Marie-Claude Senut

Detroit R&D (United States)

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Arko Sen

University of Alabama at Birmingham

Douglas M. Ruden

University of Utah

Susan Land

Institute of Electrical and Electronics Engineers

Nicole Heredia

Wayne State University

Qu Wen

Wayne State University

Mary O. Dereski

Oakland University

Xiangyi Lu

Guangzhou University of Chinese Medicine

Pablo Cingolani

Hospital Universitario Austral

Kurt Hollocher

Union College

Adriana Mercado‐García

Instituto Nacional de Salud Pública

Cooperative Institutions

Wayne State University

Harvard University

Michigan State University

Instituto Nacional de Perinatología

Emory University

Icahn School of Medicine at Mount Sinai

University of Alabama at Birmingham

Environmental Health

Michigan United

University of Michigan–Ann Arbor

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Lead exposure induces changes in 5-hydroxymethylcytosine clusters in CpG islands in human embryonic stem cells and umbilical cord blood

Epigenetics (2015)

Arko Sen Pablo Cingolani Marie-Claude Senut Susan Land Adriana Mercado‐García

Prenatal exposure to neurotoxicants such as lead (Pb) may cause stable changes in the DNA methylation (5mC) profile of the fetal genome. However, few studies have examined its effect on the DNA de-methylation pathway, specifically the dynamic changes of the 5-hydroxymethylcytosine (5hmC) profile. Therefore, in this study, we investigate the relationship between Pb exposure and 5mC and 5hmC modifications during early development. To study the changes in the 5hmC profile, we use a novel modification of the Infinium™ HumanMethylation450 assay (Illumina, Inc.), which we named HMeDIP-450K assay, in an in vitro human embryonic stem cell model of Pb exposure. We model Pb exposure-associated 5hmC changes as clusters of correlated, adjacent CpG sites, which are co-responding to Pb. We further extend our study to look at Pb-dependent changes in high density 5hmC regions in umbilical cord blood DNA from 48 mother-infant pairs from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohort. For our study, we randomly selected umbilical cord blood from 24 male and 24 female children from the 1st and 4th quartiles of Pb levels. Our data show that Pb-associated changes in the 5hmC and 5mC profiles can be divided into sex-dependent and sex-independent categories. Interestingly, differential 5mC sites are better markers of Pb-associated sex-dependent changes compared to differential 5hmC sites. In this study we identified several 5hmC and 5mC genomic loci, which we believe might have some potential as early biomarkers of prenatal Pb exposure.

CpG site

Cord blood

10.1080/15592294.2015.1050172

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Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren

Scientific Reports (2015)

Arko Sen Nicole Heredia Marie-Claude Senut Susan Land Kurt Hollocher

Abstract We report that the DNA methylation profile of a child’s neonatal whole blood can be significantly influenced by his or her mother’s neonatal blood lead levels (BLL). We recruited 35 mother-infant pairs in Detroit and measured the whole blood lead (Pb) levels and DNA methylation levels at over 450,000 loci from current blood and neonatal blood from both the mother and the child. We found that mothers with high neonatal BLL correlate with altered DNA methylation at 564 loci in their children’s neonatal blood. Our results suggest that Pb exposure during pregnancy affects the DNA methylation status of the fetal germ cells, which leads to altered DNA methylation in grandchildren’s neonatal dried blood spots. This is the first demonstration that an environmental exposure in pregnant mothers can have an epigenetic effect on the DNA methylation pattern in the grandchildren.

Blood lead level

10.1038/srep14466

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Epigenetics as an answer to Darwinâ€™s â€œspecial difficulty,â€ Part 2: natural selection of metastable epialleles in honeybee castes

Frontiers in Genetics (2015)

Douglas M. Ruden Pablo E. Cingolani Arko Sen Qu Wen Luan Wang

In a recent perspective in this journal, Brian R. Herb discussed how epigenetics is a possible mechanism to circumvent Charles Darwin’s “special difficulty” in using natural selection to explain the existence of the sterile-fertile dimorphism in eusocial insects. Darwin’s classic book “On the Origin of Species by Means of Natural Selection” explains how natural selection of the fittest individuals in a population can allow a species to adapt to a novel or changing environment. However, in bees and other eusocial insects, such as ants and termites, there exist two or more castes of genetically similar females, from fertile queens to multiple sub-castes of sterile workers, with vastly different phenotypes, lifespans, and behaviors. This necessitates the selection of groups (or kin) rather than individuals in the evolution of honeybee hives, but group and kin selection theories of evolution are controversial and mechanistically uncertain. Also, group selection would seem to be prohibitively inefficient because the effective population size of a colony is reduced from thousands to a single breeding queen. In this follow-up perspective, we elaborate on possible mechanisms for how a combination of both epigenetics, specifically, the selection of metastable epialleles, and genetics, the selection of mutations generated by the selected metastable epialleles, allows for a combined means for selection amongst the fertile members of a species to increase colony fitness. This “intra-caste evolution” hypothesis is a variation of the epigenetic directed genetic error (EDGE) hypothesis, which proposes that selected metastable epialleles increase genetic variability by directing mutations specifically to the epialleles. Natural selection of random metastable epialleles followed by a second round of natural selection of random mutations generated by the metastable epialleles would allow a way around the small effective population size of eusocial insects.

Eusociality

10.3389/fgene.2015.00060

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Epigenetics of Early-Life Lead Exposure and Effects on Brain Development

Epigenomics (2012)

Marie-Claude Senut Pablo Cingolani Arko Sen Adéle Kruger Asra N. Shaik

The epigenetic machinery plays a pivotal role in the control of many of the body's key cellular functions. It modulates an array of pliable mechanisms that are readily and durably modified by intracellular or extracellular factors. In the fast-moving field of neuroepigenetics, it is emerging that faulty epigenetic gene regulation can have dramatic consequences on the developing CNS that can last a lifetime and perhaps even affect future generations. Mounting evidence suggests that environmental factors can impact the developing brain through these epigenetic mechanisms and this report reviews and examines the epigenetic effects of one of the most common neurotoxic pollutants of our environment, which is believed to have no safe level of exposure during human development: lead.

Epigenesis

10.2217/epi.12.58

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Citations (126)

The Use of Nonneuronal Cells for Gene Delivery

Neurobiology of Disease (1997)

Evan Y. Snyder Marie-Claude Senut

Ectopic expression

10.1006/nbdi.1997.0138

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An Element in the α1-Tubulin Promoter Is Necessary for Retinal Expression during Optic Nerve Regeneration But Not after Eye Injury in the Adult Zebrafish

Journal of Neuroscience (2004)

Marie-Claude Senut Abhilasha Gulati-Leekha Daniel Goldman

We have shown previously that a 1.696 kb upstream fragment of the goldfish α1-tubulin promoter was capable of driving green fluorescent protein (GFP) expression in the developing and regenerating zebrafish CNS in a pattern closely mimicking the endogenous α1-tubulin gene. Comparison of fish and rat α1-tubulin promoters identified a 64 bp region with a conserved repetitive homeodomain (HD) consensus sequence core (TAAT) and a nearby basic helix—loop-helix binding E-box sequence (CANNTG), which led us to speculate that it could be of importance for regulating α1-tubulin gene transcription. To address this issue, we examined the ability of deletion mutants of the 1.696 kb promoter to drive expression of GFP in zebrafish retinal cells under normal conditions and after injury. Interestingly, although wild-type 1.696 kb and mutant promoters, lacking the E-box and/or HD sequences, exhibited rather similar patterns of GFP expression in the developing retina, significant differences were noticed in the mature retina. First, although the 1.696 kb promoter directed transgene expression to retinal neurons and progenitor cells, the activity of mutant promoters was drastically reduced. Second, we found that the E-box and HD sequences were necessary for transgene reinduction during optic nerve regeneration, but were not as important for transgene expression in regenerating retinal neurons after eye injury. In this latter lesion model, remarkably, both 1.696 kb and mutant promoters targeted GFP expression to Müller glia-like cells, some of which re-entered the cell cycle. These new findings will be useful for identifying the molecular signals necessary for successful CNS regeneration.

10.1523/jneurosci.2281-04.2004

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Early Life Lead Exposure Causes Gender-Specific Changes in the DNA Methylation Profile of DNA Extracted from Dried Blood Spots

Epigenomics (2015)

Arko Sen Nicole Heredia Marie-Claude Senut Matthew C. Hess Susan Land

Aims: In this paper, we tested the hypothesis that early life lead (Pb) exposure associated DNA methylation (5 mC) changes are dependent on the sex of the child and can serve as biomarkers for Pb exposure. Methods: In this pilot study, we measured the 5mC profiles of DNA extracted from dried blood spots (DBS) in a cohort of 43 children (25 males and 18 females; ages from 3 months to 5 years) from Detroit. Result & Discussion: We found that the effect of Pb-exposure on the 5-mC profiles can be separated into three subtypes: affected methylation loci which are conserved irrespective of the sex of the child (conserved); affected methylation loci unique to males (male-specific); and affected methylation loci unique to females (female-specific).

Spots

Dried blood

10.2217/epi.15.2

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Distribution of carnosine-like peptides in the nervous system of developing and adult zebrafish (Danio rerio) and embryonic effects of chronic carnosine exposure

Cell and Tissue Research (2009)

Marie-Claude Senut Seema Azher Frank L. Margolis Kamakshi Patel Ahmad Mousa

Carnosine

Danio

Immunostaining

Anserine

10.1007/s00441-009-0796-8

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Citations (7)