The Placenta as a Target Organ for Poly- and Perfluoroalkyl Substances (PFASs): Molecular Mechanisms of Toxicity

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript addresses several poly- and perfluoroalkyl substances and their impact on materno‑fetal interactions, particularly at the placental level. These substances are widely used in everyday human activities, and the topic is both highly relevant and timely. The manuscript is generally well written and well organized, the bibliography is current and appropriate, and the figureThe manuscript  and tables appear adequate. However, a few minor revisions are needed before it can be fully accepted.
There are some orthographic errors that should be corrected, such as the term methodologies in subtitle 4.2, frameworks on line 149, among others. In addition, several paragraphs throughout the text are excessively long and would benefit from being divided into shorter, clearly structured sections. Some grammatical errors are also present and should be revised.

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The review article presents a comprehensive overview of current knowledge on the effects of PFAS on the placenta, as well as the molecular mechanisms affected by exposure. The topic is topical, as the effects of PFAS on the placenta are a global and still insufficiently researched problem. The article links molecular mechanisms (oxidative stress, lipid mechanism..) as well as new methodological innovations.

I have the following comments on the article:

1. Add an explanation of the differences between legacy vs. Emerging PFAS
2. Some epidemiological associations are presented very clearly, although the evidence is often not consistent. Add a critical assessment of epidemiological studies, including inconsistent results.
3. It is necessary to add real concentrations in placentas and in serum
4. The section on NAMs lacks a discussion of the limitations of these new approaches (such as bioaccumulation, persistence, low toxicity for acute tests...), and there is no link to specific applications for PFAS toxicity.
5. I recommend replacing older reviews with newer ones, adding the latest data on emerging PFAS.
6. I recommend adding specific examples of use for PFAS to NAMs.

 

After adding comments, the article will have great potential for publication in the given journal.

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

I only have some minor comments that I thought as reading the manuscript. 

• The authors use the terms "classical" and "emerging" PFAS to describe different chemicals. I can't obviously see that a definition is provided of how these classifications are made. 
• The section on epigenetics I think either needs to be re-written or removed. Only four citations are included, one of which is a review and one appears to only look at sex specific differences and not include any actual epigenetic assays. The other two only look at DNA methylation, which the authors then claim is the primary reason for epigenetic changes (l228). 
• I think the same goes for the section on metabolic signatures. There are two references cited, and it feels like it has just been thrown into the text to fill space without serving a purpose.
• Going a little further, sections 3.3, 3.4 and 3.5 currently read like they have had significant AI input. They read quite differently to a lot of the other text and don't support the reading of it.
• I think the title of the piece threw me a bit here. The article is very human focused. Which is fine, but given the broad reaches of the title, you would expect data from model organisms to be included to support the claims. As I am assuming the authors don't want to re-write the entire manuscript to include those, I would recommend a re-wording of the title, to make clear this is a human focussed review, and that it is more of a higher level overview of emerging themes in PFAS research. I would also argue that as it currently reads, the title is grammatically a little strange. 

Comments on the Quality of English Language

There are some typos and a track change that appears to have been left in. 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

After incorporating the comments, I recommend the article for publication.

Reviewer 3 Report

Comments and Suggestions for Authors

Thank you to the authors for making those changes, I think the epigenetics section and metabolism section have been re-done well and are much more balanced. I support publication.