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Parental preconceptual α-cypermethrin exposure alters embryonic brain transcriptomics in mice: implications for autism spectrum disorder and stress vulnerability

ABSTRACT: Pyrethroid insecticides are widely used in agriculture and households, and their exposure can affect neurodevelopment. Few studies have evaluated how preconception parental exposure could also affect this process. To address knowledge gap, adult C57Bl6/J mice were gavaged daily with -cypermethrin at a human relevant low (0.3 mg/kg) or high (10 mg/kg) dose in corn oil for four weeks prior to conception. Offspring embryonic day 16 dorsal forebrain was extracted for transcriptomic analysis. In offspring forebrains of exposed compared to unexposed parents, there was increasing number of differentially expressed genes (DEGs) from paternal (least) to maternal to both parent exposure (most). A dose dependent effect was observed in offspring forebrain for paternal and maternal preconceptual exposures. Maternal and both parent exposures led to upregulated genes in offspring brain for biological processes involved in translation with predicted activation of EIF4E, a gene associated with autism. In contrast, paternal exposure upregulated cell cycle related DNA damage signaling processes. After any parent exposure, there was upregulation of biological processes involved in mitochondria function and oxidative stress and a downregulation of neuronal and synaptic processes with predicted inhibition of BDNF signaling. Weighted gene correlation network analysis identified modules associated with different parent treatment that were over-represented with DEGs with similar functional signatures as found in DEG-related pathways. Importantly, DEGs in offspring forebrain after any parent exposure were over-represented with genes related to autism spectrum disorder (ASD) and stress vulnerability. The study highlights the potential contribution of preconception parental pyrethroid exposure to aberrant brain functioning.

ORGANISM(S): Mus musculus

PROVIDER: GSE300410 | GEO | 2025/08/22

REPOSITORIES: GEO

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Project description:Parental exposure to environmental stress can result in an increased diseases risk in the offspring. Although literature on maternal contribution to hereditary diseases are growing, the paternal contribution is frequently underrecognized. Since human studies reported that 80% of transmitted mutations arise in the paternal germline, it is crucial to understand the mechanism underlying the paternally inherited genome instability. Ionizing radiation (IR) is a major source of mutagenesis through inducing DNA double-strand breaks (DSBs). Here, we used sex-separated C. elegans mutants to investigate the paternal contribution to IR-induced transgenerational effects. Specifically, we found that paternal exposure to IR leads to a transgenerational embryonic lethality, and this effect is only observed when the radiation exposure occurred close to the time of fertilization. In the offspring of the irradiated males (F1 generation), we detected various genome instability phenotypes, including DNA fragmentation, chromosomal rearrangement, and aneuploidy. These phenotypes are attributed to the usage of two error-prone repair machinery, the polymerase-theta mediated end joining (TMEJ) and the non-homologous End Joining (NHEJ). Surprisingly, depletion of a human histone H1.0 ortholog, HIS-24, can significantly rescue this transgenerational embryonic lethality. Moreover, this rescue effect is associated with the downregulation of heterochromatin marker histone 3 lysine 9 di-methylation (H3K9me2), and the knocking-down of heterochromatin protein, HPL-1, could mimic the rescue effect of HIS-24 depletion. We also noticed that removal of the histone H1 and heterochromatin marker could activate the error-free repair machinery, Homologous Recombination repair (HR), thus improving the viability of the offspring carrying paternally inherited DNA damage. Altogether, our work sheds light on the importance of paternal radiation exposure on the health of offspring. In addition, our work establishes a previously unknown mechanism underlying the transgenerational genome instability and provides a potential therapeutic target for preventing the hereditary diseases caused by paternal radiation exposure.

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Parental preconceptual α-cypermethrin exposure alters embryonic brain transcriptomics in mice: implications for autism spectrum disorder and stress vulnerability

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