Developmental pyrethroid exposure and age influence phenotypes in a Chd8 haploinsufficient autism mouse model

Abstract

Hundreds of genes have been associated with autism spectrum disorder (ASD), including loss-of-function mutations in chromodomain helicase DNA binding protein 8 (Chd8). Environmental factors also are implicated in autism risk and have the potential to exacerbate phenotypes in genetically sensitized backgrounds. Here we investigate transcriptional and behavioral phenotypes in a Chd8 haploinsufficient (Chd8V986*/+) mouse line exposed to the pesticide deltamethrin (DM) from conception to postnatal day 22. Vehicle-exposed Chd8V986*/+ mice displayed ASD-associated phenotypes, including anxiety-like behavior and altered sociability, replicating a previous study with this mouse line. A core set of genes was altered in Chd8V986*/+ mice at multiple ages, including Usp11, Wars2, Crlf2, and Eglf6, and proximity ligation data indicated direct binding of CHD8 to the 5’ region of these genes. Moreover, oligodendrocyte and neurodegenerative transcriptional phenotypes were apparent in 12 and 18 month old Chd8V986*/+ mice. Following DM exposure, the mutant mice displayed an exacerbated phenotype in the elevated plus maze, and genes associated with vascular endothelial cells were downregulated in the cerebral cortex of older Chd8V986*/+ animals. Our study reveals a gene x environment interaction with a Chd8 haploinsufficient mouse line and points to the importance of investigating phenotypes in ASD animal models across the lifespan.

Age-differential sexual dimorphisms in CHD8-S62X-mutant mouse synapses and transcriptomes

“…Previous studies on Chd8 -mutant mice and human neurons suggested multiple mechanisms that may underlie CHD8-related brain deficits ( Sugathan et al, 2014 ; Cotney et al, 2015 ; Wang et al, 2015 ; Breuss and Gleeson, 2016 ; Durak et al, 2016 ; Katayama et al, 2016 ; Gompers et al, 2017 ; Platt et al, 2017 ; Wang et al, 2017 ; Andreae and Basson, 2018 ; Jung et al, 2018 ; Suetterlin et al, 2018 ; Wade et al, 2018 ; Xu et al, 2018 ; Zhao et al, 2018 ; Hulbert et al, 2020 ; Jimenez et al, 2020 ; Sood et al, 2020 ; Cherepanov et al, 2021 ; Ding et al, 2021 ; Ellingford et al, 2021 ; Hurley et al, 2021 ; Kawamura et al, 2021 ; Kweon et al, 2021 ; Weissberg and Elliott, 2021 ; Chen et al, 2022 ; Coakley-Youngs et al, 2022 ; Dong et al, 2022 ; Haddad Derafshi et al, 2022 ; Jimenez et al, 2022 ; Kerschbamer et al, 2022 ; Lee et al, 2022 ; Paulsen et al, 2022 ; Thudium et al, 2022 ; Tu et al, 2022 ; Villa et al, 2022 ; Yu et al, 2022 ; Hayot et al, 2023 ). However, mechanisms underlying the male–female differences in CHD8-related ASD are poorly understood ( Jung et al, 2018 ; Cherepanov et al, 2021 ; Yu et al, 2022 ).…”

Urine Excretion, Organ Distribution, and Placental Transfer of 6PPD and 6PPD-Quinone in Mice and Potential Developmental Toxicity through Nuclear Receptor Pathways

“…Exposure of zebrafish embryos to 6PPD (0.22 mg/L; 2–120 h postfertilization) caused developmental toxicity and altered hormone levels and gene expressions in embryos . Although developmental effects have not been observed in mammals for 6PPD and 6PPDQ, these results suggest that the mammalian embryonic stage may also be sensitive to these chemicals due to the physiologic similarities to the model organisms. , In mammalian systems, the placenta serves as a barrier to protect the fetus from circulating environmental contaminants. , However, some contaminants with specific physicochemical properties or binding activities can cross the placental barrier, − leading to fetal exposure. − It is currently unclear whether 6PPD and 6PPDQ can be transferred from exposed mothers to their embryos in mammalian systems. Moreover, the impact of 6PPD and 6PPDQ on nuclear receptor pathways, such as thyroid hormone receptors (TRs), retinoic acid receptor (RAR), and retinoid X receptor (RXR) that are essential for embryonic development, remains unknown.…”

Prenatal stress unmasks behavioral phenotypes in genetic mouse models of neurodevelopmental disorders

“…Current understanding supports that most cases of NDDs arise from complex interactions between candidate genes and/or environmental factors ( Kim and Leventhal, 2015 ; Vorstman et al, 2017 ; Hollander et al, 2020 ). In line with this premise, mouse models with mutations in a single high-confidence gene are sometimes found to have absent or mild phenotypes related to clinical profiles, raising the possibility that an additional environmental challenge or “hit,” such as PNS, is necessary to drive the emergence of abnormal behaviors ( Jiménez et al, 2022 ; Lord et al, 2022 ). In this paper, we review the literature examining PNS in genetic mouse models of NDDs, and discuss potential experimental factors that could influence results of these studies.…”