Sex, Nutrition, and NAFLD: Relevance of Environmental Pollution
Round 1
Reviewer 1 Report
Environmental pollutants can promote NAFLD in addition to obesity, lifestyle, genetic and epigenetic factors, and gut microbiota dysbiosis. The authors summarize the knowledge about environmental pollutants, that act as endocrine and metabolic disruptors in the context of NAFLD. The review especially discusses the influenc of persistent organic pollutants (POPs), endocrine disrupting chemicals (EDCs), heavy metals, micro- and nanoplastics on the regulation of hepatic metabolism and reproductive functions in females. As environmental endocrine pollutants can be risk factors for NAFLD for the mothers as well as for the offspring, further studies are needed to elucidate the underlying mechanisms of action and to identify valuable biomarkers and interventional strategies for the treatment of NAFLD.
The manuscript provides an objective and comprehensive review of the literature on this issue. It is a well-written article with proper references cited.
Figure(s) illustrationg the major effects of POPs, EDCs, heavy metals, and nanoplastics on different aspects of NAFLD (lipid metabolism, apoptosis, inflammation, fibrosis, dysbiosis, biliary dysfunction, thermogenesis, hormone signaling and endocrine functions, …) would be desirable
Author Response
We thank the Reviewer for his/her positive feedback.
As suggested, Figures 2-6 and the related legends were added to the text to illustrate the major effects of environmental pollutants on the main pathways involved in NAFLD development.
Author Response File: 
Author Response.docx
Reviewer 2 Report
Recommendations
Comments to the author: First of all, congratulate the authors for their excellent work. This is an excellent review of the literature and has a clear objective. The discussion is very well done and corresponds to the review made.
The article does not cause any concern. The manuscript did not cause any ethical problems. A review of 288 publications has been carried out, of which 250 correspond to the last 5 years (2017-2022). It is a job that requires a very important effort, which deserves all my consideration and thanks for the work done.
I would just ask for clarification. It must explain and justify how the bibliographic search has been carried out and how the articles have been selected.
For my part, once said clarification is made, the work is publishable in its current form.
Author Response
We thank the Reviewer for his/her positive feedback.
The articles selected for this Review were English-language, full-text articles and abstracts identified by searching PubMed database. The keywords used included “liver”, “liver health”, “liver diseases”, “liver metabolism”, “NAFLD”, “hepatic steatosis”, “fatty liver”, “nutrition”, “nutrients”, “diet”, “dietary intake”, “high fat diet”, “food chain”, “food insecurity”, “contaminated food”, “lifestyle”, “obesity”, “fatty acids”, “lipids”, “lipid metabolism”, “oxidative stress”, “inflammation”, “microbiome”, “gut microbiota”, “gut dysbiosis”, “mechanisms”, “pollution”, “environmental pollutants”, “persistent organic pollutants”, “endocrine disrupting chemicals”, “bisphenol A”, “PFOA”, “PFOS”, “pesticides”, “insecticides”, “heavy metals”, “cadmium”, “lead”, “arsenic”, “microplastics”, “nanoplastics”, “air pollution”, “air particulate matter”, “PM2.5”, “climate change”, “global warming”, “microcystins”, “thermogenesis”, “sex differences”, “gender differences”, “reproduction”, “fertility”, “female subfertility”, “estrogen”, “estrogen receptor”, “nuclear receptors”, “menopause”, “ovariectomy”, “PCOS”, “ovarian dysfunctions”, “pregnancy”, “maternal exposure”, “gestational exposure”, “developmental origin”, “early life exposure”.
When possible, the searching has been restrained to the last 5 years or less.
Author Response File: Author Response.docx
Reviewer 3 Report
In this paper, Dolce and Torre aimed to review the literature about the effects of environmental pollutants on the liver, with particular emphasis on nonalcoholic fatty liver disease (NAFL). To this end, they analyzed the literature of a long list of pollutants in relation to NAFLD. It is clear the authors did an exhaustive search and reading of previous papers that covered numerous pollutants including persistent organic pollutants (POPs), endocrine disrupting chemicals (EDCs), heavy metals, micro- and nano-plastics. I commend the authors for this effort which attests to their deep knowledge of this field of research.
The review is well written, but because of the wide range of pollutants included, the manuscript is very long and exclusively as a text. It could be very helpful to the reader to present some parts of the review in Tables that could summarize the main findings of the literature.
I have a few suggestions.
11- To keep the paper focused on pollutants, I suggest to the authors to omit the part “4-climate change, food insecurity and NAFLD”, pages 534-588. This part, which is about global change and microcystins (MCs), disrupts the flow of the paper. The parts before and after this paragraph, which are about air -plastics-and other pollutants, are coherent.
2- The title of the paper, while attractive, does not reflect the content of the review which is exclusively about NAFLD. I suggest adding the name of this disease in the title.
None
Author Response
The review is well written, but because of the wide range of pollutants included, the manuscript is very long and exclusively as a text. It could be very helpful to the reader to present some parts of the review in Tables that could summarize the main findings of the literature.
Reply: To match the suggestion of this Reviewer with those of Reviewer #1 asking to include some pictures in the Review, we preferred to add representative figures instead of tables to summarize the main findings of the literature. Thus, Figures 2-6 and the related legends were added to the text to illustrate the major effects of environmental pollutants on the main pathways involved in NAFLD development.
I have a few suggestions.
1- To keep the paper focused on pollutants, I suggest to the authors to omit the part “4-climate change, food insecurity and NAFLD”, pages 534-588. This part, which is about global change and microcystins (MCs), disrupts the flow of the paper. The parts before and after this paragraph, which are about air -plastics-and other pollutants, are coherent.
Reply: Climate change and global warming are direct effects of environmental pollution and, although they have been very little investigated, may have a strong impact on NAFLD incidence. To highlight the (underestimated) relevance of pollution-induced global warming on liver health, we reported the first evidence of the effects of global warming on microcystin-mediated fatty liver/NAFLD. Since MCs are mainly ingested together with contaminated water, MCs may be a relevant cause of NAFLD, especially in the regions of the world where people have limited access to clean water sources and may face increasing difficulties in the near future due to global warming.
Furthermore, given the cross-talk between the liver and the BAT, we speculated that global warming might further promote the development of NAFLD by altering BAT functions, particularly thermogenesis.
Given the climate emergency and the increasing incidence of NAFLD, we wished to emphasize how rising temperatures resulting from pollution-induced global warming may further contribute to the increasing incidence of NAFLD in the near future. It was precisely to emphasize this connection that we wanted to include this chapter in the Review.
However, should this Reviewer and the Editor deem this chapter superfluous within this Review, even if we don't agree very much, we are willing to delete it.
2- The title of the paper, while attractive, does not reflect the content of the review which is exclusively about NAFLD. I suggest adding the name of this disease in the title.
Reply: We chose the title “Sex, nutrition, and liver health: a balance threatened by environmental pollution” not only because it is attractive.
We are well aware that liver diseases are not limited to NAFLD alone; however:
- NAFLD is the most common liver disease in the world with an incidence close to 30% and a trend to grow further;
- in its initial form, NAFLD is characterised by liver steatosis but can progress to other forms of liver diseases such as NASH, cirrhosis, fibrosis, and liver carcinoma;
- NAFLD is an endocrine-metabolic liver disease showing a sex-specific prevalence;
- NAFLD is a multifactorial disease, also influenced by nutritional status and nutrients that can alter signalling pathways triggering its development.
From this point of view, NAFLD represents a canonical example of endocrine-metabolic liver disease with a sex-specific prevalence that may be influenced by environmental pollutants taken in through the ingestion of contaminated food and water.
For all the above reasons, we would prefer to keep the title “Sex, nutrition, and liver health: a balance threatened by environmental pollution”.
If this is not possible, we suggest the following as an alternative title: “Sex, nutrition, and NAFLD: relevance of environmental pollution”.
Author Response File: Author Response.docx
