Phylogenetic and DNA methylation analysis reveal novel regions of variable methylation in the mouse IAP class of transposons

Abstract Background Select retrotransposons in the long terminal repeat (LTR) class exhibit interindividual variation in DNA methylation that is altered by developmental environmental exposures. Yet, neither the full extent of variability at these “metastable epialleles,” nor the phylogenetic relationship underlying variable elements is well understood. The murine metastable epialleles, Avy and CabpIAP, result from independent insertions of an intracisternal A particle (IAP) mobile element, and exhibit remarkably similar sequence identity (98.5%). Results Utilizing the C57BL/6 genome we identified 10802 IAP LTRs overall and a subset of 1388 in a family that includes Avy and CabpIAP. Phylogenetic analysis revealed two duplication and divergence events subdividing this family into three clades. To characterize interindividual variation across clades, liver DNA from 17 isogenic mice was subjected to combined bisulfite and restriction analysis (CoBRA) for 21 separate LTR transposons (7 per clade). The lowest and highest mean methylation values were 59% and 88% respectively, while methylation levels at individual LTRs varied widely, ranging from 9% to 34%. The clade with the most conserved elements had significantly higher mean methylation across LTRs than either of the two diverged clades (p = 0.040 and p = 0.017). Within each mouse, average methylation across all LTRs was not significantly different (71%-74%, p > 0.99). Conclusions Combined phylogenetic and DNA methylation analysis allows for the identification of novel regions of variable methylation. This approach increases the number of known metastable epialleles in the mouse, which can serve as biomarkers for environmental modifications to the epigenome.http://deepblue.lib.umich.edu/bitstream/2027.42/112312/1/12864_2012_Article_4665.pd

Mapping for prevention: GIS models for directing childhood lead poisoning prevention programs.

Environmental threats to children's health--especially low-level lead exposure--are complex and multifaceted; consequently, mitigation of these threats has proven costly and insufficient and has produced economic and racial disparities in exposure among populations. Policy makers, public health officials, child advocates, and others currently lack the appropriate infrastructure to evaluate children's risk and exposure potential across a broad range of risks. Unable to identify where the highest risk of exposure occurs, children's environmental health programs remain mitigative instead of preventive. In this article we use geographic information system spatial analysis of data from blood lead screening, county tax assessors, and the U.S. Census to predict statistically based lead exposure risk levels mapped at the individual tax parcel unit in six counties in North Carolina. The resulting model uses weighted risk factors to spatially locate modeled exposure zones, thus highlighting critical areas for targeted intervention. The methods presented here hold promise for application and extension to the other 94 North Carolina counties and nationally, as well as to other environmental health risks

GIS Modeling of Air Toxics Releases from TRI-Reporting and Non-TRI-Reporting Facilities: Impacts for Environmental Justice

The Toxics Release Inventory (TRI) requires facilities with 10 or more full-time employees that process > 25,000 pounds in aggregate or use > 10,000 pounds of any one TRI chemical to report releases annually. However, little is known about releases from non-TRI-reporting facilities, nor has attention been given to the very localized equity impacts associated with air toxics releases. Using geographic information systems and industrial source complex dispersion modeling, we developed methods for characterizing air releases from TRI-reporting as well as non-TRI-reporting facilities at four levels of geographic resolution. We characterized the spatial distribution and concentration of air releases from one representative industry in Durham County, North Carolina (USA). Inclusive modeling of all facilities rather than modeling of TRI sites alone significantly alters the magnitude and spatial distribution of modeled air concentrations. Modeling exposure receptors at more refined levels of geographic resolution reveals localized, neighborhood-level exposure hot spots that are not apparent at coarser geographic scales. Multivariate analysis indicates that inclusive facility modeling at fine levels of geographic resolution reveals exposure disparities by income and race. These new methods significantly enhance the ability to model air toxics, perform equity analysis, and clarify conflicts in the literature regarding environmental justice findings. This work has substantial implications for how to structure TRI reporting requirements, as well as methods and types of analysis that will successfully elucidate the spatial distribution of exposure potentials across geographic, income, and racial lines

Bisphenol A‐associated alterations in the expression and epigenetic regulation of genes encoding xenobiotic metabolizing enzymes in human fetal liver

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106679/1/em21823.pd

Gene‐specific DNA methylation may mediate atypical antipsychotic‐induced insulin resistance

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134192/1/bdi12422_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134192/2/bdi12422.pd

Maternal Genistein Alters Coat Color and Protects A(vy) Mouse Offspring from Obesity by Modifying the Fetal Epigenome

Genistein, the major phytoestrogen in soy, is linked to diminished female reproductive performance and to cancer chemoprevention and decreased adipose deposition. Dietary genistein may also play a role in the decreased incidence of cancer in Asians compared with Westerners, as well as increased cancer incidence in Asians immigrating to the United States. Here, we report that maternal dietary genistein supplementation of mice during gestation, at levels comparable with humans consuming high-soy diets, shifted the coat color of heterozygous viable yellow agouti (A(vy)/a) offspring toward pseudoagouti. This marked phenotypic change was significantly associated with increased methylation of six cytosine–guanine sites in a retrotransposon upstream of the transcription start site of the Agouti gene. The extent of this DNA methylation was similar in endodermal, mesodermal, and ectodermal tissues, indicating that genistein acts during early embryonic development. Moreover, this genistein-induced hypermethylation persisted into adulthood, decreasing ectopic Agouti expression and protecting offspring from obesity. Thus, we provide the first evidence that in utero dietary genistein affects gene expression and alters susceptibility to obesity in adulthood by permanently altering the epigenome

The role of environmental exposures and the epigenome in health and disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152782/1/em22311_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152782/2/em22311.pd

Perinatal bisphenol A exposure promotes hyperactivity, lean body composition, and hormonal responses across the murine life course

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154296/1/fsb2027004047.pd

Perinatal Lead (Pb) Exposure Results in Sex-Specific Effects on Food Intake, Fat, Weight, and Insulin Response across the Murine Life-Course

Developmental lead (Pb) exposure has been associated with lower body weight in human infants and late onset obesity in mice. We determined the association of perinatal Pb exposure in mice with changes in obesity-related phenotypes into adulthood. Mice underwent exposure via maternal drinking water supplemented with 0 (control), 2.1 (low), 16 (medium), or 32 (high) ppm Pb-acetate two weeks prior to mating through lactation. Offspring were phenotyped at ages 3, 6, and 9 months for energy expenditure, spontaneous activity, food intake, body weight, body composition, and at age 10 months for glucose tolerance. Data analyses were stratified by sex and adjusted for litter effects. Exposed females and males exhibited increased energy expenditure as compared to controls (p<0.0001 for both). In females, horizontal activity differed significantly from controls (p = 0.02) over the life-course. Overall, food intake increased in exposed females and males (p<0.0008 and p<0.0001, respectively) with significant linear trends at 9 months in females (p = 0.01) and 6 months in males (p<0.01). Body weight was significantly increased in males at the medium and high exposures (p = 0.001 and p = 0.006). Total body fat differed among exposed females and males (p<0.0001 and p<0.0001, respectively). Insulin response was significantly increased in medium exposure males (p<0.05). Perinatal Pb exposure at blood lead levels between 4.1 µg/dL and 32 µg/dL is associated with increased food intake, body weight, total body fat, energy expenditure, activity, and insulin response in mice. Physiological effects of developmental Pb exposure persist and vary according to sex and age