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Three-dimensional quantum close-coupling calculations are presented for the vibrational predissociation of He–ICl B state complexes containing two quanta of ICl vibrational excitation. The dynamics are evaluated for the lowest quasibound van der Waals levels of He–ICl with total angular momentum J=0 and 1. The vibrational predissociation lifetime and final ICl B(v=1, j ) rotational distribution are calculated using the golden rule approximation. The calculated ICl product rotational distributions are broadly bimodal with maxima at j=7 and 15, as experimentally observed. The computed rotational distributions exhibit pronounced oscillations, which are expected to be suppressed when averaged over the initial angular momentum distribution sampled in the experiment. The theoretical analysis points to the dominant role of final-state interactions in determining the rotational distribution of the ICl fragments. The zero-point bending motion of the He–ICl complex and the coupling between the initial and final vibrational states make only small contributions to the final ICl rotational-state distributions. The extensive rotational excitation of the ICl product is primarily due to the anisotropic intermolecular interaction between the separating ICl and He fragments. [ABSTRACT FROM AUTHOR]

Examines the classical, semiclassical and quantum mechanics of a chaotic Hamiltonian system. Adiabatic separation of the x and y motion; Connection between integrable approximation and the exact dynamics; Agreement between energy levels and energy spectrum.

Strongly peaked ICl fragment rotational distributions are observed following vibrational predissociation of ICl–He B state complexes containing two or three quanta of ICl vibrational excitation. The nascent rotational distributions of the ICl product exhibit two distinct maxima, occurring at j=7 and j=16. A theoretical analysis demonstrates that the two maxima are due to rotational rainbows, arising from the He atom scattering off of the I and Cl ends of the ICl molecule. The vibrational predissociation of ICl–He B(vB=2) is simulated with a semiclassical scattering theory which is analogous to that developed by Schinke [J. Chem. Phys. 85, 5049 (1986)] for direct photodissociation. Vibrational predissociation is modeled as a rotationally inelastic ‘‘half-collision,’’ following deactivation of the ICl vibration. The final rotational angular momentum of the ICl fragments is determined from exact classical trajectories and in a sudden limit on a model potential energy surface. The calculated ICl product rotational distribution, like the experimentally observed distributions, is bimodal. [ABSTRACT FROM AUTHOR]

The article offers information on a study regarding establishment of environmentally sensitive DNA methylation states in the very early human embryo. It mentions that women's periconceptional nutrition predicts their offspring's DNA methylation at metastable epialleles (MEs). It states that MEs are enriched for proximal enhancers and transcription start sites and are influenced by genotype.

Cancer has long been viewed as a genetic disease; however, epigenetic silencing as the result of aberrant promoter DNA methylation is frequently associated with cancer development, suggesting an epigenetic component to the disease. Nonetheless, it has remained unclear whether an epimutation (an aberrant change in epigenetic regulation) can induce tumorigenesis. Here, we exploited a functionally validated cis-acting regulatory element and devised a strategy to induce developmentally regulated genomic targeting of DNA methylation. We used this system to target DNA methylation within the p16(Ink4a) promoter in mice in vivo. Engineered p16(Ink4a) promoter hypermethylation led to transcriptional suppression in somatic tissues during aging and increased the incidence of spontaneous cancers in these mice. Further, mice carrying a germline p16(Ink4a) mutation in one allele and a somatic epimutation in the other had accelerated tumor onset and substantially shortened tumor-free survival. Taken together, these results provide direct functional evidence that p16(Ink4a) epimutation drives tumor formation and malignant progression and validate a targeted methylation approach to epigenetic engineering. [ABSTRACT FROM AUTHOR]

Cancer has long been viewed as a genetic disease; however, epigenetic silencing as the result of aberrant promoter DNA methylation is frequently associated with cancer development, suggesting an epigenetic component to the disease. Nonetheless, it has remained unclear whether an epimutation (an aberrant change in epigenetic regulation) can induce tumorigenesis. Here, we exploited a functionally validated cis-acting regulatory element and devised a strategy to induce developmentally regulated genomic targeting of DNA methylation. We used this system to target DNA methylation within the p16Ink4a promoter in mice in vivo. Engineered p16Ink4a promoter hypermethylation led to transcriptional suppression in somatic tissues during aging and increased the incidence of spontaneous cancers in these mice. Further, mice carrying a germline p16Ink4a mutation in one allele and a somatic epimutation in the other had accelerated tumor onset and substantially shortened tumor-free survival. Taken together, these results provide direct functional evidence that p16Ink4a epimutation drives tumor formation and malignant progression and validate a targeted methylation approach to epigenetic engineering. [ABSTRACT FROM AUTHOR]

Extensive human and animal model data show that nutrition and other environmental influences during critical periods of embryonic, fetal, and early postnatal life can affect the development of body weight regulatory pathways, with permanent consequences for risk of obesity. Epigenetic processes are widely viewed as a leading mechanism to explain the lifelong persistence of such "developmental programming" of energy balance. Despite meaningful progress in recent years, however, significant research obstacles impede our ability to test this hypothesis. Accordingly, this review attempts to summarize progress toward answering the following outstanding questions: Is epigenetic dysregulation a major cause of human obesity? In what cefls/tissues is epigenetic regulation most important for energy balance? Does developmental programming of human body weight regulation occur via epigenetic mechanisms? Do epigenetic mechanisms have a greater impact on food intake or energy expenditure? Does epigenetic inheritance contribute to transgenerational patterns of obesity? In each case, significant obstacles and suggested approaches to surmounting them are elaborated. [ABSTRACT FROM AUTHOR]

We use a regional-scale, three-dimensional atmospheric model to evaluate U.S. air quality effects that mould result from replacing HFC-134a in automobile air conditioners in the U.S. with HFO-1234yf. Although HFO-1234yf produces tropospheric ozone, the incremental amount is small, averaging less than 0.01% of total ozone formed during the simulation. We show that this production of ozone could be compensated for by a modest improvement in air conditioner efficiency. Atmospheric decomposition of HFO-1234yf produces trifluoroacetic acid (TFA), which is subject to wet and dry deposition. Deposition and concentrations of TFA are spatially variable due to HFO-1234yf's short atmospheric lifetime, with more localized peaks and less global transport when compared to HFC-134a. Over the 2.5 month simulation, deposition of TFA in the continental U.S. from mobile air conditioners averages 0.24 kg km-2, substantially higher than previous estimates from all sources of current hydrofluorocarbons. Automobile air conditioning HFO-1234yf emissions are predicted to produce concentrations of TFA in Eastern U.S. rainfall at least double the values currently observed from all sources, natural and man-made. Our model predicts peak concentrations in rainfall of 1264 ng L-1, a level that is 80× lower than the lowest level considered safe for the most sensitive aquatic organisms. [ABSTRACT FROM AUTHOR]

Background: Epigenetic mechanisms provide one potential explanation for how environmental influences in early life cause long-term changes in chronic disease susceptibility. Whereas epigenetic dysregulation is increasingly implicated in various rare developmental syndromes and cancer, the role of epigenetics in complex chronic diseases, such as cardiovascular disease, type 2 diabetes and obesity, remains largely uncharacterized. Extensive work in animal models is required to develop specific hypotheses that can be practicably tested in humans. Animal Models: We have developed a mouse model showing that methyl donor supplementation prevents transgenerational amplification of obesity, suggesting a role for DNA methylation in the developmental establishment of body weight regulation. Conclusions: Coupling such models with recently developed epigenomic technologies should ultimately enable us to determine if epigenetics is an important link between early life events and adult disease. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The effects of nonmutagenic environmental exposures can sometimes be transmitted for several generations, suggesting transgenerational inheritance of induced epigenetic variation. Methyl donor supplementation of female mice during pregnancy induces CpG hypermethylation at the agouti viable yellow (Avy) allele in Avy/a offspring. Epigenetic inheritance occurs at Avy; when passed through the female germ line, Avy epigenotype is not completely "reset." We therefore tested whether diet-induced epigenetic alterations at Avy are inherited transgenerationally. Female Avy/a mice were weaned onto either control (n=6) or a methyl-supplemented diet (n=5). These F0 dams were mated with a/a males. All F1 and F2 Avy/a females were weaned onto the same diet as their mothers, then mated with a/a males. F1, F2, and F3 Avy/a offspring were classified for coat color, an indicator of Avy methylation. In total, 62 F1, 98 F2, and 209 F3 Avy/a mice were studied. As expected, average Avy/a coat color was darker in the supplemented group (P<0.01). However, there was no cumulative effect of supplementation across successive generations. These results suggest that, in the female germ line, diet-induced Avy hypermethylation occurs in the absence of additional epigenetic modifications that normally confer transgenerational epigenetic inheritance at the locus. [ABSTRACT FROM AUTHOR]

BACKGROUND: Aberrant DNA methylation is common in carcinogenesis. The typical pattern appears to involve reduced expression of maintenance DNA methyltransferase, DNMT1, inducing genomic hypomethylation, whereas increased expression of de novo DNMT3a or 3b causes gene-specific hypermethylation. OBJECTIVES: During cadmium-induced malignant transformation, an unusual pattern of genomic hypermethylation occurred that we studied to provide insight into the roles of specific DNMTs in oncogenesis. METHODS: Gene expression and DNA methylation were assessed in control and chronic cadmiumtransformed prostate epithelial cells (CTPE) using reverse transcription-polymerase chain reaction (RT-PCR), Western blot analysis, methylation-specific PCR, and methyl acceptance assay. RESULTS: During the 10-weeks of cadmium exposure that induced malignant transformation, progressive increases in generalized DNMT enzymatic activity occurred that were associated with overexpression of DNMT3b without changes in DNMT1 expression. Increased DNMT3b expression preceded increased DNMT enzymatic activity. Procainamide, a specific DNMT1 inhibitor, reversed cadmium-induced genomic DNA hypermethylation. Reduced expression of the tumor suppressor genes, RASSF1A and p16, began about the time DNMT3b overexpression first occurred and progressively decreased thereafter. RASSF1A and p16 promoter regions were heavily methylated in CTPE cells, indicating silencing by hypermethylation, while the DNA demethylating agent, 5-aza-2'-deoxycytidine, reversed this silencing. DNMT1 inhibition only modestly increased RASSF1A and p16 expression in CTPE cells and did not completely reverse silencing. CONCLUSIONS: These data indicate that DNMT3b overexpression can result in generalized DNA hypermethylation and gene silencing but that DNMT1 is required to maintain these effects. The pattern of genomic DNA hypermethylation together with up-regulation of DNMT3b may provide a unique set of biomarkers to specifically identify cadmium-induced human prostate cancers. [ABSTRACT FROM AUTHOR]

Extensive human epidemiologic and animal model data indicate that during critical periods of prenatal and postnatal mammalian development, nutrition and other environmental stimuli influence developmental pathways and thereby induce permanent changes in metabolism and chronic disease susceptibility. The biologic mechanisms underlying this "developmental origins hypothesis" are poorly understood. This review focuses on the likely involvement of epigenetic mechanisms in the developmental origins of health and disease (DOHaD). We describe permanent effects of transient environmental influences on the developmental establishment of epigenetic gene regulation and evidence linking epigenetic dysregulation with human disease. We propose a definition of "epigenetic epidemiology" and delineate how this emerging field provides a basis from which to explore the role of epigenetic mechanisms in DOHaD. We suggest strategies for future human epidemiologic studies to identify causal associations between early exposures, long-term changes in epigenetic regulation, and disease, which may ultimately enable specific early-life interventions to improve human health. [ABSTRACT FROM AUTHOR]

Human epidemiologic data indicate that nutrition during prenatal and early postnatal development can affect susceptibility to various chronic diseases in adulthood (the developmental origins hypothesis). Controlled studies in animal models corroborate that nutritional exposures during critical periods of development wield lasting influences on gene expression and metabolism, but our understanding of the fundamental biological mechanisms underlying such phenomena remains rudimentary. Nutritional influences on the developmental establishment of epigenetic gene regulatory mechanisms could link early nutrition to adult chronic disease susceptibility. Just as genetic variation contributes to individual susceptibility to chronic disease, it is increasingly evident that so too does epigenetic variation. Very little is known about the factors that contribute to interindividual variation in epigenotype. It is critically important to determine whether nutrition and other environmental influences during development affect the establishment of human epigenotype. Most previous studies of nutritional influences on epigenetic regulation have focused on nutrients known to affect one-carbon metabolism. For example, supplementation during development with methyl donors including folic acid and vitamin B12 appears to induce DNA hypermethylation at specific loci by increasing the flux through the DNA methylation pathway. This article will consider the mechanisms by which fatty acid nutrition during prenatal and early postnatal nutrition might affect the establishment of epigenetic gene regulatory mechanisms. Choline, a component of the phospholipid phosphatidylcholine, stands at the intersection of lipid and one-carbon metabolism; upon conversion to betaine, its three methyl groups are available to one-carbon metabolism. Potentially much more important than providing methyl groups for DNA methylation, dietary fatty acids could affect the establishment of epigenetic mechanisms by stimulating transcription of specific genes during critical developmental windows. For example, the peroxisome proliferator activated receptor-α (PPAR-α) transcription factor is activated by a variety of fatty acids to transactivate specific genes. PPAR-α-mediated transcriptional activation during critical ontogenic periods could impede epigenetic silencing of genes involved in fatty acid metabolism. Lastly, recent data indicate that lipids and lipoprotein components interact directly with chromatin structure to influence gene expression. Hence, intake of specific dietary fatty acids during development could induce persistent changes in gene expression by altering the establishment of epigenetic mechanisms. [ABSTRACT FROM AUTHOR]

Methylation of DNA occurs at cytosines within CpG (cytosine-guanine) dinucleotides and is 1 of several epigenetic mechanisms that serve to establish and maintain tissue-specific patterns of gene expression. The methyl groups transferred in mammalian DNA methylation reactions are ultimately derived from methionine. High dietary methionine intake might therefore be expected to increase DNA methylation. Because of the circular nature of the methionine cycle, however, methionine excess may actually impair DNA methylation by inhibiting remethylation of homocysteine. Although little is known regarding the effect of dietary methionine supplementation on mammalian DNA methylation, the available data suggest that methionine supplementation can induce hypermethylation of DNA in specific genomic regions. Because locus-specific DNA hypomethylation is implicated in the etiology of various cancers and developmental syndromes, clinical trials of ‘promethylation’ dietary supplements are already under way. However, aberrant hypermethylation of DNA could be deleterious. It is therefore important to determine whether dietary supplementation with methionine can effectively support therapeutic maintenance of DNA methylation without causing excessive and potentially adverse locus-specific hypermethylation. In the viable yellow agouti (Avy mouse, maternal diet affects the coat color distribution of offspring by perturbing the establishment of methylation at the Avy metastable epiallele. Hence, the Avy mouse can be employed as a sensitive epigenetic biosensor to assess the effects of dietary methionine supplementation on locus-specific DNA methylation. Recent developments in epigenomic approaches that survey locus-specific DNA methylation on a genome-wide scale offer broader opportunities to assess the effects of high methionine intake on mammalian epigenomes. [ABSTRACT FROM AUTHOR]

Abstract: Numerous studies link arsenic exposure to human cancers in a variety of tissues, including the prostate. Our prior work showed that chronic arsenic exposure of the non-tumorigenic, human prostate epithelial cell line, RWPE-1, to low levels of (5 μM) sodium arsenite for 29 weeks resulted in malignant transformation and produced the tumorigenic CAsE-PE cell line. The present work focuses on the molecular events occurring during this arsenic-induced malignant transformation. Genomic DNA methylation was significantly reduced in CAsE-PE cells. A time course experiment showed that during malignant transformation DNA methyltransferase activity was markedly reduced by arsenic. However, DNA methyltransferase mRNA levels were not affected by arsenic exposure. Microarray screening showed that K-ras was highly overexpressed in CAsE-PE cells, a result further confirmed by Northern blot and Western blot analyses. Since ras activation is thought to be a critical event in prostate cancer progression, further detailed study was performed. Time course experiments also showed that increased K-ras expression preceded malignant transformation. Mutational analysis of codons 12, 13, and 61 indicated the absence of K-ras mutations. The K-ras gene can be activated by hypomethylation, but our study showed that CpG methylation in K-ras promoter region was not altered by arsenic exposure. Arsenic metabolism studies showed RWPE-1, CAsE-PE, and primary human prostate cells all had a very poor capacity for arsenic methylation. Thus, inorganic arsenic-induced transformation in human cells is associated with genomic DNA hypomethylation and K-ras overexpression. However, overexpression of K-ras occurred without mutations and through a mechanism other than promoter region hypomethylation. [Copyright &y& Elsevier]

Early nutrition affects adult metabolism in humans and other mammals, potentially via persistent alterations in DNA methylation. With viable yellow agouti (A[sup vy]) mice, which harbor a transposable element in the agouti gene, we tested the hypothesis that the metastable methylation status of specific transposable element insertion sites renders them epigenetically labile to early methyl donor nutrition. Our results show that dietary methyl supplementation of a/a dams with extra folic acid, vitamin B[sub 12], choline, and betaine alter the phenotype of their A[sup vy]/a offspring via increased CpG methylation at the A[sup vy] locus and that the epigenetic metastability which confers this lability is due to the A[sup vy] transposable element. These findings suggest that dietary supplementation, long presumed to be purely beneficial, may have unintended deleterious influences on the establishment of epigenetic gene regulation in humans. [ABSTRACT FROM AUTHOR]

In its continuing quest for smaller length scales, the electronics industry plans to introduce 157 nm as the next lithographic wavelength. Accordingly, there is a pressing need to develop photoresists that are more transparent, and pellicles that are both more transparent and more durable. With the advent and popularization of time-dependent density functional theory (TD-DFT), we now have a practical quantum chemical method for calculating excitation energies and transition moments in the vacuum ultraviolet (VUV) which can greatly assist in the scouting of highly transparent materials. We have performed TD-DFT calculations for a broad variety of fluorinated molecules and we will report calculated VUV photoabsorption spectra for a large family of model fluorohexanes. These calculations, which span a range from 1-fluorohexane to CH3CF2CF2CF2CF2CH3, illustrate some of the principles one may use to design low absorption polymeric materials. [Copyright &y& Elsevier]

Human epidemiologic and experimental animal studies suggest strongly that prenatal and early postnatal nutrition influence adult susceptibility to diet-related chronic disease. To elucidate biologic mechanisms linking divergent early nutritional sufficiency to adult insulin axis function in an animal model of "metabolic imprinting," this research focused on the following two objectives: 1) identify a tissue responsible for effect persistence, and 2) identify genes showing sustained differential expression in that tissue. Newborn rats were assigned randomly to small (SL), control (C) or large litters (LL) until weaning. Glucose and insulin tolerance tests were conducted directly after weaning (age 26 d) and in adulthood (ages 110 and 255 d). Glucose-stimulated insulin secretion from isolated pancreatic islets was assessed at those ages. DNA microarrays were used to identify genes showing persistent between-group differential expression in isolated islets. Glucose and insulin tolerance tests suggested persistently reduced pancreatic glucose-responsiveness in SL and LL rats. Insulin tolerance tests showed no group differences in whole-body insulin-stimulated glucose uptake. These data support the hypothesis that the endocrine pancreas contributes to primary imprinting in this model. Persistent defects in glucose-stimulated insulin secretion from isolated islets also supported this hypothesis but only in SL rats. Of 13 named islet genes showing SL vs. C differential expression at age 26 d, 10 remained differentially expressed at age 110 d. These data indicate that the endocrine pancreas plays a primary role in the putative metabolic imprinting mechanism in SL rats. [ABSTRACT FROM AUTHOR]

IR spectra for CxF2x+1CHᆖCH2 (x=1, 2, 4, 6, 8) were recorded in 700Torr of air, 298±2K. Integrated absorption cross sections (650–1800cm−1) of (1.18±0.06), (1.32±0.07), (2.43±0.12), (2.86±0.14) and (3.32±0.17)×10−16cm2molecule−1cm−1 were determined for CxF2x+1CHᆖCH2 (x=1, 2, 4, 6, 8), respectively. Radiative efficiencies of 0.159, 0.176, 0.338, 0.376, and 0.418Wm−2ppb−1 were calculated for CxF2x+1CHᆖCH2 (x=1, 2, 4, 6, 8), respectively. The title compounds have short atmospheric lifetimes (approximately 7–8 days) and 100-year global warming potentials of ≤2. CxF2x+1CHᆖCH2 (x=1, 2, 4, 6, 8) will not contribute significantly to radiative forcing of climate change. [Copyright &y& Elsevier]

A letter to the editor is presented in response to an article about the epigenetic effect of methyl donors in Auy mice by R. A. Waterland and colleagues.

Rate coefficients, k, for the gas-phase reaction of the OH radical with (E)-CF3CH=CHCF3 ((E)-1,1,1,4,4,4-hexafluoro-2-butene, HFO-1336mzz(E)) were measured over a range of temperatures (211-374 K) and bath gas pressures (20-300 Torr; He, N2) using a pulsed laser photolysis-laser-induced fluorescence (PLP-LIF) technique. k1(T) was independent of pressure over this range of conditions with k1(296 K) = (1.31 ± 0.15) × 10-13 cm3 molecule-1 s-1 and k1(T) = (6.94 ± 0.80) × 10-13exp[-(496 ± 10)/T] cm3 molecule-1 s-1, where the uncertainties are 2σ, and the pre-exponential term includes estimated systematic error. Rate coefficients for the OD reaction were also determined over a range of temperatures (262-374 K) at 100 Torr (He). The OD rate coefficients were ∼15% greater than the OH values and showed similar temperature dependent behavior with k2(T) = (7.52 ± 0.44) × 10-13exp[-(476 ± 20)/T] and k2(296 K) = (1.53 ± 0.15) × 10-13 cm3 molecule-1 s-1. The rate coefficients for reaction 1 were also measured using a relative rate technique between 296 and 375 K with k1(296 K) measured to be (1.22 ± 0.1) × 10-13 cm3 molecule-1 s-1, in agreement with the PLP-LIF results. In addition, the 296 K rate coefficient for the O3 + (E)-CF3CH=CHCF3 reaction was determined to be <5.2 × 10-22 cm3 molecule-1 s-1. A theoretical computational analysis is presented to interpret the observed positive temperature dependence for the addition reaction and the significant decrease in OH reactivity compared to the (Z)-CF3CH=CHCF3 stereoisomer reaction. The estimated atmospheric lifetime of (E)-CF3CH=CHCF3, due to loss by reaction with OH, is estimated to be ∼90 days, while the actual lifetime will depend on the location and season of its emission. Infrared absorption spectra of (E)-CF3CH=CHCF3 were measured and used to estimate the 100 year time horizon global warming potentials (GWP) of 32 (atmospherically well-mixed) and 14 (lifetime-adjusted). [ABSTRACT FROM AUTHOR]

Locomotion is a defining characteristic of animal life and plays a crucial role in most behaviors. Locomotion involves physical activity, which can have far-reaching effects on physiology and neurobiology, both acutely and chronically. In human populations and in laboratory rodents, higher levels of physical activity are generally associated with positive health outcomes, although excessive exercise can have adverse consequences. Whether and how such relationships occur in wild animals is unknown. Behavioral variation among individuals arises from genetic and environmental factors and their interactions as well as from developmental programming (persistent effects of early-life environment). Although tremendous progress has been made in identifying genetic and environmental influences on individual differences in behavior, early-life effects are not well understood. Early-life effects can in some cases persist across multiple generations following a single exposure and, in principle, may constrain or facilitate the rate of evolution at multiple levels of biological organization. Understanding the mechanisms of such transgenerational effects (e.g., exposure to stress hormones in utero, inherited epigenetic alterations) may prove crucial to explaining unexpected and/or sex-specific responses to selection as well as limits to adaptation. One area receiving increased attention is early-life effects on adult physical activity. Correlational data from epidemiological studies suggest that early-life nutritional stress can (adversely) affect adult human activity levels and associated physiological traits (e.g., body composition, metabolic health). The few existing studies of laboratory rodents demonstrate that both maternal and early-life exercise can affect adult levels of physical activity and related phenotypes. Going forward, rodents offer many opportunities for experimental studies of (multigenerational) early-life effects, including studies that use maternal exposures and cross-fostering designs. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the epigenetic epidemiology of obesity. Epigenetic epidemiology describes the study of the association between epigenetic variation and risk of disease. It is mentioned that methylated CpG island amplification coupled with microarray hybridization (MCAM) is an effective tool to identify regions of hypermethylation. MCAM also provides a new capability to perform genome-wide screens for locus-specific deoxyribonucleic acid (DNA) methylation alterations in normal tissues. Additionally, an illustration which shows the methylated CpG island amplification coupled with MCAM method is presented.

Dietary supplementation of female mice with methyl donors and cofactors before and during pregnancy induces CpG hypermethylation at the viable yellow agouti (Avy) locus in Avy/a offspring. Epigenetic inheritance occurs at Avy: when passed through the female germline, Avy epigenotype is not completely 'reset'. We therefore tested whether diet-induced epigenetic alterations at Avy are inherited transgenerationally. Female Avy/a mice (matched for Avy methylation) were weaned onto either control (NIH-31, n=6) or methyl supplemented diet (NIH-31 supplemented with extra folic acid, vitamin B12, betaine, and choline, n=5). At age 8 wk these F0 dams were mated with a/a males. All F1 and F2 Avy/a females were weaned onto the same diet as their mothers and subsequently mated with a/a males. F1, F2, and F3 Avy/a offspring were classified for coat color, an indicator of Avy methylation. In total, 62 F1, 98 F2, and 181 F3 Avy/a mice were studied. Data were analyzed by ANOVA. As expected, average Avy/a coat color was darker in the supplemented group (P=0.006). However, neither the effect of generation (P=0.73) nor the supplementation x generation interaction (P=0.60) was significant. These results indicate that either the germline lineage is protected from diet-induced hypermethylation at Avy, or such alterations are not retained during oogenesis. [ABSTRACT FROM AUTHOR]

Comments on the article by Cooney and others about the potential for metabolic imprinting to occur through epigenetic mechanisms. Perception of the importance of epigenetics to understanding diet-health relationships; Effects of maternal dietary methyl supplementation on the coat color distribution of heterozygous.

The article reports that sex-specific epigenetic mechanisms regulate neurodevelopment and demonstrates how human genomic regions are associated with body mass index in humans. It discusses the limited ontogenic windows, and sex differences in sensitivity to developmental programming of obesity and provides a resource for epigenetic analyses of developmental programming of energy balance.

The article focuses on DNA methylation at a nutritionally sensitive region of the PAX8 gene is associated with thyroid volume and function in Gambian children. Topics include PAX8 is a key thyroid transcription factor implicated in thyroid gland differentiation and function, PAX8 gene methylation is reported to be sensitive to the periconceptional environment, and Free T4 was associated with a decrease in DXA-derived body fat and bone mineral density.

During development, a small but significant number of CpG islands (CGIs) become methylated. The timing of developmentally programmed CGI methylation and associated mechanisms of transcriptional regulation during cellular differentiation, however, remain poorly characterized. Here, we used genome-wide DNA methylation microarrays to identify epigenetic changes during human embryonic stem cell (hESC) differentiation. We discovered a group of CGIs associated with developmental genes that gain methylation after hESCs differentiate. Conversely, erasure of methylation was observed at the identified CGIs during subsequent reprogramming to induced pluripotent stem cells (iPSCs), further supporting a functional role for the CGI methylation. Both global gene expression profiling and quantitative reverse transcription-PCR (RT-PCR) validation indicated opposing effects of CGI methylation in transcriptional regulation during differentiation, with promoter CGI methylation repressing and 3' CGI methylation activating transcription. By studying diverse human tissues and mouse models, we further confirmed that developmentally programmed 3' CGI methylation confers tissue- and cell-type-specific gene activation in vivo. Importantly, luciferase reporter assays provided evidence that 3' CGI methylation regulates transcriptional activation via a CTCF-dependent enhancer-blocking mechanism. These findings expand the classic view of mammalian CGI methylation as a mechanism for transcriptional silencing and indicate a functional role for 3' CGI methylation in developmental gene regulation. [ABSTRACT FROM AUTHOR]

In response to recent regulations and concern over climate change, the global automotive community is evaluating alternatives to the current refrigerant used in automobile air conditioning units, 1,1,1,2-tetrafluoroethane, HFC-134a. One potential alternative is 2,3,3,3-tetrafluoropropene (HFC-1234yf, also known as HFO-1234yf). We have developed a spatially and temporally resolved inventory of likely future HFC refrigerant emissions from the U.S. vehicle fleet in 2017, considering regular, irregular, servicing, and end-of-life leakages. We estimate the annual leak rate emissions for each leakage category for a projected 2017 U.S. vehicle fleet by state, and spatially apportion these leaks to a 36 km square grid over the continental United States. This projected inventory is a necessary first step in analyzing for potential atmospheric and ecosystem effects, such as ozone and trifluoroacetic acid production, that might result from widespread replacement of HFC-134a with HFC-1234yf. [ABSTRACT FROM AUTHOR]

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 (Avy/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. [ABSTRACT FROM AUTHOR]

Abstract: Fundulus heteroclitus (Atlantic killifish or mummichog) inhabiting a creosote-contaminated Superfund site on the Elizabeth River (VA, USA), exhibit a lack of induction of cytochrome P4501A (CYP1A) mRNA, immunodetectable protein, and catalytic activity after exposure to typical inducers. This “refractory CYP1A phenotype” is not explained by alterations in mRNA expression of known CYP1A transcription factors. Furthermore, the refractory phenotype is lost progressively during development in laboratory-reared F1 generation fish. Thus, while heritable, the refractory CYP1A phenotype does not appear to be genetically based. To test the hypothesis that cytosine methylation at CpG sites in the promoter region of CYP1A underlies the refractory CYP1A phenotype, we employed bisulfite sequencing to compare the methylation status of CpG sites in the CYP1A promoter region of DNA from killifish from the Elizabeth River and a reference site. We examined genomic DNA both from livers of wild-caught adult killifish and from pools of F1 generation embryos raised in the laboratory. In fish from both the contaminated and the reference site, cytosine methylation was not detectable at any of the 34 CpG sites examined, including 3 that are part of putative xenobiotic response elements. [Copyright &y& Elsevier]

Objective: To evaluate the effect of infertility and intracytoplasmic sperm injection (ICSI) on DNA methylation of offspring.Design: Microarray analysis of DNA methylation in archived neonatal bloodspots of in vitro fertilization (IVF)/ICSI-conceived children compared with controls born to fertile and infertile parents.Setting: Academic research laboratory.Patient(s): Neonatal blood spots of 137 newborns conceived spontaneously, through intrauterine insemination (IUI), or through ICSI using fresh or cryopreserved (frozen) embryo transfer.Intervention(s): None.Main Outcome Measure(s): The Illumina Infinium HumanMethylation450k BeadChip assay determined genome-wide DNA methylation. Methylation differences between conception groups were detected using a Bioconductor package, ChAMP, in conjunction with Adjacent Site Clustering (A-clustering).Result(s): The methylation profiles of assisted reproductive technology and IUI newborns were dramatically different from those of naturally (in vivo) conceived newborns. Interestingly, the profiles of ICSI-frozen (FET) and IUI infants were strikingly similar, suggesting that cryopreservation may temper some of the epigenetic aberrations induced by IVF or ICSI. The DNA methylation changes associated with IVF/ICSI culture conditions and/or parental infertility were detected at metastable epialleles, suggesting a lasting impact on a child's epigenome.Conclusion(s): Both infertility and ICSI alter DNA methylation at specific genomic loci, an effect that is mitigated to some extent by FET. The impact of assisted reproductive technology and/or fertility status on metastable epialleles in humans was uncovered. This study provides an expanded set of loci for future investigations on IVF populations. [ABSTRACT FROM AUTHOR]

Previous rodent studies have shown that maternal voluntary exercise during pregnancy leads to metabolic changes in adult offspring. We set out to test whether maternal voluntary exercise during pregnancy also induces persistent changes in voluntary physical activity in the offspring. Adult C57BL/6J female mice were randomly assigned to be caged with an unlocked (U) or locked (L) running wheel before and during pregnancy. Maternal running behavior was monitored during pregnancy, and body weight, body composition, food intake, energy expenditure, total cage activity, and running wheel activity were measured in the offspring at various ages. Uoffspringwere slightly heavier at birth, but no group differences in body weight or composition were observed at later ages (when mice were caged without access to running wheels). Consistent with our hypothesis, U offspring were more physically active as adults. This effect was observed earlier in female offspring (at sexual maturation). Remarkably, at 300 d of age, U females achieved greater fat loss in response to a 3-wk voluntary exercise program. Our findings show for the first time thatmaternal physical activity during pregnancy affects the offspring's lifelong propensity for physical activity and may have important implications for combating the worldwide epidemic of physical inactivity and obesity. [ABSTRACT FROM AUTHOR]

The double burden of under- and overnutrition profoundly affects human health globally. According to the World Health Organization, obesity and diabetes rates have almost doubled worldwide since 1980, and, in 2011, more than 40 million children under 5 years of age were overweight. Ecologic factors, parental genetics and fitness, and the intrauterine environment significantly influence the likelihood of offspring developing the dysmetabolic diathesis of obesity. This report examines the effects of these factors, including preconception, intrauterine and postnatal energy balance affecting programming of transgenerational transmission, and development of chronic diseases later in life-in particular, diabesity and its comorbidities. [ABSTRACT FROM AUTHOR]

Mixtures of methyl-perfluoroheptene-ethers (CH3OC7F13, MPHEs) are currently in use as replacements for perfluorinated alkanes (PFCs) and poly-ether heat transfer fluids, which are persistent greenhouse gases with lifetimes >1000 years. At present, the atmospheric processing and environmental impact from the use of MPHEs is unknown. In this work, rate coefficients at 296 K for the gas-phase reaction of the OH radical with six key isomers (including stereoisomers and enantiomers) of MPHEs used commercially were measured using a relative rate method- Rate coefficients for the six MPHE isomers ranged from ∼0.1 to 2.9 X 1012 cm3 molecule-1 s-1 with a strong stereoisomer and -OCH3 group position dependence; the (E)-stereoisomers with the -OCH3 group in an α- position relative to the double bond had the greatest reactivity. Rate coefficients measured for the dyMPHE isomer analogues showed decreased reactivity consistent with a minor contribution of H atom abstraction from the -OCH3 group to the overall reactivity. Estimated atmospheric lifetimes for the MPHE isomers range from days to months. Atmospheric lifetimes, radiative efficiencies, and global warming potentials for these short-lived MPHE isomers were estimated based on the measured OH rate coefficients along widi measured and theoretically calculated MPHE infrared absorption spectra. Our results highlight the importance of quantifying the atmospheric impact of individual components in an isomeric mixture. [ABSTRACT FROM AUTHOR]

Decades of research in rodent models has shown that early postnatal overnutrition induces excess adiposity and other components of metabolic syndrome that persist into adulthood. The specific biologic mechanisms explaining the persistence of these effects, however, remain unknown. On postnatal day 1 (P1), mice were fostered in control (C) or small litters (SL). SL mice had increased body weight and adiposity at weaning (P21), which persisted to adulthood (P180). Detailed metabolic studies indicated that female adult SL mice have decreased physical activity and energy expenditure but not increased food intake. Genomescale DNA methylation profiling identified extensive changes in hypothalamic DNA methylation during the suckling period, suggesting that it is a critical period for developmental epigenetics in the mouse hypothalamus. Indeed, SL mice exhibited subtle and sex-specific changes in hypothalamic DNA methylation that persisted from early life to adulthood, providing a potential mechanistic basis for the sustained physiological effects. Expression profiling in adult hypothalmnus likewise provided evidence of widespread sex-specific alterations in geene expression. Together, our data indicate that early postnatal overnutrition leads to a reduction in spontaneous physical activity and energy expenditure in females and suggest that early postnatal life is a critical period during which nutrition can affect hypothalamic developmental epigenetics. [ABSTRACT FROM AUTHOR]

A next-generation mobile automobile air-conditioning (MAC) refrigerant, HFO-1234yf (CF3CF = CH2), is being developed with improved environmental characteristics. In the atmosphere, it ultimately forms trifluoroacetic acid (TFA(A); CF3COOH), which is subsequently scavenged by precipitation and deposited on land and water as trifluoroacetate (TFA; CF3COO-). Trifluoroacetate is environmentally stable and has the potential to accumulate in terminal water bodies, that is, aquatic systems receiving inflow but with little or no outflow and with high rates of evaporation. Previous studies have estimated the emission rates of HFO-1234yf and have modeled the deposition concentrations and rates of TFA across North America. The present study uses multimedia modeling and geographic information system (GIS)-based modeling to assess the potential concentrations of TFA in terminal water bodies over extended periods. After 10 years of emissions, predicted concentrations of TFA in terminal water bodies across North America are estimated to range between current background levels (i.e., 0.01-0.22 µg/L) and 1 to 6 µg/L. After 50 years of continuous emissions, aquatic concentrations of 1 to 15 µg/L are predicted, with extreme concentrations of up to 50 to 200 µg/L in settings such as the Sonoran Desert along the California/Arizona (USA) border. Based on the relative insensitivity of aquatic organisms to TFA, predicted concentrations of TFA in terminal water bodies are not expected to impair aquatic systems, even considering potential emissions over extended periods. Environ. Toxicol. Chem. 2012; 31: 1957-1965. © 2012 SETAC [ABSTRACT FROM AUTHOR]

The obesity epidemic is a global issue and shows no signs of abating, while the cause of this epidemic remains unclear. Marketing practices of energy-dense foods and institutionally-driven declines in physical activity are the alleged perpetrators for the epidemic, despite a lack of solid evidence to demonstrate their causal role. While both may contribute to obesity, we call attention to their unquestioned dominance in program funding and public efforts to reduce obesity, and propose several alternative putative contributors that would benefit from equal consideration and attention. Evidence for microorganisms, epigenetics, increasing maternal age, greater fecundity among people with higher adiposity, assortative mating, sleep debt, endocrine disruptors, pharmaceutical iatrogenesis, reduction in variability of ambient temperatures, and intrauterine and intergenerational effects as contributing factors to the obesity epidemic are reviewed herein. While the evidence is strong for some contributors such as pharmaceutical-induced weight gain, it is still emerging for other reviewed factors. Considering the role of such putative etiological factors of obesity may lead to comprehensive, cause specific, and effective strategies for prevention and treatment of this global epidemic. [ABSTRACT FROM AUTHOR]

An empirical correlation has been derived between accepted atmospheric lifetimes of a set of hydrofluorocarbons and hydrofluoroethers and relative rates of reaction with photolyzed chlorine in excess at ambient temperature. These kinetic systems were studied by nuclear magnetic resonance (NMR) spectroscopy in the gas phase, marking the first application of NMR spectroscopy to this field. The square of the Pearson coefficient R for the linear correlation between observed reaction rates and accepted atmospheric lifetimes was 0.87 for compounds of lifetime less than 20 years. The method was extended to the study of ethene and propene; the rate of reaction of propene was found to be 1.25 times that of ethene at 23 °C. The chief advantage of this method is its simplicity and reliance only on common tools and techniques of an industrial chemical laboratory. [ABSTRACT FROM AUTHOR]

The role of CpG island methylation in normal development and cell differentiation is of keen interest, but remains poorly understood. We performed comprehensive DNA methylation profiling of promoter regions in normal peripheral blood by methylated CpG island amplification in combination with microarrays. This technique s allowed us to simultaneously determine the methylation status of 6,177 genes, 92% of which include dense CpG islands. Among these 5,549 autosomal genes with dense CpG island promoters, we have identified 4.0% genes that are nearly completely methylated in normal blood, providing another exception to the general rule that CpG island methylation in normal tissue is limited to X inactivation and imprinted genes. We examined seven genes in detail, including ANKRD30A, FLJ40201, INSL6, SOHLH2, FTMT, C12orf12, and DPPA5. Dense promoter CpG island methylation and gene silencing were found in normal tissues studied except testis and sperm. In both tissues, bisulfite cloning and sequencing identified cells carrying unmethylated alleles. Interestingly, hypomethylation of several genes was associated with gene activation in cancer. Furthermore, reactivation of silenced genes could be induced after treatment with a DNA demethylating agent or in a cell line lacking DNMT1 and/or DNMT3b. Sequence analysis identified five motifs significantly enriched in this class of genes, suggesting that cis-regulatory elements may facilitate preferential methylation at these promoter CpG islands. We have identified a group of non-X-linked bona fide promoter CpG islands that are densely methylated in normal somatic tissues, escape methylation in germline cells, and for which DNA methylation is a primary mechanism of tissue-specific gene silencing. [ABSTRACT FROM AUTHOR]

A high spatial and temporal resolution atmospheric model is used to evaluate the potential contribution of fluorotelomer alcohol (FTOH) and perfluorocarboxylate (PFCA) emissions associated with the manufacture, use, and disposal of DuPont fluorotelomer-based products in North America to air concentrations of FTOH, perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) in North America and the Canadian Arctic. A bottom-up emission inventory for PFCAs and FTOHs was developed from sales and product composition data. A detailed FTOH atmospheric degradation mechanism was developed to simulate FTOH degradation to PFCAs and model atmospheric transport of PFCAs and FTOHs. Modeled PFCA yields from FTOH degradation agree with experimental smog-chamber results supporting the degradation mechanism used. Estimated PFCA and FTOH air concentrations and PFCA deposition fluxes are compared to monitoring data and previous global modeling. Predicted FTOH air concentrations are generally in agreement with available monitoring data. Overall emissions from the global fluorotelomer industry are estimated to contribute approximately 1–2% of the PFCAs in North American rainfall, consistent with previous global emissions estimates. Emission calculations and modeling results indicate that atmospheric inputs of PECAs in North America from fluorotelomer-based products will decline by an order of magnitude in the near future as a result of current industry commitments to reduce manufacturing emissions and lower the residual fluorotelomer alcohol raw material and trace PFCA product content. [ABSTRACT FROM AUTHOR]

Vapor pressure and aqueous solubility are important parameters used to estimate the potential for transport of chemical substances in the atmosphere. For fluorotelomer alcohols (FTOHs), currently under scrutiny by environmental scientists as potential precursors of persistent perfluorocarboxylates (PFCAs), vapor pressure is the more significant property since these compounds are only very sparingly soluble in water. We have measured the vapor pressures of a homologous series of fluorotelomer alcohols, F(CF2CF2)nCH2CH2OH (n = 2−5), in the temperature range 21−250 °C by three independent methods: (a) a method suitable for very low vapor pressures at ambient temperatures (gas-saturation method), (b) an improved boiling point method at controlled pressures (Scott method), and (c) a novel method, requiring milligram quantities of substance, based on gas-phase NMR, a technique largely unfamiliar to chemists and holding promise for studies of relevance to environmental chemistry. The concordant values obtained indicate that recently published vapor pressure data overestimate the vapor pressure at ambient temperature, and therefore the volatility, of this series of fluorinated compounds. It was suggested that substantial intramolecular −O−H···F− hydrogen bonding between the hydroxylic proton and the two fluorines next to the ethanol moiety was responsible for their putative high volatility. Therefore, we have used gas-phase NMR, gas-phase FTIR, 2D NMR heteronuclear Overhauser effect measurements, and high-level ab initio computations to investigate the intramolecular hydrogen bonding in fluorotelomer alcohols. Our studies unequivocally show that hydrogen bonding of this type is not significant and cannot contribute to and cause unusual volatility. The substantially lower vapor pressure at ambient temperatures than previously reported resulting from our work is important in developing a valid understanding of the environmental transport behavior of this class of compounds. [ABSTRACT FROM AUTHOR]

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are persistent organic pollutants which may alter prenatal development, potentially through epigenetic modifications. Prior studies examining PFOS/PFOA and DNA methylation have relatively few subjects (n < 200) and inconsistent results. We examined relations of PFOA/PFOS with DNA methylation among 597 neonates in the Upstate KIDS cohort study. PFOA/PFOS were quantified in newborn dried blood spots (DBS) using high-performance liquid chromatography/tandem mass spectrometry. DNA methylation was measured using the Infinium MethylationEPIC BeadChip with DNA extracted from DBS. Robust linear regression was used to examine the associations of PFOA/PFOS with DNA methylation at individual CpG sites. Covariates included sample plate, estimated cell type, epigenetically derived ancestry, infant sex and plurality, indicators of maternal socioeconomic status, and prior pregnancy loss. In supplemental analysis, we restricted the analysis to 2242 CpG sites previously identified as Correlated Regions of Systemic Interindividual Variation (CoRSIVs) which include metastable epialleles. At FDR<0.05, PFOA concentration >90th percentile was related to DNA methylation at cg15557840, near SCRT2, SRXN1 ; PFOS>90th percentile was related to 2 CpG sites in a sex-specific manner (cg19039925 in GVIN1 in boys and cg05754408 in ZNF26 in girls). When analysis was restricted to CoRSIVs, log-scaled, continuous PFOS concentration was related to DNA methylation at cg03278866 within PTBP1. In conclusion, there was limited evidence of an association between high concentrations of PFOA/PFOS and DNA methylation in newborn DBS in the Upstate KIDS cohort. These findings merit replication in populations with a higher median concentration of PFOA/PFOS. • PFOS and PFOA were measured in newborn dried blood spots (DBS). • DNA was extracted from DBS to study methylation. • High PFOA/PFOS (>90th percentile) is related to DNA methylation at select CpG sites. • Findings are limited and need replication in cohorts with higher PFOA/PFOS exposure. [ABSTRACT FROM AUTHOR]