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. 2022 Nov 11;23(22):13930.
doi: 10.3390/ijms232213930.

Differential Expression of Endogenous Retroviruses and Inflammatory Mediators in Female and Male Offspring in a Mouse Model of Maternal Immune Activation

Chiara Cipriani  1 , Anna Maria Tartaglione  2 , Martina Giudice  1 , Erica D'Avorio  1 , Vita Petrone  1 , Nicola Toschi  3   4 , Flavia Chiarotti  2 , Martino Tony Miele  1 , Gemma Calamandrei  2 , Enrico Garaci  5   6 , Claudia Matteucci  1 , Paola Sinibaldi-Vallebona  1   7 , Laura Ricceri  2 , Emanuela Balestrieri  1
Affiliations

Differential Expression of Endogenous Retroviruses and Inflammatory Mediators in Female and Male Offspring in a Mouse Model of Maternal Immune Activation

Chiara Cipriani et al. Int J Mol Sci. .

Abstract

Maternal infections during pregnancy and the consequent maternal immune activation (MIA) are the major risk factors for autism spectrum disorder (ASD). Epidemiological evidence is corroborated by the preclinical models in which MIA leads to ASD-like behavioral abnormalities and altered neuroinflammatory profiles, with an increase in pro-inflammatory cytokines and microglial markers. In addition to neuroinflammatory response, an abnormal expression of endogenous retroviruses (ERVs) has been identified in neurodevelopmental disorders and have been found to correlate with disease severity. Our aim was to evaluate the transcriptional profile of several ERV families, ERV-related genes, and inflammatory mediators (by RT real-time PCR) in mouse offspring of both sexes, prenatally exposed to polyinosinic:polycytidylic acid (Poly I:C), a synthetic double-stranded RNA molecule targeting TLR-3 that mimics viral maternal infection during pregnancy. We found that prenatal exposure to Poly I:C deregulated the expression of some ERVs and ERV-related genes both in the prefrontal cortex (PFC) and hippocampus, while no changes were detected in the blood. Interestingly, sex-related differences in the expression levels of some ERVs, ERV-related genes, and inflammatory mediators that were higher in females than in males emerged only in PFC. Our findings support the tissue specificity of ERV and ERV-related transcriptional profiles in MIA mice.

Keywords: Poly I:C; autism spectrum disorder; cytokines; endogenous retroviruses (ERVs); gene expression; maternal immune activation (MIA); neuroinflammation; social behavior.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Relative expression of several ERV families (a), ERV-related genes (b), and inflammatory mediators (c) in prefrontal cortex (PFC) of Vehicle and Poly I:C mice (both sexes pooled). Data are represented as box plots with median value (black horizontal line) and first/third interquartile range. * p < 0.05 (Poly I:C vs. Vehicle). PCA and hierarchical clustering of the transcriptional levels of the same genes in PFC samples of Poly I:C mice (d). Percentage of total variance explained by the component is reported in the head columns between parentheses; red indicates positive association, blue indicates negative associations, and color intensity refers to association strength.
Figure 2
Figure 2
Relative expression of several ERV families (a), ERV-related genes (b), and inflammatory mediators (c) in hippocampus (HP) of Vehicle and Poly I:C mice (both sexes pooled). Data are represented as box plots with median value (black horizontal line) and first/third interquartile range. * p < 0.05 (Poly I:C vs. Vehicle). PCA and hierarchical clustering of the transcriptional levels of the same genes in HP samples of Poly I:C mice (d). Percentage of total variance explained by the component is reported in the head columns between parentheses; red indicates positive association, blue indicates negative associations, and color intensity refers to association strength.
Figure 3
Figure 3
Relative expression of several ERV families (a), ERV-related genes (b), and inflammatory mediators (c) in blood (BL) of Vehicle and Poly I:C mice (both sexes pooled). Data are represented as box plots with median value (black horizontal line) and first/third interquartile range(Poly I:C vs. Vehicle). PCA and hierarchical clustering of the transcriptional levels of the same genes in BL samples of Poly I:C mice (d). Percentage of total variance explained by the component is reported in the head columns between parentheses; red indicates positive association, blue indicates negative associations, and color intensity refers to association strength.
Figure 4
Figure 4
Relative expression of several ERV families (a), ERV-related genes (b), and inflammatory mediators (c) in prefrontal cortex (PFC) of Poly I:C male and female mice. Data are represented as box plots with median value (black horizontal line) and first/third interquartile range. * p < 0.05 (males vs. females). PCA and hierarchical clustering of the transcriptional levels of the same genes in PFC samples of Poly I:C male (d) and female (e) mice. Percentage of total variance explained by the component is reported in the head columns between parentheses; red indicates positive association, blue indicates negative associations, and color intensity refers to association strength.
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