Mammalian genome : official journal of the International Mammalian Genome Society最新文献

{"title":"Three-dimensional microCT imaging of murine embryonic development from immediate post-implantation to organogenesis: application for phenotyping analysis of early embryonic lethality in mutant animals.","authors":"Olga Ermakova,&nbsp;Tiziana Orsini,&nbsp;Alessia Gambadoro,&nbsp;Francesco Chiani,&nbsp;Glauco P Tocchini-Valentini","doi":"10.1007/s00335-017-9723-6","DOIUrl":"https://doi.org/10.1007/s00335-017-9723-6","url":null,"abstract":"<p><p>In this work, we applied three-dimensional microCT imaging to study murine embryogenesis in the range from immediate post-implantation period (embryonic day 5.5) to mid-gestation (embryonic day 12.5) with the resolution up to 1.4 µm/voxel. Also, we introduce an imaging procedure for non-invasive volumetric estimation of an entire litter of embryos within the maternal uterine structures. This method allows for an accurate, detailed and systematic morphometric analysis of both embryonic and extra-embryonic components during embryogenesis. Three-dimensional imaging of unperturbed embryos was performed to visualize the egg cylinder, primitive streak, gastrulation and early organogenesis stages of murine development in the C57Bl6/N mouse reference strain. Further, we applied our microCT imaging protocol to determine the earliest point when embryonic development is arrested in a mouse line with knockout for tRNA splicing endonuclease subunit Tsen54 gene. Our analysis determined that the embryonic development in Tsen54 null embryos does not proceed beyond implantation. We demonstrated that application of microCT imaging to entire litter of non-perturbed embryos greatly facilitate studies to unravel gene function during early embryogenesis and to determine the precise point at which embryonic development is arrested in mutant animals. The described method is inexpensive, does not require lengthy embryos dissection and can be applicable for detailed analysis of mutant mice at laboratory scale as well as for high-throughput projects.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"245-259"},"PeriodicalIF":2.5,"publicationDate":"2018-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00335-017-9723-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35581621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and characterization of a novel chemically induced allele at the planar cell polarity gene Vangl2.","authors":"Abdul-Rahman El-Hassan,&nbsp;Vicki Leung,&nbsp;Fares Kharfallah,&nbsp;Marie-Claude Guyot,&nbsp;Redouane Allache,&nbsp;Philippe Gros,&nbsp;Zoha Kibar","doi":"10.1007/s00335-017-9721-8","DOIUrl":"https://doi.org/10.1007/s00335-017-9721-8","url":null,"abstract":"<p><p>Planar cell polarity (PCP) signaling controls a number of morphogenetic processes including convergent extension during gastrulation and neural tube formation. Defects in this pathway cause neural tube defects (NTD), the most common malformations of the central nervous system. The Looptail (Lp) mutant mouse was the first mammalian mutant implicating a PCP gene (Vangl2) in the pathogenesis of NTD. We report on a novel chemically induced mutant allele at Vangl2 called Curly Bob that causes a missense mutation p.Ile268Asn (I268N) in the Vangl2 protein. This mutant segregates in a semi-dominant fashion with heterozygote mice displaying a looped tail appearance, bobbing head, and a circling behavior. Homozygote mutant embryos suffer from a severe form of NTD called craniorachischisis, severe PCP defects in the inner hair cells of the cochlea and posterior cristae, and display a distinct defect in retinal axon guidance. This mutant genetically interacts with the Lp allele (Vangl2 ^S464N ) in neural tube development and inner ear hair cell polarity. The Vangl2^I268N protein variant is expressed at very low levels in affected neural and retinal tissues of mutant homozygote embryos. Biochemical studies show that Vangl2^I268N exhibits impaired targeting to the plasma membrane and accumulates in the endoplasmic reticulum. The Vangl2^I268N variant no longer physically interacts with its PCP partner DVL3 and has a reduced protein half-life. This mutant provides an important model for dissecting the role of Vangl2 in the development of the neural tube, establishment of polarity of sensory cells of the auditory and vestibular systems, and retinal axon guidance.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"229-244"},"PeriodicalIF":2.5,"publicationDate":"2018-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00335-017-9721-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35636568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Congenic mapping and candidate gene analysis for streptozotocin-induced diabetes susceptibility locus on mouse chromosome 11.","authors":"Tomoki Maegawa,&nbsp;Yuki Miyasaka,&nbsp;Misato Kobayashi,&nbsp;Naru Babaya,&nbsp;Hiroshi Ikegami,&nbsp;Fumihiko Horio,&nbsp;Masahide Takahashi,&nbsp;Tamio Ohno","doi":"10.1007/s00335-018-9742-y","DOIUrl":"https://doi.org/10.1007/s00335-018-9742-y","url":null,"abstract":"<p><p>Streptozotocin (STZ) has been widely used to induce diabetes in rodents. Strain-dependent variation in susceptibility to STZ has been reported; however, the gene(s) responsible for STZ susceptibility has not been identified. Here, we utilized the A/J-11^SM consomic strain and a set of chromosome 11 (Chr. 11) congenic strains developed from A/J-11^SM to identify a candidate STZ-induced diabetes susceptibility gene. The A/J strain exhibited significantly higher susceptibility to STZ-induced diabetes than the A/J-11^SM strain, confirming the existence of a susceptibility locus on Chr. 11. We named this locus Stzds1 (STZ-induced diabetes susceptibility 1). Congenic mapping using the Chr. 11 congenic strains indicated that the Stzds1 locus was located between D11Mit163 (27.72 Mb) and D11Mit51 (36.39 Mb). The Mpg gene, which encodes N-methylpurine DNA glycosylase (MPG), a ubiquitous DNA repair enzyme responsible for the removal of alkylated base lesions in DNA, is located within the Stzds1 region. There is a close relationship between DNA alkylation at an early stage of STZ action and the function of MPG. A Sanger sequence analysis of the Mpg gene revealed five polymorphic sites in the A/J genome. One variant, p.Ala132Ser, was located in a highly conserved region among rodent species and in the minimal region for retained enzyme activity of MPG. It is likely that structural alteration of MPG caused by the p.Ala132Ser mutation elicits increased recognition and excision of alkylated base lesions in DNA by STZ.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"273-280"},"PeriodicalIF":2.5,"publicationDate":"2018-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00335-018-9742-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35900217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of the zona pellucida-binding protein 2 (Zpbp2) gene in mice impacts airway hypersensitivity and lung lipid metabolism in a sex-dependent fashion.","authors":"Cynthia Kanagaratham,&nbsp;Victoria Chiwara,&nbsp;Bianca Ho,&nbsp;Sanny Moussette,&nbsp;Mina Youssef,&nbsp;David Venuto,&nbsp;Lucie Jeannotte,&nbsp;Guillaume Bourque,&nbsp;Juan Bautista de Sanctis,&nbsp;Danuta Radzioch,&nbsp;Anna K Naumova","doi":"10.1007/s00335-018-9743-x","DOIUrl":"https://doi.org/10.1007/s00335-018-9743-x","url":null,"abstract":"<p><p>The human chromosomal region 17q12-q21 is one of the best replicated genome-wide association study loci for childhood asthma. The associated SNPs span a large genomic interval that includes several protein-coding genes. Here, we tested the hypothesis that the zona pellucida-binding protein 2 (ZPBP2) gene residing in this region contributes to asthma pathogenesis using a mouse model. We tested the lung phenotypes of knock-out (KO) mice that carry a deletion of the Zpbp2 gene. The deletion attenuated airway hypersensitivity (AHR) in female, but not male, mice in the absence of allergic sensitization. Analysis of the lipid profiles of their lungs showed that female, but not male, KO mice had significantly lower levels of sphingosine-1-phosphate (S1P), very long-chain ceramides (VLCCs), and higher levels of long-chain ceramides compared to wild-type controls. Furthermore, in females, lung resistance following methacholine challenge correlated with lung S1P levels (Pearson correlation coefficient 0.57) suggesting a link between reduced AHR in KO females, Zpbp2 deletion, and S1P level regulation. In livers, spleens and blood plasma, however, VLCC, S1P, and sphingosine levels were reduced in both KO females and males. We also find that the Zpbp2 deletion was associated with gain of methylation in the adjacent DNA regions. Thus, we demonstrate that the mouse ortholog of ZPBP2 has a role in controlling AHR in female mice. Our data also suggest that Zpbp2 may act through regulation of ceramide metabolism. These findings highlight the importance of phospholipid metabolism for sexual dimorphism in AHR.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"281-298"},"PeriodicalIF":2.5,"publicationDate":"2018-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00335-018-9743-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35910545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Individual susceptibility to arsenic-induced diseases: the role of host genetics, nutritional status, and the gut microbiome.","authors":"Liang Chi,&nbsp;Bei Gao,&nbsp;Pengcheng Tu,&nbsp;Chih-Wei Liu,&nbsp;Jingchuan Xue,&nbsp;Yunjia Lai,&nbsp;Hongyu Ru,&nbsp;Kun Lu","doi":"10.1007/s00335-018-9736-9","DOIUrl":"https://doi.org/10.1007/s00335-018-9736-9","url":null,"abstract":"<p><p>Arsenic (As) contamination in water or food is a global issue affecting hundreds of millions of people. Although As is classified as a group 1 carcinogen and is associated with multiple diseases, the individual susceptibility to As-related diseases is highly variable, such that a proportion of people exposed to As have higher risks of developing related disorders. Many factors have been found to be associated with As susceptibility. One of the main sources of the variability found in As susceptibility is the variation in the host genome, namely, polymorphisms of many genes involved in As transportation, biotransformation, oxidative stress response, and DNA repair affect the susceptibility of an individual to As toxicity and then influence the disease outcomes. In addition, lifestyles and many nutritional factors, such as folate, vitamin C, and fruit, have been found to be associated with individual susceptibility to As-related diseases. Recently, the interactions between As exposure and the gut microbiome have been of particular concern. As exposure has been shown to perturb gut microbiome composition, and the gut microbiota has been shown to also influence As metabolism, which raises the question of whether the highly diverse gut microbiota contributes to As susceptibility. Here, we review the literature and summarize the factors, such as host genetics and nutritional status, that influence As susceptibility, and we also present potential mechanisms of how the gut microbiome may influence As metabolism and its toxic effects on the host to induce variations in As susceptibility. Challenges and future directions are also discussed to emphasize the importance of characterizing the specific role of these factors in interindividual susceptibility to As-related diseases.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"63-79"},"PeriodicalIF":2.5,"publicationDate":"2018-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00335-018-9736-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35818387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging human genetic and adverse outcome pathway (AOP) data to inform susceptibility in human health risk assessment.","authors":"Holly M Mortensen, John Chamberlin, Bonnie Joubert, Michelle Angrish, Nisha Sipes, Janice S Lee, Susan Y Euling","doi":"10.1007/s00335-018-9738-7","DOIUrl":"10.1007/s00335-018-9738-7","url":null,"abstract":"<p><p>Estimation of susceptibility differences in human health risk assessment (HHRA) has been challenged by a lack of available susceptibility and variability data after exposure to a specific environmental chemical or pharmaceutical. With the increasingly large number of available data sources that contain polymorphism and other genetic data, human genetic variability that informs susceptibility can be better incorporated into HHRA. A recent policy, the 2016 The Frank R. Lautenberg Chemical Safety for the twenty-first Century Act, requires the US Environmental Protection Agency to evaluate new and existing toxic chemicals with explicit consideration of susceptible populations of all types (life stage, exposure, genetic, etc.). We propose using the adverse outcome pathway (AOP) construct to organize, identify, and characterize human genetic susceptibility in HHRA. We explore how publicly available human genetic datasets can be used to gain mechanistic understanding of molecular events and characterize human susceptibility for an adverse outcome. We present a computational method that implements publicly available human genetic data to prioritize AOPs with potential for human genetic variability. We describe the application of this approach across multiple described AOPs for health outcomes of interest, and by focusing on a single molecular initiating event. This contributes to a long-term goal to improve estimates of human susceptibility for use in HHRA for single and multiple chemicals.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"190-204"},"PeriodicalIF":0.0,"publicationDate":"2018-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9074075/pdf/nihms-958853.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35859744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inter-individual variation in health and disease associated with pulmonary infectious agents.","authors":"Kirsten C Verhein, Heather L Vellers, Steven R Kleeberger","doi":"10.1007/s00335-018-9733-z","DOIUrl":"10.1007/s00335-018-9733-z","url":null,"abstract":"<p><p>Respiratory infectious diseases resulting from bacterial or viral pathogens such as Mycobacterium tuberculosis, Streptococcus pneumoniae, respiratory syncytial virus (RSV), or influenza, are major global public health concerns. Lower respiratory tract infections are leading causes of morbidity and mortality, only behind ischemic heart disease and stroke (GBD 2015 LRI Collaborators in Lancet Infect Dis 17(11):1133-1161, 2017). Developing countries are particularly impacted by these diseases. However, while many are infected with viruses such as RSV (> 90% of all individuals are infected by age 2), only sub-populations develop severe disease. Many factors may contribute to the inter-individual variation in response to respiratory infections, including gender, age, socioeconomic status, nutrition, and genetic background. Association studies with functional single nucleotide polymorphisms in biologically plausible gene candidates have been performed in human populations to provide insight to the molecular genetic contribution to pulmonary infections and disease severity. In vitro cell models and genome-wide association studies in animal models of genetic susceptibility to respiratory infections have also identified novel candidate susceptibility genes, some of which have also been found to contribute to disease susceptibility in human populations. Genetic background may also contribute to differential efficacy of vaccines against respiratory infections. Development of new genetic mouse models such as the collaborative cross and diversity outbred mice should provide additional insight to the mechanisms of genetic susceptibility to respiratory infections. Continued investigation of susceptibility factors should provide insight to novel strategies to prevent and treat disease that contributes to global morbidity and mortality attributed to respiratory infections.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"38-47"},"PeriodicalIF":0.0,"publicationDate":"2018-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35754379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The road less traveled: from genotype to phenotype in flies and humans.","authors":"Robert R H Anholt,&nbsp;Trudy F C Mackay","doi":"10.1007/s00335-017-9722-7","DOIUrl":"https://doi.org/10.1007/s00335-017-9722-7","url":null,"abstract":"<p><p>Understanding how genomic variation gives rise to phenotypic variation is essential for elucidating mechanisms of adaptive evolution, plant and animal breeding, and precision medicine. However, identifying causal links between DNA sequence variants and variation in phenotypes is challenging in human populations, due to large blocks of linkage disequilibrium in the genome and heterogeneous developmental histories, lifestyles, and social and physical environments. Drosophila melanogaster presents a powerful genetic model, since linkage disequilibrium decays rapidly, facilitating assignment of causality to polymorphisms associated with phenotypic variation, and large numbers of individuals can be reared under defined environmental conditions, economically, and without regulatory restrictions. The D. melanogaster Genetic Reference Panel (DGRP), a population of 205 sequenced, inbred wild-derived flies, has enabled genome-wide association studies of morphological, physiological, behavioral, and life history traits, and demonstrated that genetic architectures of complex traits are highly polygenic, sexually dimorphic, and context dependent with extensive sex-, environment-, and genetic background (epistatic) effects. These features together with a modular organization of the transcriptome illustrate a dynamic integrative genetic architecture for complex traits. The complexity of the genetic architectures for complex traits in Drosophila provides important caveats for the interpretation of genetic studies in human populations. Aspects of the genetic underpinnings of complex traits can be represented as simplified gene networks on which human orthologues can be superimposed to provide blueprints for subsequent studies on analogous traits in human populations. Fundamental principles of the genetic architectures of Drosophila complex traits are likely applicable across phyla, from the DGRP to human populations.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"5-23"},"PeriodicalIF":2.5,"publicationDate":"2018-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00335-017-9722-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35536285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population genetic diversity in zebrafish lines.","authors":"Michele Balik-Meisner,&nbsp;Lisa Truong,&nbsp;Elizabeth H Scholl,&nbsp;Robert L Tanguay,&nbsp;David M Reif","doi":"10.1007/s00335-018-9735-x","DOIUrl":"https://doi.org/10.1007/s00335-018-9735-x","url":null,"abstract":"<p><p>Toxicological and pharmacological researchers have seized upon the many benefits of zebrafish, including the short generation time, well-characterized development, and early maturation as clear embryos. A major difference from many model organisms is that standard husbandry practices in zebrafish are designed to maintain population diversity. While this diversity is attractive for translational applications in human and ecological health, it raises critical questions on how interindividual genetic variation might contribute to chemical exposure or disease susceptibility differences. Findings from pooled samples of zebrafish support this supposition of diversity yet cannot directly measure allele frequencies for reference versus alternate alleles. Using the Tanguay lab Tropical 5D zebrafish line (T5D), we performed whole genome sequencing on a large group (n = 276) of individual zebrafish embryos. Paired-end reads were collected on an Illumina 3000HT, then aligned to the most recent zebrafish reference genome (GRCz10). These data were used to compare observed population genetic variation across species (humans, mice, zebrafish), then across lines within zebrafish. We found more single nucleotide polymorphisms (SNPs) in T5D than have been reported in SNP databases for any of the WIK, TU, TL, or AB lines. We theorize that some subset of the novel SNPs may be shared with other zebrafish lines but have not been identified in other studies due to the limitations of capturing population diversity in pooled sequencing strategies. We establish T5D as a model that is representative of diversity levels within laboratory zebrafish lines and demonstrate that experimental design and analysis can exert major effects when characterizing genetic diversity in heterogeneous populations.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"90-100"},"PeriodicalIF":2.5,"publicationDate":"2018-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00335-018-9735-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35765290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect sensitivity to developmental polychlorinated biphenyl exposure in mice: relevance to studies of human neurological disorders.","authors":"Kelsey Klinefelter,&nbsp;Molly Kromme Hooven,&nbsp;Chloe Bates,&nbsp;Breann T Colter,&nbsp;Alexandra Dailey,&nbsp;Smitha Krishnan Infante,&nbsp;Izabela Kania-Korwel,&nbsp;Hans-Joachim Lehmler,&nbsp;Alejandro López-Juárez,&nbsp;Clare Pickering Ludwig,&nbsp;Christine Perdan Curran","doi":"10.1007/s00335-017-9728-1","DOIUrl":"https://doi.org/10.1007/s00335-017-9728-1","url":null,"abstract":"<p><p>Polychlorinated biphenyls (PCBs) are persistent organic pollutants that remain a human health concern with newly discovered sources of contamination and ongoing bioaccumulation and biomagnification. Children exposed during early brain development are at highest risk of neurological deficits, but highly exposed adults reportedly have an increased risk of Parkinson's disease. Our previous studies found allelic differences in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) affect sensitivity to developmental PCB exposure, resulting in cognitive deficits and motor dysfunction. High-affinity Ahr ^b Cyp1a2(-/-) mice were most sensitive compared with poor-affinity Ahr ^d Cyp1a2(-/-) and wild-type Ahr ^b Cyp1a2(+/+) mice. Our follow-up studies assessed biochemical, histological, and gene expression changes to identify the brain regions and pathways affected. We also measured PCB and metabolite levels in tissues to determine if genotype altered toxicokinetics. We found evidence of AHR-mediated toxicity with reduced thymus and spleen weights and significantly reduced thyroxine at P14 in PCB-exposed pups. In the brain, the greatest changes were seen in the cerebellum where a foliation defect was over-represented in Cyp1a2(-/-) mice. In contrast, we found no difference in tyrosine hydroxylase immunostaining in the striatum. Gene expression patterns varied across the three genotypes, but there was clear evidence of AHR activation. Distribution of parent PCB congeners also varied by genotype with strikingly high levels of PCB 77 in poor-affinity Ahr ^d Cyp1a2(-/-) while Ahr ^b Cyp1a2(+/+) mice effectively sequestered coplanar PCBs in the liver. Together, our data suggest that the AHR pathway plays a role in developmental PCB neurotoxicity, but we found little evidence that developmental exposure is a risk factor for Parkinson's disease.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"112-127"},"PeriodicalIF":2.5,"publicationDate":"2018-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00335-017-9728-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35216184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}