Genetic Influences on the Amount of Cell Death in the Neural Tube of BXD Mice Exposed to Acute Ethanol at Midgestation

Abstract

Background: Fetal alcohol spectrum disorders (FASD) have a strong genetic component although the genes that underlie this are only beginning to be elucidated. In the present study, one of the most common phenotypes of FASD, cell death within the early developing neural tube, was examined across a genetic reference population in a reverse genetics paradigm with the goal of identifying genetic loci that could influence ethanol (EtOH)-induced apoptosis in the early developing neural tube.Methods: BXD recombinant inbred mice as well as the parental strains were used to evaluate genetic differences in EtOH-induced cell death after exposure on embryonic day 9.5. Dams were given either 5.8 g/kg EtOH or isocaloric maltose-dextrin in 2 doses via intragastric gavage. Embryos were collected 7 hours after the initial exposure and cell death evaluated via TUNEL staining in the brainstem and forebrain. Genetic loci were evaluated using quantitative trait locus (QTL) analysis at GeneNetwork.org.Results: Significant strain differences were observed in the levels of EtOH-induced cell death that were due to genetic effects and not confounding variables such as differences in developmental maturity or cell death kinetics. Comparisons between the 2 regions of the developing neural tube showed little genetic correlation with the QTL maps exhibiting no overlap. Significant QTLs were found on murine mid-chromosome 4 and mid-chromosome 14 only in the brainstem. Within these chromosomal loci, a number of interesting candidate genes were identified that could mediate this differential sensitivity including Nfia (nuclear factor I/A) and Otx2 (orthodenticle homeobox 2).Conclusions: These studies demonstrate that the levels of EtOH-induced cell death occur in strainand region-dependent manners. Novel QTLs on mouse Chr4 and Chr14 were identified that modulate the differential sensitivity to EtOH-induced apoptosis in the embryonic brainstem. The genes underlying these QTLs could identify novel molecular pathways that are critical in this phenotype.

A platform for experimental precision medicine: The extended BXD mouse family

“…The BXD Family Is the Largest and the Most Deeply Phenotyped Mammalian Genetic Reference Panel Data sets for the BXD encompass multiple levels-from single molecules to complex behavioral repertoires and to traits measured with environmental perturbations, including exposure to alcohol and drugs of abuse (Dickson et al, 2019;Mulligan et al, 2018;Thé berge et al, 2019;Zhou et al, 2018), infectious agents (Boon et al, 2014;Chella Krishnan et al, 2016;Russo et al, 2015), dietary modifications (Fleet et al, 2016;Jha et al, 2018bJha et al, , 2018aJones and Jellen, 2017;Reyes Fernandez et al, 2016;Rodrigues et al, 2017), stress (Diessler et al, 2018;Jung et al, 2017), and even as a function of age (Sandoval-Sierra et al, 2020;Williams et al, 2020). This phenome is linked to over 500 publications, including state-of-the-art proteome, metabolome (Williams et al, 2018(Williams et al, , 2020, epigenome (Baker et al, 2019;Sandoval-Sierra et al, 2019), and metagenome (Perez-Munoz et al, 2019) data sets available on GeneNetwork.org.…”

Private and sub-family specific mutations of founder haplotypes in the BXD family reveal phenotypic consequences relevant to health and disease

“…The BXDs are well suited to studying gene-by-environmental interactions (GXE) and for experimental precision medicine 11 . For almost 50 years, they have been used to study the genetic and environmental factors that underlie a diverse collection of phenotypes, including environmental toxicant exposures, alcohol and drugs of abuse [64][65][66][67][68] , infectious agents [69][70][71][72][73] , diets [74][75][76][77][78][79] , and stressors 80,81 . Beyond this, there are also extensive -omics data available for many BXD family members, including over 100 transcriptome datasets (e.g, 82,83 ), as well as more recent miRNA 84,85 , proteome [86][87][88] , metabolome 83,88,89 , epigenome 16,90 , and metagenome 91,92 profiles.…”

Recombinant Inbred Mice as Models for Experimental Precision Medicine and Biology

“…The BXDs have been used to test specific developmental and evolutionary hypotheses [49,100,101]. They have allowed the study of gene-by-environmental interactions, with environmental exposures including alcohol and drugs of abuse [86,[102][103][104][105], infectious agents [71,[106][107][108][109], dietary modifications [110][111][112][113][114][115], and stress [116,117]. The consequences of interventions and treatments as a function of genome, diet, age, and sex have been quantified [90,96,115,[118][119][120], and gene pleiotropy has been identified [121].…”