Impact of Micro and Nanoplastics on Reproductive Cancer and the Potential Anticancer Benefits of Prolonged Ginger, Garlic, and Turmeric Consumption: A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

This article Impact of Micro and Nanoplastics on Reproductive Cancer and the Potential Anticancer Benefits of Prolonged Ginger, Garlic, and Turmeric Consumption, provides a comprehensive review of the nutritional benefits of ginger, garlic and turmeric as nutritional supplements for the suppression of tumors and amelioration of inflammation and oxidative stress. However some points (see below and on main document) need to be addressed by the authors to improve the quality of the work. Globally, the manuscript requires Major Revisions.

1. Title should specify the REVIEW aspect of the work. Because it is not an original research work and it should be specified in the title : Review
2. Review the ‘Abstract’ adding element on the methodology (how the information was gathered), the key findings and conclusions.
3. The rational for the study is not clearly stated. Also, the introduction should end with a strong and clear objective(s) of the study
4. The key words are absent from the abstract and should be used in directing the purpose of the study.
5. ``The infiltration of micro- and nanoplastics into tissues and their interaction with steroid receptors have been linked to hormonal dysregulation, oxidative stress, chronic inflammation``. Can the specific receptors be unveiled for better understanding of the mechanism of action of MP/NPs?
6. Figure 2. 5.1: properly edit it; it seems to have 2 titles.
7. Figure 3. 1.3: Reformulate it as ‘Main phytochemical constituents of garlic’.
8. The authors kindly should mention the pathways affected or dysregulated. E.g. WNT/β-Catenin pathway dysregulation which is implicated in cancer development?
9. Visual aids should be used to demonstrate mechanisms and pathways to improve visibility and interpretability
10. Can the authors mention the sampling procedure use?
11. Can the authors provide the inclusion and exclusion criteria for articles selection?
12. Can the authors mention the source or major databases articles used in writing the review were sourced from?
13. What was the test of robustness carried out on the selections?
14. Do correct the figures and tables numbering format.
15. Though the authors presented an interesting point on ‘Public Health Perspectives and Future Research Directions’, it will important to either reformulate this sub-title to include the conclusions or add the section ‘Conclusions’.
16. Thoroughly review the ‘References’ section following the authors’ guidelines. The references should be cross-checked and correct form of citations should be implemented.

Comments for author File: Comments.pdf

Comments on the Quality of English Language

Some English language revisions are needed.

Author Response

Comment 1: Title should specify the REVIEW aspect of the work.

Response: Thank you for this valuable suggestion. The title has been revised to clearly indicate that the manuscript is a review article. Specifically, the phrase “A Narrative Review” has been incorporated into the title to reflect the nature and scope of the work.

Comment 2: Full stop addition in the abstract section.

Response: Thank you for the suggestion. A full stop has been added as instructed

Comment 3:  absent key terms. Kindly insert key terms

Response: We thank the reviewer for the observation. A set of relevant keywords has been added below the abstract as instructed to improve the indexing and discoverability of the article.

Comment 3:  reference citation?

Response: We thank the reviewer for the valuable suggestion.  Relevant references have been added as instructed.

Comment 4: APA format?

Response: References has been changed to APA format as suggested

Comment 5: sentences should normally not begin by references

Response: We thank the reviewer for the observation. The sentences have been modified as suggested

Comment 6: Can the specific receptors affected be included?

Response: The specific receptors have been included as requested

Comment 7: Review citation format. Why not at the end?

Response 7: Thank you for the observation. The citation format has been reviewed as instructed.

Comment 8: Kindly mention the pathways affected or dysregulated. Example WNT/β-Catenin pathway dysregulation

Response 8: We thank the reviewer for the valuable suggestion. We have described the pathways as suggested

Comment 9: the introduction should end with a strong and well-defined objective(s

Response: Thank you for this important suggestion. The Introduction section has been revised to conclude with a clearly articulated objective that defines the scope and purpose of this review.

Comment 10: study requires a clear rational

Response 10: Thank you for this insightful comment. The Introduction has been revised to clearly articulate the scientific rationale for this review.

Comment 11: How does MP/NPs function as catalyst in biological systems

Response 11: The statement has been deleted

Comment 12: is this peculiar to all cells exposed to MP/NPs or only to reproductive cells

Response 12: Thank you for this important clarification. Oxidative stress induced by micro- and nanoplastics (MPs/NPs), particularly through increased reactive oxygen species (ROS) production and lipid peroxidation, has been reported across multiple cell types and tissues. However, reproductive tissues appear to be particularly vulnerable due to their high metabolic activity, hormone sensitivity, and the susceptibility of germ cells to oxidative damage. To clarify this point, the manuscript has been revised to indicate that ROS-mediated oxidative stress is a generalized cellular response to MP/NP exposure but may have pronounced consequences in reproductive tissues, where disruption of cellular homeostasis can directly impair reproductive function and contribute to carcinogenic processes.

Comment 13:  Could this be attributed to actual human studies previously done with MP/NPs

Response 13: Thank you for this important observation. We acknowledge that much of the mechanistic evidence demonstrating depletion of antioxidant enzymes following micro- and nanoplastic (MP/NP) exposure has been derived primarily from experimental animal and aquatic models. Direct mechanistic evidence from human studies remains limited due to ethical and methodological challenges in assessing controlled MP/NP exposure. However, emerging human biomonitoring studies have reported the presence of microplastics in biological samples such as blood, placental tissue, lung tissue, and reproductive fluids, suggesting potential systemic exposure and biological relevance. To clarify this distinction, the manuscript has been revised to explicitly state that the oxidative stress mechanisms described are largely supported by experimental models, while human studies currently provide indirect evidence through exposure detection and biomonitoring data.

Comment 14: appropriate diagrams are necessary to illustrate the pathway visually for better comprehension.

Response 14: Thank you for this valuable suggestion. To improve clarity and facilitate better understanding of the mechanistic pathways discussed, a schematic diagram has been included in Figure 2.5.1

Comment 15: cross-check statement.  the question to be answered is if they induce inflammation

Response 15: Thank you for this important comment. The statement has been carefully revised to clarify that exposure to micro- and nanoplastics can indeed induce inflammatory responses.

Comment 16:  visual presentation of implicated pathways absent

Response 16: Thank you for this valuable suggestion. To improve clarity and facilitate better understanding of the mechanistic pathways discussed, a schematic diagram has been included in Figure 2.5.2

Comment 17: reference citation

Response 17: Relevant references have been added as suggested.

Comment 18: Can this pathway be visually presented

Response 18: The visual pathway has been presented as instructed

Reviewer 2 Report

Comments and Suggestions for Authors

Micro- and nanoplastics (MPs/NPs) may be environmental factors linked to reproductive cancer (ovary, cervix, prostate, and testis), according to a careful evaluation of the evidence in this manuscript. The authors identify the toxicological processes at play, including genotoxicity, endocrine disruption, chronic inflammation, and oxidative stress. Interestingly, the authors claim that the phytochemicals (gingerols, curcuminoids, and sulfur compounds) in ginger, turmeric, and garlic may have a modulatory or chemoprotective effect.According to the authors, the manuscript's main contribution was the integration of environmental toxicity, reproductive cancer biology, and functional nutrition. They postulated a mechanistic junction between biological pathways controlled by spices and harm caused by plastic. Public health can benefit from this innovative translational approach.

1) 

The authors did not, however, make it apparent if this was a narrative review, systematic review, etc. They did not supply time periods, search strategies, inclusion/exclusion criteria, databases (PubMed, Scopus, WoS), or evaluations of study quality. The methodological rigor is severely undermined by all of this. Furthermore, there is very little causative evidence in human cases, and the authors primarily offered observational connections and preclinical evidence (in vitro/animal). Because clinical trials and cell studies are combined without clear prioritization, the hierarchy of evidence is not well defined.

2) Reproductive toxicity, oxidative stress, and biomarkers are used to infer carcinogenesis. This is not confirmed, yet it makes biological sense. The authors ought to emphasize that there is currently insufficient direct proof of causality in humans. In terms of epidemiology, the authors did not address crucial components such sample size, bias, confounding, and external validity and only referenced a small number of human studies (Xu et al., Montano et al.). Studies directly connecting MP/NP + spices + cancer do not exist. The authors should specifically identify this as a hypothesis as the interaction is indirect and occurs through shared pathways.

3) The manuscript contains several grammatical errors, such as: “MP/NPs -induced chronic inflammation” has incorrect spacing before the hyphen. “MN/NPs” appears alternately with “MP/NPs,” representing terminological inconsistency. The authors make excessive use of long sentences (>40 words) that impair readability (i.e., “Oxidative stress induced by MP/NPs also activates the MAPK signaling pathway and the NF-κB inflammatory transcription factor, while inactivating the antioxidant transcription factor Nrf2, cellular responses aimed at counteracting the oxidative insult”). This should be split into two sentences. There is ambiguous use of “recent findings support a causal role”; the authors should change it to “support a potential association.”

4) Although Figure 2.5.1 is schematic, the authors do not identify the source, make it clear whether it is original, or depict interactions between paths (just a list). An integrated diagram should be included by the authors, in my viewpoint: MP/NP → ROS → inflammation → hormonal disturbance → genotoxicity → cancer. The language and the chemical figures (garlic, turmeric, and ginger) match up nicely. Nonetheless, it is required to specify if they were written by the authors, modified, or protected by copyright. Real clinical trials and small-scale, poorly designed adjunct investigations are mixed together in Table 3.1. Although the authors should specify the sample size and outcome type (PSA, OS, biomarkers), it is a very helpful description.

5) To increase the manuscript's scientific rigor, I encourage the authors to respond to the following queries:

Which method of literature search was applied?

Which criteria were used for inclusion and exclusion?

Which type of evidence—clinical vs in vitro—was given priority?

What cutoff point do you think is appropriate to discuss carcinogenesis rather than toxicity alone?
Do realistic human doses that are comparable to those used in animal models have any data?How can the effects of additives (BPA, phthalates) be distinguished from those of the polymer?
Why were EGCG and resveratrol, two other pertinent phytochemicals, left out?
Did you take into account publication bias, which only considers favorable effects?

6) Several kinds of issues were found with the references in the document. There are references that seem generic ("Stoian, 2025"), some that are hard to confirm, and some that might be fake (a major risk). Not every reference that is listed is directly related to the findings in the text. It is advised that the writers independently verify cell, animal, and clinical studies as well as each reference with its DOI. Furthermore, I recommend them to examine and reference this source (DOI: 10.1016/j.envpol.2025.127343).

With an intriguing fusion of functional nutrition and environmental toxicity, the manuscript tackles an innovative and pertinent issue.   It needs thorough reference validation, makes poor causal conclusions, and lacks a defined methodological framework as a scientific review. The verdict: Major revision

Author Response

Comment 1: The authors did not, however, make it apparent if this was a narrative review, systematic review, etc. They did not supply time periods, search strategies, inclusion/exclusion criteria, databases (PubMed, Scopus, WoS), or evaluations of study quality. The methodological rigor is severely undermined by all of this. Furthermore, there is very little causative evidence in human cases, and the authors primarily offered observational connections and preclinical evidence (in vitro/animal). Because clinical trials and cell studies are combined without clear prioritization, the hierarchy of evidence is not well defined.

Response 1: We thank the reviewer for this important and constructive comment. The manuscript has been revised to clarify the methodological framework and scope of the review.

First, we now explicitly state in the title, abstract, and introduction that the present study is a narrative review.

Second, we acknowledge that narrative reviews do not typically follow the same methodological framework as systematic reviews or meta-analyses. However, to improve transparency and methodological clarity, we have now added a brief literature search description in the Introduction/methodology section, indicating the databases consulted and the general search strategy used to identify relevant studies. Specifically, relevant studies were identified through searches of major scientific databases, including PubMed, Scopus, and Web of Science, focusing on publications addressing micro- and nanoplastics, oxidative stress, inflammation, genotoxicity, reproductive toxicity, and reproductive cancers. Priority was given to peer-reviewed articles published 2008 to 2026.

Third, we agree with the reviewer that direct causal evidence in humans remains limited. The revised manuscript now explicitly acknowledges this limitation and clarifies that the current body of evidence is largely derived from experimental models (in vitro studies and animal models), observational biomonitoring studies in humans, and human epidemiological data linking microplastic exposure to reproductive cancer.

Finally, to improve the clarity of the evidence hierarchy, the manuscript has been revised to better distinguish between human biomonitoring studies, experimental animal studies, and in vitro mechanistic investigations.

Comment 2: Reproductive toxicity, oxidative stress, and biomarkers are used to infer carcinogenesis. This is not confirmed, yet it makes biological sense. The authors ought to emphasize that there is currently insufficient direct proof of causality in humans. In terms of epidemiology, the authors did not address crucial components such sample size, bias, confounding, and external validity and only referenced a small number of human studies (Xu et al., Montano et al.). Studies directly connecting MP/NP + spices + cancer do not exist. The authors should specifically identify this as a hypothesis as the interaction is indirect and occurs through shared pathways.

Response 2: We thank the reviewer for this insightful and constructive comment.

First, we have revised the manuscript to explicitly state that direct causal evidence linking micro- and nanoplastic (MP/NP) exposure to reproductive cancers in humans is currently limited. The mechanistic pathways discussed in the review, such as oxidative stress, chronic inflammation, endocrine disruption, and genotoxicity, are now clearly described as biologically plausible mechanisms primarily supported by experimental and preclinical studies rather than confirmed causal relationships in human populations.

Second, we acknowledge that the available human epidemiological evidence remains limited, and most studies currently focus on biomonitoring and exposure detection rather than disease outcomes. The revised manuscript now includes a subsection discussing human biomonitoring evidence and explicitly highlights limitations commonly encountered in emerging exposure studies.  Also, the revised manuscript now addresses epidemiological issues like small sample sizes, potential selection bias, confounding factors, and limited external validity. We have added other human studies as requested

Third, we agree with the reviewer that direct studies linking MP/NP exposure, dietary spices, and cancer risk have not yet been conducted. The manuscript has therefore been revised to clearly present this relationship as a hypothesis based on shared molecular pathways rather than a demonstrated causal interaction. We have revised the relevant sections to clearly state that the proposed interaction between MP/NP exposure and dietary phytochemicals represents a conceptual framework that warrants further investigation.

Comment 3: The manuscript contains several grammatical errors, such as: “MP/NPs -induced chronic inflammation” has incorrect spacing before the hyphen. “MN/NPs” appears alternately with “MP/NPs,” representing terminological inconsistency. The authors make excessive use of long sentences (>40 words) that impair readability (i.e., “Oxidative stress induced by MP/NPs also activates the MAPK signaling pathway and the NF-κB inflammatory transcription factor, while inactivating the antioxidant transcription factor Nrf2, cellular responses aimed at counteracting the oxidative insult”). This should be split into two sentences. There is ambiguous use of “recent findings support a causal role”; the authors should change it to “support a potential association

Response 3: We thank the reviewer for the observations. The grammatical errors have been corrected. Excessively long sentences have been split as instructed, and the ambiguous use of “recent findings support a causal role” has been changed.

 Comment 4: Although Figure 2.5.1 is schematic, the authors do not identify the source, make it clear whether it is original, or depict interactions between paths (just a list). An integrated diagram should be included by the authors, in my viewpoint: MP/NP → ROS → inflammation → hormonal disturbance → genotoxicity → cancer. The language and the chemical figures (garlic, turmeric, and ginger) match up nicely. Nonetheless, it is required to specify if they were written by the authors, modified, or protected by copyright. Real clinical trials and small-scale, poorly designed adjunct investigations are mixed together in Table 3.1. Although the authors should specify the sample size and outcome type (PSA, OS, biomarkers), it is a very helpful description.

Response 4: We appreciate the reviewer’s observation regarding Figure 2.5.1. We confirm that all figures are original schematics created by the authors. We have included a more integrated mechanistic pathway, as depicted in the following new figures: Figure 2.1.4.1, 2.1.2.1 and 2.1.1.1. Table 3.1 has been revised to clearly distinguish between clinical trials and smaller-scale studies.

 

Comment 5: To increase the manuscript's scientific rigor, I encourage the authors to respond to the following queries:

Which method of literature search was applied?

Which criteria were used for inclusion and exclusion?

Which type of evidence—clinical vs in vitro—was given priority?

What cutoff point do you think is appropriate to discuss carcinogenesis rather than toxicity alone?
Do realistic human doses that are comparable to those used in animal models have any data? How can the effects of additives (BPA, phthalates) be distinguished from those of the polymer?
Why were EGCG and resveratrol, two other pertinent phytochemicals, left out?
Did you take into account publication bias, which only considers favorable effects?

Response 5:

Which method of literature search was applied?

Which criteria were used for inclusion and exclusion?

Relevant studies were identified through searches of major scientific databases, including PubMed, Scopus, and Web of Science. We have explicitly defined the eligibility criteria as requested.

Which type of evidence—clinical vs in vitro—was given priority?

We have clarified that human clinical and epidemiological evidence was prioritized. However, due to the limited number of human studies in this field, mechanistic insights from in vitro and in vivo models were incorporated to support biological plausibility. The revised manuscript now clearly distinguishes these evidence tiers.

What cutoff point do you think is appropriate to discuss carcinogenesis rather than toxicity alone?

We appreciate the reviewer’s important question. In this narrative review, we did not apply an arbitrary quantitative cutoff to distinguish carcinogenesis from general toxicity, as such thresholds are not universally established and may vary across experimental systems. Instead, we adopted a mechanism-based interpretative framework consistent with established cancer biology.

Do realistic human doses that are comparable to those used in animal models have any data?

We acknowledge this critical point, but we have stated in the research challenges section that many experimental studies employ exposure levels higher than typical human environmental exposure.

How can the effects of additives (BPA, phthalates) be distinguished from those of the polymer?

We thank the reviewer for this important point. We would like to clarify that the primary focus of this narrative review is on micro- and nanoplastics (MP/NPs). References to other plastic-related toxicants, such as BPA and phthalates, were included selectively to provide a mechanistic context, particularly in instances where direct evidence specific to MP/NPs remains limited.

Did you take into account publication bias, which only considers favorable effects?

We thank the reviewer for this important observation. We critically considered the potential for bias by including studies with neutral or inconsistent findings where available.

Why were EGCG and resveratrol, two other pertinent phytochemicals, left out?

We thank the reviewer for this observation. We basically focus this narrative review on widely consumed dietary phytochemicals (turmeric/curcumin, garlic, and ginger) with previous anticancer reports.

Comment 6: Several kinds of issues were found with the references in the document. There are references that seem generic ("Stoian, 2025"), some that are hard to confirm, and some that might be fake (a major risk). Not every reference that is listed is directly related to the findings in the text. It is advised that the writers independently verify cell, animal, and clinical studies as well as each reference with its DOI. Furthermore, I recommend them to examine and reference this source (DOI: 10.1016/j.envpol.2025.127343).

Response 6: All issues regarding reference and referencing have been addressed.

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript addresses a timely and potentially relevant topic, namely the possible contribution of MP/NPs to reproductive carcinogenesis and the potential modulatory role of commonly consumed dietary spices such as ginger, garlic, and turmeric. The attempt to connect environmental exposure, molecular mechanisms of toxicity, and nutritional factors is interesting and may appeal to readers working at the intersection of environmental toxicology, cancer biology, and public health. The manuscript also compiles a considerable amount of literature related to oxidative stress, inflammatory signaling, endocrine disruption, and other pathways frequently discussed in this context.

At the same time, the review would benefit from a clearer methodological framework and a more critical treatment of the available evidence. In its current form, several aspects of the manuscript limit the scientific rigor and balance of the narrative.

To begin with, the manuscript does not describe how the literature included in the review was identified. Even for a narrative review, it would be helpful if the authors briefly indicated which databases were consulted, the approximate time frame covered by the literature, and whether any general inclusion criteria were applied when selecting studies. Without this information, the review reads more as a broad compilation of references than as a transparently assembled synthesis.

Another issue concerns the way different types of evidence are presented. Findings derived from in vitro experiments, animal models, and human studies are frequently discussed together within the same sections, without clearly distinguishing their respective levels of evidence. The manuscript would benefit from a clearer separation between human exposure or biomonitoring data, experimental animal studies, and mechanistic observations derived from cellular systems.

The discussion of the potential protective effects of phytochemicals from ginger, garlic, and turmeric would also benefit from a more cautious interpretation. In several instances, the manuscript appears to rely on mechanistic parallels, particularly the involvement of oxidative stress and inflammatory signaling, to support the idea that these compounds may mitigate MP/NP-induced toxicity. While such mechanistic overlaps are plausible, they do not necessarily constitute direct experimental evidence. Much of the cited literature relates either to other environmental toxicants or to the general antioxidant properties of these phytochemicals. It would therefore strengthen the review if the authors more clearly acknowledged that the evidence supporting a direct modulatory effect in the specific context of MP/NP exposure remains limited.

The MP/NP literature itself could also be discussed in a more critical way. Issues such as the marked heterogeneity in particle size, shape, polymer composition, and surface chemistry, as well as the potential role of plastic additives and adsorbed contaminants, have important implications for interpreting toxicological findings. Likewise, the analytical challenges associated with detecting and quantifying MP/NPs in biological samples remain a major limitation in the field. Integrating these considerations more consistently into the main narrative would improve the overall balance of the review.

The section discussing ginger, garlic, and turmeric would also benefit from a clearer discussion of translational limitations. For instance, aspects such as the limited bioavailability of compounds like curcumin, the difference between concentrations used in experimental systems and those achievable through dietary exposure, and the still limited clinical evidence supporting anticancer effects in humans deserve more explicit attention.

Regarding the reference framework, the manuscript cites a large and relatively recent body of literature, but the selection of references could be further refined. In several sections, secondary reviews appear to be used where primary studies would be more appropriate, particularly when specific mechanistic or translational claims are made. In addition, some references appear only loosely connected to the specific focus of the manuscript on reproductive carcinogenesis associated with MP/NP exposure. There is also a tendency to discuss MP/NPs together with other plastic-related toxicants such as BPA, phthalates, and plasticizers as if they represented a single and directly comparable body of evidence. A more selective and hierarchized use of references would improve the precision of the review.

With respect to the graphical material, the figures currently included in the manuscript provide relatively limited additional insight beyond what is already presented in the text. In several cases, they appear to illustrate broad conceptual ideas rather than synthesizing the literature in a way that directly supports the central argument of the manuscript. The review would benefit if the figures were redesigned so that they more clearly represent the proposed relationships between MP/NP exposure, the molecular pathways implicated in reproductive carcinogenesis, and the potential points of intervention associated with the phytochemicals discussed.

Finally, a few editorial issues should also be addressed. There appear to be some inconsistencies in the presentation of scientific names for plant species across the manuscript, and the authors may wish to review the text to ensure that botanical nomenclature follows standard conventions. In addition, several minor typographical issues, punctuation inconsistencies, and occasional incomplete sentences were noted during reading. A careful proofreading of the manuscript would therefore improve clarity and readability.

In summary, while the manuscript addresses an interesting and relevant topic, several aspects of the current version would benefit from further clarification and critical refinement.

Overall, the topic of the review is relevant and potentially valuable. However, the manuscript would benefit from greater methodological transparency, clearer stratification of different levels of evidence, and a more cautious interpretation of the proposed mechanistic links between MP/NP exposure and phytochemical modulation. Addressing these aspects would substantially strengthen the scientific balance and clarity of the work.

Comments on the Quality of English Language

The manuscript is generally understandable; however, the English language would benefit from careful revision to improve clarity and consistency. Several minor grammatical and typographical errors were noted throughout the text, including occasional punctuation issues and incomplete sentences. In addition, there are inconsistencies in the use of scientific nomenclature for plant species and some stylistic variations across sections. A thorough language editing would improve readability and help ensure that the scientific arguments are communicated more clearly.

Author Response

Comment 1: To begin with, the manuscript does not describe how the literature included in the review was identified. Even for a narrative review, it would be helpful if the authors briefly indicated which databases were consulted, the approximate time frame covered by the literature, and whether any general inclusion criteria were applied when selecting studies. Without this information, the review reads more as a broad compilation of references than as a transparently assembled synthesis.

Response 1: We acknowledge that narrative reviews do not typically follow the same methodological framework as systematic reviews or meta-analyses. However, to improve transparency and methodological clarity, we have now added a brief literature search description in the Introduction/methodology section, indicating the databases consulted and the general search strategy used to identify relevant studies. Specifically, relevant studies were identified through searches of major scientific databases, including PubMed, Scopus, and Web of Science, focusing on publications addressing micro- and nanoplastics, oxidative stress, inflammation, genotoxicity, reproductive toxicity, and reproductive cancers. Priority was given to peer-reviewed articles published from 2008 to 2026. We have explicitly defined the eligibility criteria as requested.

Comment 2: Another issue concerns the way different types of evidence are presented. Findings derived from in vitro experiments, animal models, and human studies are frequently discussed together within the same sections, without clearly distinguishing their respective levels of evidence. The manuscript would benefit from a clearer separation between human exposure or biomonitoring data, experimental animal studies, and mechanistic observations derived from cellular systems.

Response 2: We thank the reviewer for the insightful comment. The manuscript has been revised to more clearly distinguish among human biomonitoring studies, experimental animal studies, and in vitro mechanistic investigations.

Comment 3: The discussion of the potential protective effects of phytochemicals from ginger, garlic, and turmeric would also benefit from a more cautious interpretation. In several instances, the manuscript appears to rely on mechanistic parallels, particularly the involvement of oxidative stress and inflammatory signaling, to support the idea that these compounds may mitigate MP/NP-induced toxicity. While such mechanistic overlaps are plausible, they do not necessarily constitute direct experimental evidence. Much of the cited literature relates either to other environmental toxicants or to the general antioxidant properties of these phytochemicals. It would therefore strengthen the review if the authors more clearly acknowledged that the evidence supporting a direct modulatory effect in the specific context of MP/NP exposure remains limited.

Response 3: We thank the reviewer for this important and insightful comment. In response, we have carefully revised the relevant sections of the manuscript (especially Section 4.0) to ensure a more cautious and balanced interpretation of the potential protective effects of phytochemicals derived from ginger, garlic, and turmeric. The discussion has been reframed to present the role of these compounds as part of a hypothesis-driven conceptual framework, highlighting plausible biological interactions while acknowledging the current lack of direct validation in the context of MP/NP exposure.

Comment 4: The MP/NP literature itself could also be discussed in a more critical way. Issues such as the marked heterogeneity in particle size, shape, polymer composition, and surface chemistry, as well as the potential role of plastic additives and adsorbed contaminants, have important implications for interpreting toxicological findings. Likewise, the analytical challenges associated with detecting and quantifying MP/NPs in biological samples remain a major limitation in the field. Integrating these considerations more consistently into the main narrative would improve the overall balance of the review.

Response 4: We thank the reviewer for this thoughtful and valuable observation. We agree that factors such as heterogeneity in particle size, shape, polymer composition, surface chemistry, as well as the influence of plastic additives and adsorbed contaminants, are important considerations in interpreting MP/NP toxicological findings. We also acknowledge that analytical limitations in the detection and quantification of MP/NPs in biological matrices remain a key challenge in the field. However, we would like to clarify that these aspects have been implicitly considered in the interpretation of the reviewed studies, particularly in sections discussing mechanistic variability and limitations of current evidence. Given the scope and focus of this narrative review, centered primarily on biological mechanisms and potential health implications, a more extensive methodological critique of MP/NP characterization and detection techniques is beyond the intended depth of this work.

Comment 5: The section discussing ginger, garlic, and turmeric would also benefit from a clearer discussion of translational limitations. For instance, aspects such as the limited bioavailability of compounds like curcumin, the difference between concentrations used in experimental systems and those achievable through dietary exposure, and the still limited clinical evidence supporting anticancer effects in humans deserve more explicit attention.

Response 5: We thank the reviewer for this thoughtful comment. While we agree that an expanded discussion of bioavailability and clinical translation is valuable, such detail would extend beyond the defined scope of this review and is more appropriately addressed in dedicated pharmacological or clinical-focused analyses. The manuscript already clearly emphasizes that the proposed protective roles of these phytochemicals are not based on direct clinical or translational evidence, but rather on shared molecular mechanisms, including oxidative stress modulation, inflammatory signaling, and genotoxic pathways.

 

Comment 6: Regarding the reference framework, the manuscript cites a large and relatively recent body of literature, but the selection of references could be further refined. In several sections, secondary reviews appear to be used where primary studies would be more appropriate, particularly when specific mechanistic or translational claims are made. In addition, some references appear only loosely connected to the specific focus of the manuscript on reproductive carcinogenesis associated with MP/NP exposure. There is also a tendency to discuss MP/NPs together with other plastic-related toxicants such as BPA, phthalates, and plasticizers as if they represented a single and directly comparable body of evidence. A more selective and hierarchized use of references would improve the precision of the review

Response 6: We thank the reviewer observation and comment. We have carefully revised the reference framework throughout the manuscript to improve precision, relevance, and scientific rigor.

Regarding the tendency of discussing MP/NPs together with other plastic-related toxicants as if they represented a single and directly comparable body of evidence: We would like to clarify that the primary focus of this narrative review is on micro- and nanoplastics (MP/NPs). References to other plastic-related toxicants, such as BPA and phthalates, were included selectively to provide mechanistic context, particularly in instances where direct evidence specific to MP/NPs remains limited.

Comment 7: With respect to the graphical material, the figures currently included in the manuscript provide relatively limited additional insight beyond what is already presented in the text. In several cases, they appear to illustrate broad conceptual ideas rather than synthesizing the literature in a way that directly supports the central argument of the manuscript. The review would benefit if the figures were redesigned so that they more clearly represent the proposed relationships between MP/NP exposure, the molecular pathways implicated in reproductive carcinogenesis, and the potential points of intervention associated with the phytochemicals discussed.

Response 7: We thank the reviewer for this valuable suggestion regarding the graphical material. We have redesigned and improved the figures. These improvements are reflected in the newly revised figures (Figures 2.1.1.1, 2.1.2.1, and 2.1.4.1), which now go beyond broad conceptual representations to provide a more coherent and structured visualization of pathway interactions, including oxidative stress, inflammatory signaling, endocrine disruption, and genotoxic mechanisms, along with their potential points of intervention.

Comment 8: Finally, a few editorial issues should also be addressed. There appear to be some inconsistencies in the presentation of scientific names for plant species across the manuscript, and the authors may wish to review the text to ensure that botanical nomenclature follows standard conventions. In addition, several minor typographical issues, punctuation inconsistencies, and occasional incomplete sentences were noted during reading. A careful proofreading of the manuscript would therefore improve clarity and readability.

Response 8: We thank the reviewer for this observation. We have standardized the presentation of scientific names for plant species to ensure compliance with accepted botanical nomenclature conventions throughout the text. In addition, the manuscript has undergone thorough proofreading to correct typographical errors, punctuation inconsistencies, and incomplete sentences.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors,

The manuscript has been substantially improved. Overall, the manuscript requires minor corrections (see below) to meet the journal's publication standards.

. 

Abstract

• This section requires more revision in term of organization of the information. The authors should reduce the background information; provide an objective, brief methodology and key findings obtained from analysis of different literatures.
• Keywords: order them alphabetically.

General comments

• Correct the format numbering of tables and figures, e.g. Figure 2.1.1.1 should be numbered Figure 1.
• Edit the font type and size for figures to match that of the text.
• Review the document for typos correction.

Author Response

Comment: This section requires more revision in term of organization of the information. The authors should reduce the background information; provide an objective, brief methodology and key findings obtained from analysis of different literatures.

Response: Thank you for the comment. The abstract has been revised as requested

 

Comment: Keywords; order them alphabetically.

Response: Keywords have been arranged in alphabetical order

 

Comment: Correct the format numbering of tables and figures, e.g. Figure 2.1.1.1 should be numbered Figure 1.

Response: Thank you for the comment. The numbering of figures and tables has been modified as instructed

 

Comment: Edit the font type and size for figures to match that of the text.

Response: Thank you for the comment. We have edited the figure font type to match the text. We did not change the font size for easy and better visualization

 

Comment: Review the document for typos correction.

Response: All typo errors corrected as instructed

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Editor,

Dear authors,

After making the necessary changes based on my suggestions, I believe the paper ”Impact of Micro and Nanoplastics on Reproductive Cancer and the Potential Anticancer Benefits of Prolonged Ginger, Garlic, and Turmeric Consumption: A Narrative Review" is ready for publication in your prestigious journal.

 

Author Response

Comment: After making the necessary changes based on my suggestions, I believe the paper ”Impact of Micro and Nanoplastics on Reproductive Cancer and the Potential Anticancer Benefits of Prolonged Ginger, Garlic, and Turmeric Consumption: A Narrative Review" is ready for publication in your prestigious journal.

Response. Thank you for the comment

Reviewer 3 Report

Comments and Suggestions for Authors

I appreciate the effort made to revise the manuscript. The new version is clearer than the original in several aspects. In particular, the inclusion of a brief description of the literature search (databases, time frame, and general criteria) improves transparency, and the attempt to separate human data, animal studies, and in vitro evidence is a positive step. The reformulation of Section 4 as a more hypothesis-driven discussion, rather than as direct evidence, is also an important improvement.

However, despite these advances, several key issues remain only partially addressed and still limit the overall strength of the manuscript.

First, in Section 4 (interaction between MP/NPs and phytochemicals), the interpretation is now more cautious than in the previous version, but the argument still relies heavily on mechanistic overlap (oxidative stress, NF-κB, MAPK, etc.) rather than on direct experimental evidence in the specific context of MP/NP exposure. For example, many of the cited effects of ginger, garlic, and turmeric are derived from studies on other toxicants or general anticancer mechanisms, but they are still presented in a way that may suggest a more direct relevance to MP/NP-induced carcinogenesis than is currently supported. It would help to explicitly mark these sections as indirect evidence and to clearly distinguish what is demonstrated from what remains hypothetical.

Second, although the manuscript now separates different types of evidence more clearly, the discussion still does not consistently reflect their different levels of strength. In sections dealing with reproductive toxicity and carcinogenic pathways (e.g., Sections 2 and 3), findings from in vitro systems, animal models, and human observations are often presented in sequence but without clearly indicating how much weight should be given to each. Given the limited availability of direct human evidence in this field, a more explicit stratification of evidence would improve the scientific balance of the review.

Third, the conceptual distinction between micro/nanoplastics and other plastic-related chemicals (such as BPA, phthalates, and plasticizers) remains somewhat blurred. This is noticeable in multiple sections where these are discussed within the same mechanistic narrative. While the intention to provide context is understandable, these exposures are not equivalent from a toxicological perspective. It would strengthen the manuscript if these were more clearly separated, indicating when evidence refers specifically to MP/NPs and when it comes from chemically distinct compounds.

Fourth, the discussion of translational limitations in the phytochemical section is still relatively limited. While the revised version acknowledges the lack of direct clinical evidence, it would be important to address more explicitly issues such as the low bioavailability of curcumin, the dependence on formulation, and the gap between experimental concentrations and realistic dietary exposure. These aspects are central for interpreting the real-world relevance of the proposed protective effects.

Fifth, regarding the reference framework, the manuscript includes a large and recent body of literature, which is positive. However, in several places (particularly in mechanistic descriptions), secondary reviews are still used where primary studies would be more appropriate. In addition, some references appear only loosely connected to the specific focus on MP/NP-related reproductive carcinogenesis. A more selective use of references, prioritizing primary evidence where possible, would improve precision.

Regarding the figures, the revised version includes additional graphical material and some of the mechanistic diagrams (for example, Figures 2.1.1.1, 2.1.2.1, and 2.1.4.1) are clearer than in the previous version. However, many figures still function mainly as simplified linear schemes rather than as integrative representations of the underlying biology. In these cases, the figures largely repeat information already described in the text, without adding new insight or showing interactions between pathways.

This is particularly noticeable in the phytochemical section (Figures 3.1.1, 3.1.3, and 3.2.1), where several figures appear more descriptive than analytical. Some of them resemble schematic summaries of compounds or pathways but are not clearly connected to the central question of MP/NP-induced carcinogenesis. In addition, there are instances where the visual and textual quality of the figures could be improved, including inconsistencies in wording and formatting within the figure panels.

A related issue concerns the numbering of figures and tables. The manuscript currently uses a hierarchical numbering system (e.g., Figure 2.1.1.1), which makes it difficult to follow and is not aligned with the standard format used in most scientific journals, including MDPI. Figures and tables are typically numbered sequentially (Figure 1, Figure 2, etc.), regardless of section structure. I would strongly recommend revising this to a simple sequential numbering system to improve clarity and facilitate cross-referencing within the text.

The authors may benefit from consulting recent high-quality reviews in the field where figures are used not only to illustrate concepts but to integrate exposure routes, biological mechanisms, and outcomes in a more structured and visually informative manner.
10.1021/acs.est.7b00423
https://doi.org/10.1016/j.scitotenv.2019.134455
https://doi.org/10.3390/biomedicines14010001
https://doi.org/10.3390/ijerph17051509

Finally, although the manuscript is improved in terms of language, some editorial issues still remain. There are minor inconsistencies in phrasing and formatting, and typographical conventions should be standardized. For example, Latin expressions such as in vitro and in vivo should consistently appear in italics throughout the text and figure legends. A final careful proofreading would further improve readability.

Overall, the manuscript has improved compared to the initial submission, and the authors have addressed several comments constructively. However, further revision is still needed to strengthen conceptual clarity, better differentiate levels of evidence, refine the use of references, and improve the quality and contribution of the graphical material.

Comments on the Quality of English Language

The English language requires improvement to enhance clarity and consistency throughout the manuscript. Several sections contain grammatical inaccuracies, punctuation issues, and occasional incomplete sentences that affect readability. Additionally, there are inconsistencies in the use of scientific terminology (e.g., formatting of in vitro and in vivo), which should be standardized according to conventional scientific writing.

Author Response

Comment: First, in Section 4 (interaction between MP/NPs and phytochemicals), the interpretation is now more cautious than in the previous version, but the argument still relies heavily on mechanistic overlap (oxidative stress, NF-κB, MAPK, etc.) rather than on direct experimental evidence in the specific context of MP/NP exposure. For example, many of the cited effects of ginger, garlic, and turmeric are derived from studies on other toxicants or general anticancer mechanisms, but they are still presented in a way that may suggest a more direct relevance to MP/NP-induced carcinogenesis than is currently supported. It would help to explicitly mark these sections as indirect evidence and to clearly distinguish what is demonstrated from what remains hypothetical.

Response: We thank the reviewer for this insightful comment. We acknowledge that, in Section 4, some of the discussed effects of ginger, garlic, and turmeric are supported by evidence derived from broader toxicological and anticancer studies.

However, the primary aim of this section is not to present definitive causal evidence specific to MP/NP-induced carcinogenesis, but rather to highlight plausible mechanistic intersections based on well-established biological pathways (e.g., oxidative stress, NF-κB, MAPK signaling) that are consistently implicated across both MP/NP toxicity and carcinogenesis more broadly. Given the current scarcity of direct experimental studies investigating phytochemical effects specifically in MP/NP exposure models, reliance on mechanistic convergence is both necessary and widely accepted in hypothesis-generating reviews.

Importantly, the manuscript does not claim direct efficacy of these phytochemicals against MP/NP-induced carcinogenesis, but instead aims to contextualize their potential relevance within a mechanistic framework. We consider this approach valuable for identifying knowledge gaps and future research directions.

Comment: Second, although the manuscript now separates different types of evidence more clearly, the discussion still does not consistently reflect their different levels of strength. In sections dealing with reproductive toxicity and carcinogenic pathways (e.g., Sections 2 and 3), findings from in vitro systems, animal models, and human observations are often presented in sequence but without clearly indicating how much weight should be given to each. Given the limited availability of direct human evidence in this field, a more explicit stratification of evidence would improve the scientific balance of the review.

Response: We thank the reviewer for this thoughtful comment. We agree that distinguishing between levels of evidence (in vitro, animal, and human studies) is important when interpreting findings in this field. However, the available literature on MP/NP-related reproductive toxicity and carcinogenic pathways is inherently heterogeneous and still emerging, with limited direct human data. As such, presenting evidence across experimental systems in parallel is intended to provide a comprehensive and biologically coherent overview, rather than to imply equivalence in evidentiary weight.

Importantly, the manuscript does not draw causal conclusions based on single lines of evidence, but instead uses converging findings across in vitro, in vivo, and human-relevant observations to highlight consistent mechanistic patterns. We consider this integrative approach to be both standard and appropriate for hypothesis-generating narrative reviews in evolving fields.

A formal stratification or grading of evidence, while valuable in systematic reviews or risk assessment frameworks, would extend beyond the intended scope of this work and may inadvertently fragment the mechanistic narrative we aim to present.

Nevertheless, we have ensured that interpretations remain appropriately cautious, particularly where human data are limited, and that no undue weight is assigned to any single study type.

                                 

Comment: Third, the conceptual distinction between micro/nanoplastics and other plastic-related chemicals (such as BPA, phthalates, and plasticizers) remains somewhat blurred. This is noticeable in multiple sections where these are discussed within the same mechanistic narrative. While the intention to provide context is understandable, these exposures are not equivalent from a toxicological perspective. It would strengthen the manuscript if these were more clearly separated, indicating when evidence refers specifically to MP/NPs and when it comes from chemically distinct compounds.

Response: We thank the reviewer for this comment. While we acknowledge that micro/nanoplastics (MP/NPs) and plastic-associated chemicals (e.g., bisphenols and phthalates) are toxicologically distinct under controlled conditions, we respectfully maintain that their integrated discussion is appropriate within the scope of this work.

This manuscript is a broad narrative review aimed at reflecting real-world exposure scenarios, where these agents co-occur and interact rather than exist in isolation. Notably, the evidence base itself is complementary: human biomonitoring studies largely focus on plastic-associated chemicals, whereas mechanistic and emerging carcinogenic evidence is more developed for MP/NPs. Addressing them in parallel is therefore necessary to provide a balanced and comprehensive analysis.

Our inclusion criteria intentionally encompass both particulate and chemical exposures, consistent with the co-exposure paradigm, and the shared downstream biological effects reported across studies.

Importantly, the manuscript does not imply equivalence between these entities but rather contextualizes their interacting and convergent effects. A strict separation would risk oversimplifying the mixture-driven nature of plastic-related toxicity.

Accordingly, we consider this integrated approach to be scientifically justified and aligned with the current direction of the field.

 

Comment: Fourth, the discussion of translational limitations in the phytochemical section is still relatively limited. While the revised version acknowledges the lack of direct clinical evidence, it would be important to address more explicitly issues such as the low bioavailability of curcumin, the dependence on formulation, and the gap between experimental concentrations and realistic dietary exposure. These aspects are central for interpreting the real-world relevance of the proposed protective effects.

Response: We thank the reviewer for this important observation. We agree that factors such as bioavailability, formulation dependency (particularly for curcumin), and the gap between experimental and dietary exposure levels are relevant when considering translational applicability.

However, we respectfully note that the primary aim of this section is to provide a mechanistic and hypothesis-generating overview of the potential interactions between phytochemicals and MP/NP-related pathways, rather than a detailed evaluation of clinical efficacy or pharmacokinetics. As such, an in-depth discussion of formulation strategies, bioavailability enhancement, and dose translation falls beyond the intended scope of this narrative review.

That said, the revised manuscript already acknowledges the lack of direct clinical evidence and translational constraints, which we consider sufficient to appropriately contextualize the findings without overextending the discussion. Expanding further into these aspects would shift the focus toward a pharmacological or clinical framework, which is not the objective of the present work

Comment: Fifth, regarding the reference framework, the manuscript includes a large and recent body of literature, which is positive. However, in several places (particularly in mechanistic descriptions), secondary reviews are still used where primary studies would be more appropriate. In addition, some references appear only loosely connected to the specific focus on MP/NP-related reproductive carcinogenesis. A more selective use of references, prioritizing primary evidence where possible, would improve precision.

Response: We thank the reviewer for this constructive comment regarding the reference framework. Given the breadth and interdisciplinary nature of this topic, spanning MP/NPs, reproductive toxicity, carcinogenic pathways, and phytochemical modulation, high-quality review articles were intentionally incorporated in sections dealing with established or widely recognized mechanisms (e.g., oxidative stress, inflammatory signaling pathways). At the same time, primary studies have been preferentially cited in areas more directly relevant to MP/NP exposure and emerging evidence, particularly where mechanistic or experimental specificity is critical. The apparent inclusion of some references that may seem indirectly related reflects the current limitations of the field, where direct evidence linking MP/NPs to reproductive carcinogenesis remains relatively sparse. In these cases, carefully selected studies from adjacent domains were included to contextualize biological plausibility and support a coherent mechanistic framework, which is consistent with the aims of a hypothesis-generating narrative review.

Comment: Regarding the figures, the revised version includes additional graphical material and some of the mechanistic diagrams (for example, Figures 2.1.1.1, 2.1.2.1, and 2.1.4.1) are clearer than in the previous version. However, many figures still function mainly as simplified linear schemes rather than as integrative representations of the underlying biology. In these cases, the figures largely repeat information already described in the text, without adding new insight or showing interactions between pathways.

Response: Thank you for the insightful comments. We have removed figures that doesn’t add new insight from the text

Comment: This is particularly noticeable in the phytochemical section (Figures 3.1.1, 3.1.3, and 3.2.1), where several figures appear more descriptive than analytical. Some of them resemble schematic summaries of compounds or pathways but are not clearly connected to the central question of MP/NP-induced carcinogenesis. In addition, there are instances where the visual and textual quality of the figures could be improved, including inconsistencies in wording and formatting within the figure panels.

Response: We thank the reviewer for this insightful comment. The figures in question were intentionally designed to classify and summarize the bioactive compounds present in ginger, turmeric, and garlic, thereby providing a clear and concise reference framework for readers. The proposed interaction between MP/NP-induced carcinogenic pathways and these bioactive compounds is instead synthesized in Figure 7, which serves as the central integrative illustration.

We respectfully note that expanding additional figures to separately depict each mechanistic interaction would lead to redundancy and reduced clarity, particularly within the constraints of a narrative review. Moreover, limitations on the number of figures and overall manuscript length, as per journal guidelines and other reviewer recommendations, necessitated a selective and strategic presentation of visual material.

Comment: A related issue concerns the numbering of figures and tables. The manuscript currently uses a hierarchical numbering system (e.g., Figure 2.1.1.1), which makes it difficult to follow and is not aligned with the standard format used in most scientific journals, including MDPI. Figures and tables are typically numbered sequentially (Figure 1, Figure 2, etc.), regardless of section structure. I would strongly recommend revising this to a simple sequential numbering system to improve clarity and facilitate cross-referencing within the text.

Response: Thank you for the comment. Numbering of figures and tables have modified as instructed

Comment: Finally, although the manuscript is improved in terms of language, some editorial issues still remain. There are minor inconsistencies in phrasing and formatting, and typographical conventions should be standardized. For example, Latin expressions such as in vitro and in vivo should consistently appear in italics throughout the text and figure legends. A final careful proofreading would further improve readability.

Response: We have improved the language as suggested and minor inconsistencies in phrasing and formatting modified