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Skinner, 2007

Skinner MK1, “Endocrine disruptors and epigenetic transgenerational disease etiology,” Pediatric Research, 2007, 61:5 Pt 2.

ABSTRACT: Exposure to an environmental factor (e.g. endocrine disruptor) during embryonic gonadal sex determination appears to be epigenetically reprogram the male germ-line and subsequently promote transgenerational adult-onset disease. Disease phenotypes resulting from this epigenetic phenomenon include testis abnormalities, prostate disease, kidney disease, tumor development, and immune abnormalities. The epigenetic mechanism is hypothesized to involve the induction of new imprinted-like DNA sequences in the germ-line to transgenerationally transmit disease phenotypes. This epigenetic transgenerational disease mechanism provides a unique perspective from which to view adult onset disease and ultimately offers new insights into novel diagnostic and therapeutic strategies.  FULL TEXT

Skinner et al., 2012

Skinner MK, Manikkam M, Haque MM, Zhang B, Savenkova MI, “Epigenetic transgenerational inheritance of somatic transcriptomes and epigenetic control regions,” Genome Biology, 2012, 13:10, DOI: 10.1186/gb-2012-13-10-r91.


BACKGROUND: Environmentally induced epigenetic transgenerational inheritance of adult onset disease involves a variety of phenotypic changes, suggesting a general alteration in genome activity.

RESULTS: Investigation of different tissue transcriptomes in male and female F3 generation vinclozolin versus control lineage rats demonstrated all tissues examined had transgenerational transcriptomes. The microarrays from 11 different tissues were compared with a gene bionetwork analysis. Although each tissue transgenerational transcriptome was unique, common cellular pathways and processes were identified between the tissues. A cluster analysis identified gene modules with coordinated gene expression and each had unique gene networks regulating tissue-specific gene expression and function. A large number of statistically significant over-represented clusters of genes were identified in the genome for both males and females. These gene clusters ranged from 2-5 megabases in size, and a number of them corresponded to the epimutations previously identified in sperm that transmit the epigenetic transgenerational inheritance of disease phenotypes.

CONCLUSIONS: Combined observations demonstrate that all tissues derived from the epigenetically altered germ line develop transgenerational transcriptomes unique to the tissue, but common epigenetic control regions in the genome may coordinately regulate these tissue-specific transcriptomes. This systems biology approach provides insight into the molecular mechanisms involved in the epigenetic transgenerational inheritance of a variety of adult onset disease phenotypes.   FULL TEXT

Skinner et al., 2013a

Skinner MK, Guerrero-Bosagna C, Haque M, Nilsson E, Bhandari R, McCarrey JR, “Environmentally induced transgenerational epigenetic reprogramming of primordial germ cells and the subsequent germ line,” PLoS One, 2013, 8:7, DOI: 10.1371/journal.pone.0066318.  (Erratum in PLoS One. 2013;8(7). DOI:10.1371/annotation/7683bb48-85db-4c7e-87c0-304a7d53a587.)

ABSTRACT: A number of environmental factors (e.g. toxicants) have been shown to promote the epigenetic transgenerational inheritance of disease and phenotypic variation. Transgenerational inheritance requires the germline transmission of altered epigenetic information between generations in the absence of direct environmental exposures. The primary periods for epigenetic programming of the germ line are those associated with primordial germ cell development and subsequent fetal germline development. The current study examined the actions of an agricultural fungicide vinclozolin on gestating female (F0 generation) progeny in regards to the primordial germ cell (PGC) epigenetic reprogramming of the F3 generation (i.e. great-grandchildren). The F3 generation germline transcriptome and epigenome (DNA methylation) were altered transgenerationally. Interestingly, disruptions in DNA methylation patterns and altered transcriptomes were distinct between germ cells at the onset of gonadal sex determination at embryonic day 13 (E13) and after cord formation in the testis at embryonic day 16 (E16). A larger number of DNA methylation abnormalities (epimutations) and transcriptional alterations were observed in the E13 germ cells than in the E16 germ cells. These observations indicate that altered transgenerational epigenetic reprogramming and function of the male germline is a component of vinclozolin induced epigenetic transgenerational inheritance of disease. Insights into the molecular control of germline transmitted epigenetic inheritance are provided.   FULL TEXT

Skinner et al., 2013b

Skinner MK, Manikkam M, Tracey R, Guerrero-Bosagna C, Haque M, Nilsson EE, “Ancestral dichlorodiphenyltrichloroethane (DDT) exposure promotes epigenetic transgenerational inheritance of obesity,” BMC Medicine, 2013, 11:228, DOI: 10.1186/1741-7015-11-228.


BACKGROUND: Ancestral environmental exposures to a variety of environmental factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. The present work examined the potential transgenerational actions of the insecticide dichlorodiphenyltrichloroethane (DDT) on obesity and associated disease.

METHODS: Outbred gestating female rats were transiently exposed to a vehicle control or DDT and the F1 generation offspring bred to generate the F2 generation and F2 generation bred to generate the F3 generation. The F1 and F3 generation control and DDT lineage rats were aged and various pathologies investigated. The F3 generation male sperm were collected to investigate methylation between the control and DDT lineage male sperm.

RESULTS: The F1 generation offspring (directly exposed as a fetus) derived from the F0 generation exposed gestating female rats were not found to develop obesity. The F1 generation DDT lineage animals did develop kidney disease, prostate disease, ovary disease and tumor development as adults. Interestingly, the F3 generation (great grand-offspring) had over 50% of males and females develop obesity. Several transgenerational diseases previously shown to be associated with metabolic syndrome and obesity were observed in the testis, ovary and kidney. The transgenerational transmission of disease was through both female (egg) and male (sperm) germlines. F3 generation sperm epimutations, differential DNA methylation regions (DMR), induced by DDT were identified. A number of the genes associated with the DMR have previously been shown to be associated with obesity.

CONCLUSIONS: Observations indicate ancestral exposure to DDT can promote obesity and associated disease transgenerationally. The etiology of disease such as obesity may be in part due to environmentally induced epigenetic transgenerational inheritance.   FULL TEXT

Nilsson et al., 2012

Nilsson E, Larsen G, Manikkam M, Guerrero-Bosagna C, Savenkova MI, Skinner MK, “Environmentally induced epigenetic transgenerational inheritance of ovarian disease,” PLoS ONE, 2012, 7:5, DOI: 10.1371/journal.pone.0036129.

ABSTRACT:  The actions of environmental toxicants and relevant mixtures in promoting the epigenetic transgenerational inheritance of ovarian disease was investigated with the use of a fungicide, a pesticide mixture, a plastic mixture, dioxin and a hydrocarbon mixture. After transient exposure of an F0 gestating female rat during embryonic gonadal sex determination, the F1 and F3 generation progeny adult onset ovarian disease was assessed. Transgenerational disease phenotypes observed included an increase in cysts resembling human polycystic ovarian disease (PCO) and a decrease in the ovarian primordial follicle pool size resembling primary ovarian insufficiency (POI). The F3 generation granulosa cells were isolated and found to have a transgenerational effect on the transcriptome and epigenome (differential DNA methylation). Epigenetic biomarkers for environmental exposure and associated gene networks were identified. Epigenetic transgenerational inheritance of ovarian disease states was induced by all the different classes of environmental compounds, suggesting a role of environmental epigenetics in ovarian disease etiology.   FULL TEXT

Manikkam et al., 2012b

Manikkam M, Guerrero-Bosagna C, Tracey R, Haque MM, Skinner MK, “Transgenerational actions of environmental compounds on reproductive disease and identification of epigenetic biomarkers of ancestral exposures,” PLoS One, 2012, 7:2.
Environmental factors during fetal development can induce a permanent epigenetic change in the germ line (sperm) that then transmits epigenetic transgenerational inheritance of adult-onset disease in the absence of any subsequent exposure. The epigenetic transgenerational actions of various environmental compounds and relevant mixtures were investigated with the use of a pesticide mixture (permethrin and insect repellant DEET), a plastic mixture (bisphenol A and phthalates), dioxin (TCDD) and a hydrocarbon mixture (jet fuel, JP8). After transient exposure of F0 gestating female rats during the period of embryonic gonadal sex determination, the subsequent F1-F3 generations were obtained in the absence of any environmental exposure. The effects on the F1, F2 and F3 generations pubertal onset and gonadal function were assessed. The plastics, dioxin and jet fuel were found to promote early-onset female puberty transgenerationally (F3 generation). Spermatogenic cell apoptosis was affected transgenerationally. Ovarian primordial follicle pool size was significantly decreased with all treatments transgenerationally. Differential DNA methylation of the F3 generation sperm promoter epigenome was examined. Differential DNA methylation regions (DMR) were identified in the sperm of all exposure lineage males and found to be consistent within a specific exposure lineage, but different between the exposures. Several genomic features of the DMR, such as low density CpG content, were identified. Exposure-specific epigenetic biomarkers were identified that may allow for the assessment of ancestral environmental exposures associated with adult onset disease.  FULL TEXT

Manikkam et al., 2012

Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK, “Pesticide and insect repellent mixture (permethrin and DEET) induces epigenetic transgenerational inheritance of disease and sperm epimutations,” Reproductive Toxicology, 2012,  34:4,  DOI: 10.1016/j.reprotox.2012.08.010.


Environmental compounds are known to promote epigenetic transgenerational inheritance of disease. The current study was designed to determine if a “pesticide mixture” (pesticide permethrin and insect repellent N,N-diethyl-meta-toluamide, DEET) promotes epigenetic transgenerational inheritance of disease and associated DNA methylation epimutations in sperm. Gestating F0 generation female rats were exposed during fetal gonadal sex determination and the incidence of disease evaluated in F1 and F3 generations. There were significant increases in the incidence of total diseases in animals from pesticide lineage F1 and F3 generation animals. Pubertal abnormalities, testis disease, and ovarian disease (primordial follicle loss and polycystic ovarian disease) were increased in F3 generation animals. Analysis of the pesticide lineage F3 generation sperm epigenome identified 363 differential DNA methylation regions (DMR) termed epimutations. Observations demonstrate that a pesticide mixture (permethrin and DEET) can promote epigenetic transgenerational inheritance of adult onset disease and potential sperm epigenetic biomarkers for ancestral environmental exposures.  FULL TEXT

Kabasenche and Skinner, 2014

Kabasenche WP, Skinner MK, “DDT, epigenetic harm, and transgenerational environmental justice,” Environmental Health, 2014, 13:62, DOI: 10.1186/1476-069X-13-62.


Although the environmentally harmful effects of widespread dichlorodiphenyltrichloroethane (DDT) use became well-known following Rachel Carson’s Silent Spring (1962), its human health effects have more recently become clearer. A ban on the use of DDT has been in place for over 30 years, but recently DDT has been used for malaria control in areas such as Africa. Recent work shows that DDT has transgenerational effects in progeny and generations never directly exposed to DDT. These effects have health implications for individuals who are not able to have any voice in the decision to use the pesticide. The transgenerational effects of DDT are considered in light of some widely accepted ethical principles. We argue that this reframes the decision to use DDT, requiring us to incorporate new considerations, and new kinds of decision making, into the deliberative process that determines its ongoing use. Ethical considerations for intergenerational environmental justice are presented that include concern and respect for autonomy, nonmaleficence, and justice. Here, we offer a characterization of the kinds of ethical considerations that must be taken into account in any satisfactory decisions to use DDT. FULL TEXT

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