Dataset Information

Proteome analysis of cumulative antenatal and postnatal environmental exposure in the brain of mice

ABSTRACT: Environmental exposures across critical developmental windows can significantly influence brain development and contribute to the risk of neurodevelopmental disorders (NDDs). Importantly, emerging clinical evidence suggests that multiple environmental factors during early development result in more pronounced disease phenotypes in offspring. To expand upon this existing notion, we developed a ‘triple-hit’ mouse model to examine the combined effects of maternal social stress, chronic high-fat diet consumption, and early life poly(I:C) exposure on long-term developmental outcomes in offspring. We observed that ‘triple-hit’ male offspring displayed autism-like social deficits and an overall increased susceptibility to NDD-like behavioural alterations in adulthood. Single-cell RNA (scRNA) transcriptomic and bulk proteomic analyses were performed in male triple hit offspring in brain tissue. The results are discussed in the associated publication.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Mark Graham

LAB HEAD: Markus Hofer

PROVIDER: PXD060752 | Pride | 2026-01-19

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	Deamidation_NQ_Sites.txt	Txt
	MusMusculus_CanIso_2023_10_05.fasta	Fasta
	Oxidation_M_Sites.txt	Txt
	allPeptides.txt	Txt
	allSpectra.HCD.FTMS.iso_0.apl	Other

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Publications

Cumulative environmental exposures adversely impact social behaviour and are associated with dysregulation of genes and proteins involved in epigenetic, ribosomal, and immune regulation in male mice.

Bucknor Morgan C MC Keating Brooke A BA Han Velda X VX Gloss Brian S BS Dey Pinki P Aryamanesh Nader N Marshall Lee L LL Graham Mark E ME Dissanayake Ruwani R Lau Xianzhong X Patel Shrujna S Petkova Stela P SP Valtchev Peter P Gururajan Anand A Dale Russell C RC Hofer Markus J MJ

Inflammation research : official journal of the European Histamine Research Society ... [et al.] 20260108 1

<h4>Objective</h4>This study investigated how cumulative environmental exposures influence offspring behaviour and inflammation-related molecular signatures in the brain and peripheral immune system.<h4>Methods</h4>A novel "triple-hit" mouse model was developed using C57Bl/6JAusB mice (N = 70), combining preconceptual social stress, antenatal high-fat diet, and a postnatal immune challenge (poly(I:C), 10 mg/kg). At 12 weeks, offspring underwent behavioural tests relevant to neurodevelopmental di ...[more]

PMID: 41504877

Similar Datasets

Project description:Environmental exposures across critical developmental windows can significantly influence brain development and contribute to the risk of neurodevelopmental disorders (NDDs). Importantly, emerging clinical evidence suggests that multiple environmental factors during early development synergise and result in more pronounced disease phenotypes in offspring. To expand upon this existing notion, we developed a ‘triple-hit’ mouse model to examine the combined effects of maternal social stress, chronic high-fat diet consumption, and early life poly(I:C) exposure on long-term developmental outcomes in offspring. We observed that ‘triple-hit’ male offspring displayed autism-like social deficits and an overall increased susceptibility to NDD-like behavioural alterations in adulthood. Single-cell RNA (scRNA) transcriptomic and bulk proteomic analyses were performed in male triple hit offspring across both brain tissue and peripheral blood leukocytes. scRNA sequencing revealed consistent dysregulation in critical glial cell processes, ribosomal functions and chromatin remodelling across all brain glial cell types. Similar themes were observed across peripheral blood leukocytes - displaying immune and ribosomal dysregulation at the transcriptional level. However, innate and adaptive immune cells displayed variations in directional expression of change. Proteomics analyses revealed significant reductions in proteins associated with ribosomal biogenesis, translation and chromatin remodelling pathways between brain and peripheral blood cells. Furthermore, significantly upregulated proteins associated with synaptic structure and function were observed between both compartments. Overall, using our unique triple hit model and by harnessing a systems-level approach, we demonstrate that early life environmental perturbations synergistically drive NDD-associated behaviours and complimentary transcriptional reprogramming between the central nervous system (CNS) and periphery in male offspring

Project description:Background: Consumption of high fat diets has negative impacts on health and well-being, some of which may be epigenetically regulated. Selenium and folate are two compounds which influence epigenetic mechanisms. We investigated the hypothesis that post-weaning supplementation with adequate levels of selenium and folate in mouse offspring fed a high fat, low selenium and folate diet during gestation and lactation will lead to epigenetic changes of potential importance for long-term health. Female offspring of mothers fed the experimental diet were either maintained on this diet (HF-low-low), or weaned onto a high-fat diet with sufficient levels of selenium and folate (HF-low-suf), for 8 weeks. Gene and protein expression, DNA methylation, and histone modifications were measured in colon and liver of female offspring. Results: Adequate levels of selenium and folate post-weaning affected gene expression in colon and liver of offspring, including decreasing Slc2a4 gene expression. Protein expression was only altered in the liver. There was no effect of adequate levels of selenium and folate on global histone modifications in the liver. Global liver DNA methylation was decreased in mice switched to adequate levels of selenium and folate, but there was no effect on methylation of specific CpG sites within the Slc2a4 gene in liver. Conclusions: Post-weaning supplementation with adequate levels of selenium and folate in female offspring of mice fed high-fat diets during gestation and lactation can alter global DNA methylation in liver. This may be one mechanism by which the negative effects of a poor diet during early life can be ameliorated. Further research is required to establish what role epigenetic changes play in mediating observed changes in gene and protein expression, and the relevance of these changes to health. Female wild type C57BL/6 mice (Animal Resource Centre, Western Australia) were fed a High Fat diet containing low levels of selenium and folate (HF-Low) for 7 days prior to mating with male C57BL/6 mice (Ruakura Small Animal Facility, Hamilton, New Zealand). Mothers were maintained on the HF-Low diet throughout gestation and lactation. Offspring of these female mice were randomly assigned to one of two different dietary treatments: either the same diet as the mothers (HF-Low), or a High Fat diet containing adequate selenium and folate (HF-Suf). At 12 weeks of age, mice were euthanized and colon and liver samples taken for microarray, proteomics, and DNA methylation analyses. Genomic DNA, total RNA and protein from whole colon and liver tissue was extracted using an AllPrepM-BM-. DNA/RNA/Protein mini kit (Qiagen, Cat number 80004). Colon and liver RNA from six female offspring on the HF-Low diet was compared with colon and liver RNA from six female offspring on the HF-Suf diet. All individual RNA samples were hybridized against a common reference RNA on separate arrays. The reference RNA was prepared by pooling in equimolar proportions RNA extracted from the intestine and liver of twelve female C57BL/6 mice, these being all of the mice from which samples were derived for microarray analysis in the current study.