Environmental Impact on Health across Generations: Policy Meets Biology. A Review of Animal and Human Models

Round  1

Reviewer 1 Report

Lonnebotn et al have written a review on the impact of the environment on trans-generational health effects. Overall it is a well written review that is presented in a logical and concise manner, however, the authors need to have their manuscript read by a native speaker to avoid minor grammatical errors such as hyphenation of early-life (as a compound modifier before a noun it should be "early-life exposure", but "early life" otherwise), or using a plural"s" when not warranted (e.g. exposures, the plural of exposure is exposure). The hypotheses underlying this manuscript are sound and well argued. I have three major criticisms that need to be addressed before the manuscript can be considered acceptable for publication:

The manuscript is focused on the impact of the early-life environment on asthma and allergic disease, although the authors try and broaden this to the wider immune system. Unfortunately a wide body of research from Miller GE, Turner JD, or Gunnar ME on the effects of the early-life environment on the human immune system have not been considered. References such as PMIDs: 30016711, 29528197, 29667347, 29133294, 29089944, 28549270, should be included, as these references highlight the fundamental role that the early-life environment plays in determining the broad transcriptional identity of circulating lymphocytes. This would help put the literature into a broader immunological context. The PMIDs cited clearly show that the early-life environment has a very strong influence on T-cells. When we consider that atopic asthma (the most common form) ultimately results in the activation of Th2-like T cells together with a Th2-mediated chronic inflammation there is significant scope for the authors to provide novel insight into the role of epigenetic programming of T cells, including T follicular helper cells, tissue-resident T, cells and Th2 effector cells.

Secondly, the manuscript is very "dry". The authors need to represent more of the concepts presented in a graphical or tabular manner in addition to the descriptive text.

Thirdly, although the manuscript adequately covers the existing literature, it needs to move beyond this and provide novel insight into the subject. In providing a broader immunological context, the authors can then also provide more insight, and critically, further perspectives in their review

Author Response

Response to Reviewer 1 Comments

Point 1:

Lonnebotn et al have written a review on the impact of the environment on trans-generational health effects. Overall it is a well written review that is presented in a logical and concise manner, however, the authors need to have their manuscript read by a native speaker to avoid minor grammatical errors such as hyphenation of early-life (as a compound modifier before a noun it should be "early-life exposure", but "early life" otherwise), or using a plural"s" when not warranted (e.g. exposures, the plural of exposure is exposure).

Response 1:

Thank you for this comment. A native English-speaking person has read the revised manuscript.

The hypotheses underlying this manuscript are sound and well argued. I have three major criticisms that need to be addressed before the manuscript can be considered acceptable for publication:

Point 2:

The manuscript is focused on the impact of the early-life environment on asthma and allergic disease, although the authors try and broaden this to the wider immune system. Unfortunately a wide body of research from Miller GE, Turner JD, or Gunnar ME on the effects of the early-life environment on the human immune system have not been considered. References such as PMIDs: 30016711, 29528197, 29667347, 29133294, 29089944, 28549270, should be included, as these references highlight the fundamental role that the early-life environment plays in determining the broad transcriptional identity of circulating lymphocytes. This would help put the literature into a broader immunological context. The PMIDs cited clearly show that the early-life environment has a very strong influence on T-cells. When we consider that atopic asthma (the most common form) ultimately results in the activation of Th2-like T cells together with a Th2-mediated chronic inflammation there is significant scope for the authors to provide novel insight into the role of epigenetic programming of T cells, including T follicular helper cells, tissue-resident T, cells and Th2 effector cells.

Response 2:

Thank you, we have in the revised manuscript included your comment and references as follows, chapter 4, page 12, lines 241-244:

“A wide  body of research highlight the fundamental role the early life environment plays in determining the broad transcriptional identity of circulating lymphocytes and showing that the early-life environment has a very strong influence on T-cells, ref.:

Austin, M.K.; Chen, E.; Ross, K.M.; McEwen, L.M.; Maclsaac, J.L.; Kobor, M.S.; Miller, G.E. Early-life socioeconomic disadvantage, not current, predicts accelerated epigenetic aging of monocytes. Psychoneuroendocrinology 2018, 97, 131-134, doi:10.1016/j.psyneuen.2018.07.007.

Miller, G.E.; Chen, E.; Shalowitz, M.U.; Story, R.E.; Leigh, A.K.K.; Ham, P.; Arevalo, J.M.G.; Cole, S.W. Divergent transcriptional profiles in pediatric asthma patients of low and high socioeconomic status. Pediatric pulmonology 2018, 53, 710-719, doi:10.1002/ppul.23983.

Turner, J.D. Holistic, personalized, immunology? The effects of socioeconomic status on the transcriptional milieu of immune cells. Pediatric pulmonology 2018, 53, 696-697, doi:10.1002/ppul.23986.

Elwenspoek, M.M.C.; Hengesch, X.; Leenen, F.A.D.; Schritz, A.; Sias, K.; Schaan, V.K.; Meriaux, S.B.; Schmitz, S.; Bonnemberger, F.; Schachinger, H., et al. Proinflammatory T Cell Status Associated with Early Life Adversity. Journal of immunology (Baltimore, Md. : 1950) 2017, 199, 4046-4055, doi:10.4049/jimmunol.1701082.

Elwenspoek, M.M.C.; Sias, K.; Hengesch, X.; Schaan, V.K.; Leenen, F.A.D.; Adams, P.; Meriaux, S.B.; Schmitz, S.; Bonnemberger, F.; Ewen, A., et al. T Cell Immunosenescence after Early Life Adversity: Association with Cytomegalovirus Infection. Frontiers in immunology 2017, 8, 1263, doi:10.3389/fimmu.2017.01263.

Elwenspoek, M.M.C.; Kuehn, A.; Muller, C.P.; Turner, J.D. The effects of early life adversity on the immune system. Psychoneuroendocrinology 2017, 82, 140-154, doi:10.1016/j.psyneuen.2017.05.012.

We have also attempted to make it more clearly in the revised manuscript that the main focus of the manuscript is on the impact of the environment across generations and exposures in parents long before conception, while the impact of early life environment mainly is discussed in order to place this research field in context. The manuscript is based on session 4: “Transgenerational perspectives - policy meets biology” from the InVIVO 7^th annual workshop in Canmore, Canada this year.

Point 3:

Secondly, the manuscript is very "dry". The authors need to represent more of the concepts presented in a graphical or tabular manner in addition to the descriptive text.

Response 3:

Thank you, we agree and we have now added one figure in chapter 2, showing the principles of intergenerational and transgenerational epigenetic inheritance, and in chapter 5 we have added a table showing the human studies related to asthma and allergy.

Point 4:

Thirdly, although the manuscript adequately covers the existing literature, it needs to move beyond this and provide novel insight into the subject. In providing a broader immunological context, the authors can then also provide more insight, and critically, further perspectives in their review

Response 4:

We are glad that you consider the literature review adequate. In the revised manuscript, we have attempted to move beyond the existing literature, by widening the context in which the review is placed in the first paragraph of the introduction, by reference to abstracts with new results, and by broadening the perspective in the conclusion.

Author Response File: Author Response.pdf

Reviewer 2 Report

This review into novel mechanisms of inheritance and the transmission of environmental experience is timely. The article reads well and covers some of the latest findings from the field. The authors discuss the implications of transgenerational epigenetic inheritance, providing evidence for completely new perspectives on how early environments may possibly give rise to semi-stable traits that can be passed on to future generations. Transgenerational epigenetic inheritance suggests novel timescales of exposure and experience that interlink multigenerational lives in complex ways, and the authors discuss this with implications for policy. 

Suggestions to enhance the manuscript:

lines 84-99: For clarity it would be good to make the distinction between mechanisms that are mitotically heritable (eg 'memory of state') versus inherited through germline (transgenerational). 

In section 4 on maternal pre-conceptual environment you could include some discussion around developmental plasticity and the predictive adaptive response hypothesis from Gluckman and colleagues.

While it is of course of uttermost importance to under- stand the detrimental effects of environmental toxins, trauma or other biosocial exposures, it is equally important to consider the possible social impact of scientific research focused often almost exclusively on harm. This could warrant a brief discussion if a message of damage without hope of reversibility might contribute to the stigmatization of individuals and groups, potentially across generations. 

Thanks

Author Response

Response to Reviewer 2 Comments

This review into novel mechanisms of inheritance and the transmission of environmental experience is timely. The article reads well and covers some of the latest findings from the field. The authors discuss the implications of transgenerational epigenetic inheritance, providing evidence for completely new perspectives on how early environments may possibly give rise to semi-stable traits that can be passed on to future generations. Transgenerational epigenetic inheritance suggests novel timescales of exposure and experience that interlink multigenerational lives in complex ways, and the authors discuss this with implications for policy. 

Suggestions to enhance the manuscript:

Point 1:

lines 84-99: For clarity it would be good to make the distinction between mechanisms that are mitotically heritable (eg 'memory of state') versus inherited through germline (transgenerational). 

Response 1:

Thank you for this comment. We have now added a sentence and also a figure (Figure 2) to make it more clear, chapter 2, page 6, lines 123-124: “….Finally epigenetics is used to refer to complex patterns of inheritance that cannot be explained by changes to the primary DNA sequence and that are passed via the germline over >2 generations”.

Point 2:

In section 4 on maternal pre-conceptual environment you could include some discussion around developmental plasticity and the predictive adaptive response hypothesis from Gluckman and colleagues.

Response 2:

Thank you for this comment. We have now added this sentence and reference to chapter 4,

page 12, lines 251-252: “Such long lasting change to an offsprings immune system resulting

from an early-life effect can be termed a Predictive Adaptive Response”. (REF: Bateson, P.;

Gluckman, P.; Hanson, M. The biology of developmental plasticity and the Predictive

Adaptive Response hypothesis. J Physiol 2014, 592, 2357-2368, doi:10.1113/jphysiol.2014.271460.)

Point 3:

While it is of course of uttermost importance to under- stand the detrimental effects of environmental toxins, trauma or other biosocial exposures, it is equally important to consider the possible social impact of scientific research focused often almost exclusively on harm. This could warrant a brief discussion if a message of damage without hope of reversibility might contribute to the stigmatization of individuals and groups, potentially across generations. 

Comment 3:

Thank you for pointing out this. In the revised manuscript the last paragraph of the conclusion now runs as follows:

“…This provides a tremendous opportunity for efficient intervention with regard to improving human health. However, there is a large burden on the individual, to improve own health and now also that of future generations, through personal health achievement. Further, our research usually focuses on risk factors and harm, rather than advantageous behavior and environmental factors. Our life at home, in the community, and in the nation, is all part of the planetary environment guided by political and social system (ref. Susan Prescott and Alan C. Logan, Explore 2018, Planetary Health: From the wellspring of holistic medicine to personal and public health imperative). The society can promote health through the built environment, school systems, pollution control, food and drug safety, health education, etc. The scientific community should increase the focus on advantageous behaviors and environmental factors. It is of key importance that intervention towards better health is not a matter of personal achievement, but of the society. ….”

Round  2

Reviewer 1 Report

The authors have adequately replied to my comments.