Request for Information (RFI): Priorities for Transgenerational Research

Notice Number: NOT-ES-10-010

Key Dates
Release Date: May 6, 2010
Response Date: June 30, 2010

Issued by
National Institute of Environmental Health Sciences (NIEHS) (
National Toxicology Program (NTP) (
National Institute of Environmental Health Sciences (NIEHS) Division of Extramural Research and Training (DERT) (

This Request for Information (RFI) is for information and planning purposes only and should not be construed as a solicitation or as an obligation on the part of the Federal Government, the National Institutes of Health (NIH), and/or the National Institute of Environmental Health Sciences (NIEHS).  The NIEHS does not intend to make any awards based on responses to this RFI or to otherwise pay for the preparation of any information submitted or for the Government's use of such information.


The NIEHS is seeking input from the scientific community, health professionals, patient advocates, community-based organizations, students, and the general public about current and emerging priorities in transgenerational (TG) research that offer the greatest potential for improving the nation’s health and well-being.  This input will inform the NIEHS’ strategic planning process and help the NIEHS meet its mission of pursuing opportunities for improving the environmental health of the American people

Definition: For the purposes of this RFI, TG effects are defined as those effects that are transmitted via the germ line for at least three generations. Thus, in humans, exposure would be during pregnancy or other windows of sensitivity to environmental chemicals and would result in altered disease/dysfunction not only in the offspring but in the offspring’s children and grandchildren.  In an animal model, exposure would be to the pregnant dam and the effect would be detectable in the F1, F2, and F3 offspring when the F1 males or females are mated to control males or females and the resulting F2 males or females are mated to control males or females to produce an F3 generation.  


There are studies that show that certain environmental toxicants can alter developmental programming, resulting in adverse health effects in animals three or more generations removed from the initial exposure. This finding has enormous public health implications, as it suggests that toxicants encountered today could contribute to the disease burden for generations to come, even long after exposure to a given toxicant has ceased.  It also suggests that some of the disease burden of the current population could be due to environmental exposures of our grandparents and great-grandparents.  In fact, some epidemiological studies have described occurrences of TG inheritance in human populations, with regard to dietary changes and smoking.

The mechanism(s) by which this phenomenon occurs is not known, and may differ depending on the inducing agent.  However, preliminary evidence suggests that this effect is mediated at least in part by epigenetic changes that are not appropriately corrected in the germ line of the first generation post-exposure.  The interplay between epigenetics and disease is a scientific priority, both at NIEHS and across the NIH, indicating that the time is appropriate for furthering research into this phenomenon.  There are very limited human TG data. Although the concept of TG inheritance in mammals has been somewhat controversial, several recent publications/ presentations indicate that a growing range of toxicants appear to induce TG inheritance in animal models including mice and rats.  Toxicologists and endocrinologists are studying TG effects using animal models of disease and linking developmental exposures to disease susceptibility via genomic and epigenetic analysis.

The current approaches include in life experimentation and data analysis over 4-5 generations.  In addition, it is anticipated that the mechanism will involve alterations in the epigenetic markings (although other mechanisms should not be excluded) and it is expensive, time consuming and technologically challenging to examine all aspects of the epigenetic “system” across many tissues and generations.  Few laboratories have the capability for the large long term animal studies and the expertise and core facilities to examine all aspects of the transcriptome and epigenome needed to define the defect that allows for TG transmission of information and the bioinformatics to analyze and interpret the data.  There are no high throughput screens that would indicate potential for TG effects (there are high throughput screens to detect epigenetic changes) and there are few human studies due to the long time required.

These shortcomings, as well as the clinical imperative to improve health care outcomes, underscore the need for transformative changes in the field of TG research. Thus, there is the need for information from the community to aid in the development of a long-range program to evaluate fully the mechanism(s) for TG and their importance for human health.

Information Requested

This RFI seeks information that will help NIH to identify priorities for research to identify the role of environmental exposures on TG inheritance. Ideas for both short-term (1-3 years) and long-term (4-10 years) research projects focusing on in vitro, animal models and human diseases are welcome.  Members of the scientific community, scientific organizations, healthcare professionals, patient advocates, and the public are invited to respond to the following:

  1. The Challenge — Describe the critical gaps in the science of the role of environmental exposures in TG inheritance. Gaps can be at the level of basic mechanisms, measurement, approaches, methodology, bioinformatics and/or intervention/prevention strategies using in vitro systems, a variety of animal models or human epidemiology studies.

  2. The Potential Solution — Describe what you believe to be the most innovative research approaches to address these challenges. Solutions should focus on potential research models, approaches and methodologies that could address the scientific gaps and provide the data to carefully evaluate the TG hypothesis and, if appropriate, define its mechanism(s).   Approaches, models, and methods should also define the window(s) of sensitivity; characterize the types/classes of chemicals that can result in TG effects; evaluate the extent of transgenerationally-induced disease/dysfunctions; identify the mechanism(s) responsible for TG effects; support the development of screens to detect chemicals that can cause TG effects; and propose intervention strategies. We are particularly interested in approaches that would be able to detect TG effects in a short period of time in model system(s) that would easily be extrapolatable to humans and in the development of biomarkers that could be used in human studies. We are also interested to know about cohorts of study populations that could be sued to test TG hypotheses.


Responses will be accepted until June 30, 2010 via email to: Dr. Lisa Chadwick at
Please mark your responses with this RFI identifier NOT-ES-10-010.  For each suggested research idea or approach, provide brief background information, define the challenge and outline the potential solution.  Reponses are expected to be no longer than 700 words or one page.

Respondents will receive an email confirmation acknowledging receipt of their response, but will not receive individualized feedback.

Any identifiers (e.g., names, institutions, e-mail addresses, etc) will be removed when responses are compiled. Only the processed, anonymized results will be shared internally with scientific working groups convened by the NIEHS, as appropriate.  Nonetheless, no proprietary information should be submitted.


Jerrold (Jerry) Heindel, Ph.D.
Chief Cellular, Organs and Systems Pathobiology Branch
National Institute of Environmental Health Sciences
Division of Extramural Research and Training
P.O. Box 12233 
Keystone Building, MD K3-15
Research Triangle Park, NC, 27709-2233
Telephone:  (919) 541-0781
FAX:  (919)541-5064

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