Genetic background influences the effect of thirdhand smoke exposure on anxiety and memory in Collaborative Cross mice

Abstract

Growing evidence indicates that thirdhand smoke (THS) exposure induces many adverse health effects. However, it is unclear how THS exposure affects behavior and how host genetic background modulates phenotypic changes. Here we used the Collaborative Cross (CC) mouse population-based model to assess behavioral alterations immediately after THS exposure from 4 to 9 weeks of age. We first measured anxiety-like behavior in six strains using light/dark box combined with a custom multivariate mouse tracking system. We developed an anxiety risk scoring system based on anxiety-related traits and then evaluated the THS impact on them. THS exposure significantly decreased anxiety risk in CC019 (P = 0.002) and CC051 (P = 0.009), but increased anxiety risk in CC036 (P < 0.001), while the other three strains did not show significant changes in anxiety-related traits. Such differences were driven by female mice for the six measures of anxiety-like behavior. Memory potential was measured in the same cohort of mice using the passive avoidance assay. Both THS-exposed male and female CC019 mice displayed significant memory loss compared to controls while no significant changes were found in the other five strains. This study provides strong evidence that THS exposure leads to strain-dependent changes in anxiety-like behavior and memory, suggesting that host genetic variations play a critical role in individual susceptibility to THS-induced effects.

Forward genetic screen of homeostatic antibody levels in the Collaborative Cross identifies MBD1 as a novel regulator of B cell homeostasis

“…Recent work has highlighted the important role of epigenetic regulators in B cell activation and differentiation. For example, EZH2 (Herviou et al, 2019), LSD1 (Haines et al, 2018), and DNA methylation (Barwick et al, 2016;Barwick et al, 2018) have all been shown to regulate some aspect antibody secreting cell differentiation. Given the role of MBD1 in cellular differentiation in other tissues as well as our data presented here, it is likely that MBD1 is regulating chromatin dynamics necessary for altering gene expression profiles that promote antibody secreting cell differentiation.…”

“…Importantly, this genetic variation exists across the genome, ensuring no blind spots for genetic mapping analyses. This genetic diversity has resulted in discovery of several genetic loci associated with a variety of biomedically relevant traits (Ferris et al, 2013, He et al, 2021; Graham et al, 2021; Gu et al, 2020; Smith et al, 2019; Noll et al, 2020; Hampton et al, 2021, Preprint ). We and others have shown that there is extensive variation in splenic T cell populations (Graham et al, 2017), antibody glycosylation patterns (Krištić et al, 2018), as well as variation in the general immune landscape of the spleen (Collin et al, 2019), across the CC population.…”

Policy-relevant differences between secondhand and thirdhand smoke: strengthening protections from involuntary exposure to tobacco smoke pollutants

“…59 In vivo studies in laboratory animals have demonstrated that THS exposure increases lung cancer risk, alters behavioural phenotypes, impairs wound healing and causes changes to the immune system. [60][61][62][63][64][65] Controlled clinical human exposure studies have shown that acute inhalation exposure to THS causes changes in the human nasal epithelial transcriptome (eg, upregulated DNA repair mechanisms, stress-induced mitochondrial hyperfusion). 66 A recent proteomics study of dermal exposure to THS in humans revealed alterations in numerous cellular pathways indicative of the potential to cause diseases (eg, atherosclerosis, inflammatory response, dermatitis), changes similar to those found in Table 1 Chemicals found in thirdhand smoke that are identified by California's Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65) to cause cancer, birth defects or other reproductive harm, and their classification by the IARC 18 69 84 91 120-130 Special communication cigarette smokers.…”

A susceptibility gene signature for ERBB2-driven mammary tumor development and metastasis in Collaborative Cross mice with human translational value

“…[13][14][15] Moreover, large CC strain-dependent variations in many phenotypes, such as spontaneous tumor development, have been reported. [16][17][18][19][20][21][22][23][24][25][26][27][28][29] In this study, we identified host genetic variants that predispose Erbb2-driven tumor development and metastasis using the CC mouse resource. Additionally, we systematically evaluated the clinical value for prognosis and therapeutic responses of a mouse mammary tumor susceptibility gene signature in human BC using publicly available cohorts, including clinical trial cohorts.…”