11.24.06

New Research: Epigenetic Transgenerational Adult-Onset Disease

Posted in environmental alterations, imprinting, methylation, research articles at 4:45 pm by Trevor

New research from the laboratory of Dr. Michael Skinner at Washington State University shows that the endocrine disruptor vinclozolin, a fungicide used in agricultural crops such as grapes grown for the wine industry, can induce adult-onset diseases in the offspring of an exposed pregnant female rat such as prostate disease, kidney disease, immune system abnormalities, and tumor development that remain highly prevalent in four generations of offspring.

The December issue of the journal Endocrinology contains two articles related to the studies in the lab of Dr. Skinner, including “Endocrine Disruptor Vinclozolin Induced Epigenetic Transgenerational Adult-Onset Disease” by Anway et. al and “Epigenetic Imprinting of the Male Germ-Line by Endocrine Disruptor Exposure During Gonadal Sex Determination” by Chang et. al. These research articles provide further insights into the phenomenon first described in the June 2005 issue of Science, “Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility.”

The fetal basis of adult disease is poorly understood on a molecular level and cannot be solely attributed to genetic mutations or a single etiology. Embryonic exposure to environmental compounds has been shown to promote various disease states or lesions in the first generation (F1). The current study used the endocrine disruptor vinclozolin (antiandrogenic compound) in a transient embryonic exposure at the time of gonadal sex determination in rats. Adult animals from the F1 generation and all subsequent generations examined (F1–F4) developed a number of disease states or tissue abnormalities including prostate disease, kidney disease, immune system abnormalities, testis abnormalities, and tumor development (e.g. breast). In addition, a number of blood abnormalities developed including hypercholesterolemia. The incidence or prevalence of these transgenerational disease states was high and consistent across all generations (F1–F4) and, based on data from a previous study, appears to be due in part to epigenetic alterations in the male germ line. The observations demonstrate that an environmental compound, endocrine disruptor, can induce transgenerational disease states or abnormalities, and this suggests a potential epigenetic etiology and molecular basis of adult onset disease.While one research article explores the disease prevalence across four generations of offspring after a single exposure to a pregnant female rat, the other characterizes specific genes and non-coding regions that exhibit altered methylation profiles in F2 and F3 generation males.

Embryonic exposure to the endocrine disruptor vinclozolin at the time of gonadal sex determination was previously found to promote transgenerational disease states. The actions of vinclozolin appear to be due to epigenetic alterations in the male germline that are transmitted to subsequent generations. Analysis of the transgenerational epigenetic effects on the male germline (i.e. sperm) identified 25 candidate DNA sequences with altered methylation patterns in the vinclozolin generation sperm. These sequences were identified and mapped to specific genes and noncoding DNA regions. Bisulfite sequencing was used to confirm the altered methylation pattern of 15 of the candidate DNA sequences. Alterations in the epigenetic pattern (i.e. methylation) of these genes/DNA sequences were found in the F2 and F3 generation germline. Therefore, the reprogramming of the male germline involves the induction of new imprinted-like genes/DNA sequences that acquire an apparent permanent DNA methylation pattern that is passed at least through the paternal allele. The expression pattern of several of the genes during embryonic development were found to be altered in the vinclozolin F1 and F2 generation testis. A number of the imprinted-like genes/DNA sequences identified are associated with epigenetic linked diseases. In summary, an endocrine disruptor exposure during embryonic gonadal sex determination was found to promote an alteration in the epigenetic (i.e. induction of imprinted-like genes/DNA sequences) programming of the male germline, and this is associated with the development of transgenerational disease states.This research has a number of potential implications:

Disease etiology and development mechanisms could involve this epigenetic transgenerational phenomenon and be a factor in disease development that is not currently not understood. What aspects of disease are due to DNA sequence mutations versus epigenetics involving chemical modification of the DNA?
Since this is an environmental effect that is multigenerational, it could explain why different sub-populations in different regions may develop different diseases.
This new phenomena may provide alternate approaches for disease diagnosis and therapy.
The influence of environmental toxicant exposures on disease development for offspring of exposed pregnant mothers needs to be further explored.

Disclosure: The publisher of Epigenetics News is a member of the laboratory involved in this research. No information related to this research that has not been published in a peer-reviewed scientific journal is contained in this article.