and SETDB1, as well as of all the HERV genes tested, except for HERV-W-pol, were found in ASD, as compared with HC. Positive correlations were observed between the mRNA levels of TRIM28 or SETDB1 and every HERV gene in ASD patients, but not in HC. Overexpression of TRIM28/SETDB1 and several HERVs in children with ASD and the positive correlations between their transcriptional levels suggest that these may be main players in pathogenetic mechanisms leading to ASD.

show abstract

Section: Discussionmentioning

confidence: 99%

Enhanced Expression of Human Endogenous Retroviruses, TRIM28 and SETDB1 in Autism Spectrum Disorder

Tovo

Davico

Marcotulli

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…However, in addition to genetic factors, studies conducted to date indicate that environmental pollutants may also be involved as risk factors in the etiology of autism. For example, previous studies have shown that environmental pollutants can cause oxidative damage to DNA, disrupt epigenetic mechanisms (i.e., DNA methylation), and induce systemic neuroinflammation (for example, through the up/downregulation of cytokines) (Biswas, 2016; Frye et al, 2021; Theoharides et al, 2013); all of these mechanisms are known to be involved in the etiology and pathogenesis of autism. Two Chinese mother–child cohorts have similarly demonstrated that exposure to PAHs is associated with disruption of LINE1 methylation during neurodevelopment, which might disturb or aggravate alterations to normal neuronal plasticity and diversity (Kalia et al, 2017; Lee et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Association of urinary polycyclic aromatic hydrocarbon metabolites with symptoms among autistic children: A case–control study in Tianjin, China

Yang

et al. 2022

Autism Research

View full text Add to dashboard Cite

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants that are associated with altered neurodevelopment and various neurodevelopmental disorders. However, studies evaluating internal biomarkers of PAH exposure in reference to the severity of autism spectrum disorder (ASD) symptomology and autistic behaviors are scarce. Hence, we conducted a case-control study evaluating 12 urinary hydroxylated PAH metabolites (i.e., hydroxy-PAHs) in 101 children with autism and 101 neurotypical children, matching according to sex and age in a 1:1 ratio. In children with ASD, the severity of symptomology and autistic behaviors were assessed using the child autism rating scale (CARS) and the autism behavior checklist (ABC). We found that urinary levels of nine of the hydroxy-PAHs were statistically significantly higher in the ASD group, with the exception of 2-hydroxynaphthalene (2-OHNap) and 4-hydroxyphenanthrene (4-OHPhe). Moreover, urinary hydroxy-PAH levels were associated with ASD risk, with odds ratios ranging from 1.86 to 17.19. Exposures to 1-hydroxynaphthalene (1-OHNap, β = 3.32), hydroxyphenanthrenes (1/2/3 + 9-OHPhes, β = 3.41-5.12), 1-hydroxypyrene (1-OH-Pyr; β = 3.91), 2-hydroxybenzofuran (2-OHDBF; β = 3.93), and P OH-PAHs (β = 4.67) were positively associated with CARS scores after adjusting for covariates (all p < 0.05). When applying the ABC scale, 1-OHPyr levels were positively associated with ABC total scores (β = 18.54), with the strongest associations evidenced in regard to the social relatedness (β = 6.51) and language domains (β = 6.51) (all p < 0.05). Bayesian kernel machine regression (BKMR) showed consistent positive exposure responses for 1-OHNap, 1-OHPhe, and 3 + 9-OHPhe levels in regard to CARS scores, and for 1-OHPyr levels in regard to ABC total scores. Our findings suggest that children with ASD may have higher urinary levels of hydroxy-PAHs, and that these biomarker levels are associated with an increased odds of ASD, an increased severity of autism symptomology, and increased autistic behaviors in children with autism. K E Y W O R D S autism spectrum disorder, behavioral characteristics, case-control study, children, internal exposure, polycyclic aromatic hydrocarbon Peiying Li and Qiaoyun Yang contributed equally to this work, and they shared co-first authorship.

show abstract

“…The fact that there is high heritability within families has driven the search for a genetic cause for ASD, but the empirical evidence suggests that the etiology is much more complex than a simple Mendelian inherited disorder [ 13 ]. Evidence now points to the importance of environmental–genetic interactions playing a prominent role in the etiology of ASD [ 14 ], particularly the prenatal environment [ 15 ]. Third, it is becoming clear that many children with ASD are medically complex [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

A Personalized Multidisciplinary Approach to Evaluating and Treating Autism Spectrum Disorder

Frye

2022

JPM

Self Cite

View full text Add to dashboard Cite

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder without a known cure. Current standard-of-care treatments focus on addressing core symptoms directly but have provided limited benefits. In many cases, individuals with ASD have abnormalities in multiple organs, including the brain, immune and gastrointestinal system, and multiple physiological systems including redox and metabolic systems. Additionally, multiple aspects of the environment can adversely affect children with ASD including the sensory environment, psychosocial stress, dietary limitations and exposures to allergens and toxicants. Although it is not clear whether these medical abnormalities and environmental factors are related to the etiology of ASD, there is evidence that many of these factors can modulate ASD symptoms, making them a potential treatment target for improving core and associated ASD-related symptoms and improving functional limitation. Additionally, addressing underlying biological disturbances that drive pathophysiology has the potential to be disease modifying. This article describes a systematic approach using clinical history and biomarkers to personalize medical treatment for children with ASD. This approach is medically comprehensive, making it attractive for a multidisciplinary approach. By concentrating on treatable conditions in ASD, it is possible to improve functional ability and quality of life, thus providing optimal outcomes.

show abstract

Physiological mediators of prenatal environmental influences in autism spectrum disorder

Cited by 17 publications

References 97 publications

Enhanced Expression of Human Endogenous Retroviruses, TRIM28 and SETDB1 in Autism Spectrum Disorder

Enhanced Expression of Human Endogenous Retroviruses, TRIM28 and SETDB1 in Autism Spectrum Disorder

Association of urinary polycyclic aromatic hydrocarbon metabolites with symptoms among autistic children: A case–control study in Tianjin, China

A Personalized Multidisciplinary Approach to Evaluating and Treating Autism Spectrum Disorder

Contact Info

Product

Resources

About