Dear Dr. Ha,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jun 07 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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Li Yang, M.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

Reviewer #2: No

Reviewer #3: Partly

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2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

Reviewer #1: The manuscript titled 'Exposure to heavy metals, bisphenol A, and phthalates: Implications for precocious or delayed puberty' is interesting and written well. I have only a few remarks:

Comment 1: In introduction, the author needs to put forward the hypothesis of this study and clarify the content and significance of his own research. In addition, What are the differences or innovations between this study and these findings?

Comment 2: In line 128-129, the authors need to add detailed test procedures or add references.

Comment 3: In table 1, need to label units, especially in Blood and urinary measurement of heavy metals, like table 2.

Comment 4: In results, it is suggested to add the corresponding figures, here are all tables. In addition, is there any correlation analysis that can be done between these data?

Comment 5: in discussion, it is suggested that the authors further enhance the depth of the discussion section of this paper.

Reviewer #2: The manuscript has several major shortcomings that impact its overall scientific rigor. The abstract (lines 38–54) does not clearly highlight the cross-sectional nature of the study, which significantly limits any causal interpretation between exposure to environmental chemicals and puberty outcomes. The reliance on self-assessed Tanner stages (line 43) introduces potential bias due to misclassification, especially among younger participants who may lack the ability to accurately evaluate their developmental stage. Although the study employs mixture models (lines 45–46), the results are frequently described as imprecise (lines 52–53, 260), suggesting that the findings may lack robustness and could be due to chance. Among the nine chemicals measured, only mono-benzyl phthalate (MBzP) showed a statistically significant association with delayed puberty in girls (lines 49–51, 259), while associations for other chemicals were weak and inconsistent, particularly in boys. The analysis lacks a detailed discussion of dose-response relationships, which is critical for establishing the biological plausibility of the reported associations. The paper reviews inconsistent findings from previous literature (lines 265–275) but does not adequately explain how the current study design resolves these inconsistencies or adds clarity. The identification of lead as a key driver of delayed puberty in mixture analysis (lines 276–278) is not thoroughly validated by sex-specific or stratified analyses, weakening the strength of the conclusion. The number of identified cases of precocious and delayed puberty is relatively small (lines 47–48), raising concerns about the statistical power of the study and the reliability of the regression models used. These issues collectively limit the interpretability and generalizability of the study’s findings.

Reviewer #3: Here is a list of specific comments. Note: line and page numbering in reviews and comments is based on

ruler applied in Editorial Manager-generated PDF.

1. Page 3, line 48: There might be issues due to the small number of events per variable in the models, especially the multi-exposure models. The first limitation in the Discussion section addressed the low power issue. I suggest expanding the limitation to other issues such as overfitting, biased estimation, model instability, etc.

2. Page 5, lines 91–92: I suggest reporting the number of participants excluded due to missing information on pubertal development, missing blood samples, and missing urine samples separately.

3. Page 7, lines 135–145: It might be worth considering two separate cohorts, one for the precocious puberty and the other for the delayed puberty. The precocious puberty cohort would consist of girls with age 10 years or younger and boys with age 8 or younger. The delayed puberty cohort would consist of girls with age 13 or older and boys with age 14 or older. In other words, Table S1 would be split into two tables.

4. Page 7, lines 148–150: I suggest rewriting the sentence as follows. ‘The selected covariates included participants’ age at the time of the tests, body mass index (BMI), presence of siblings, urban residence, and socioeconomic status (SES).’

5. Page 7, line 150: BMI is a well-known metric and does not require a definition. If you would like to keep the sentence, I suggest revising the sentence as ‘BMI was calculated as weight in kilograms divided by height in meters squared.’

6. Page 7, lines 153–154: I suggest revising “the median” as ‘the median household income for 2014’ and removing the subsequent sentence, “the median household income for 2014 was . . . .” I suggest being specific about the median household income for 2014.

7. Page 7, lines 157–158: I suggest rewriting the sentence as follows. ‘Descriptive statistics summarized the baseline clinical characteristics of the study sample.’

8. Page 8, lines 158–159: I suggest rewriting the sentence as follows. ‘Due to their skewness, the urine levels of the measured environmental chemicals were log-transformed in regression models.’

9. Page 8, lines 159–160: I suggest stating the purpose of examining the correlations among the environmental chemicals.

10. Page 8, lines 161–162: I suggest revising the sentence as ‘each single-exposure model adjusted for age, BMI, presence of siblings, urban residence, and SES,’ and relocating the revised sentence to line 165 (after the next sentence).

11. Page 8, line 163: I suggest unifying the use of “environmental chemicals” and “heavy metals, BPA, or phthalate metabolites.”

12. Page 8, line 166: The two blood chemicals, Pb and Hg, were not log-transformed. The phrase was not applicable to all chemicals.

13. Page 8, line 169: I suggest revising “all covariates” as ‘all covariates listed in the single-exposure models.’

14. Page 8, lines 174–175: Please clarify if it was the one-quartile change in average chemical exposure or in average ‘log’ chemical exposure because the urine levels were log-transformed.

15. Page 8, line 180: There was no Table S3. Did you mean Table S1?

16. Table 1: I suggest not reporting characteristics by the outcome status. I suggest replacing the current Table 1 with Table S1 (after revision).

17. Figure 1: For the same reason as Comment 16 above, I suggest removing Figure 1.

18. Page 10, lines 209–210: Following Comment 9 above, what was the implication of these observed high correlations? If the purpose of reporting correlations was to avoid collinearity, these high correlations might distort the estimates of the multi-exposure models.

19. Table 2: I suggest providing a better indication of which exposures were log-transformed.

20. Table S1: Different age categories in girls and boys made the distributions difficult to interpret. Please consider the two-cohort approach suggested in Comment 3 above.

21. Figure S3: I suggest clarifying what EDC stands for.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

**********

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Attachments

Attachment

Submitted filename: PONE-D-25-12742_reviewer.docx

Dear Dr. Ha,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Major concerns:

1. Statistical power and model reliability: The number of cases of precocious puberty (50 cases) and delayed puberty (54 cases) is too low. Especially, the exposure model includes 9 chemicals, which may lead to overfitting of the model and unstable estimates (e.g., OR for boys with precocious puberty = 2.34, 95% CI: 0.36 - 15.14). The authors mentioned that the test power is only about 60% (assuming OR = 1.5), but did not fully discuss its potential impact on negative results (such as the possibility that no association with other chemicals may be due to insufficient power). I think the discussion section needs to be expanded to clearly explain the impact of small sample size on the mixed model (such as the risk of overfitting) and suggest the required sample size for future studies. Add sensitivity analysis and add model stability tests (such as Bootstrap method to verify the confidence interval of OR).

2. Limitations of exposure assessment: Relying solely on a single biological sample (blood/urine) cannot reflect the dynamic of long-term exposure, especially for heavy metals with long half-lives (such as lead accumulation in bones). Other environmental pollutants (such as pesticides, flame retardants) were not included, which may miss important confounding factors. The authors need to strengthen the discussion and clearly state the limitations of single measurement in the "Limitations" section. It is recommended that future studies adopt a longitudinal design or cumulative exposure indicators. Supplementary analysis: If the data permit, analyze the interactions between chemical substances (such as heavy metals and phthalates).

3. Rigor of result interpretation: Only MBzP showed a significant effect on girls' delayed puberty (OR = 2.75), while the other associations were not significant or had wide confidence intervals. However, the conclusion that "chemical mixtures are associated with delayed puberty" may be an overinterpretation. The discussion on the mechanism of urban-rural differences (with a higher proportion of girls experiencing delayed puberty in rural areas) is insufficient (such as whether it is related to pollutant exposure levels or social economic factors?). Please revise the conclusion statement to avoid suggesting a "wide correlation of mixtures", and focus on the significance of MBzP and the potential role of lead in boys. Delve deeper into the differences between urban and rural areas, and supplement with literature support (such as citing Oh et al. 2024's discussion on air pollution and precocious puberty). Distinguish the effects of pollution exposure from those of confounding factors such as obesity.

4. Methodological details and data accuracy: In Table 3, "MBaP" should be "MBzP" (Page 21). Inconsistent ethical approval numbers: The main text states 2013-05-004-001 (Page 12), but the supplementary material is 2013-05-004_(III).pdf (Page 38). The correlation coefficients are extremely high (such as MEOHP-MEHHP, ρ=0.97) and the impact of multicollinearity on the model has not been discussed. The authors should correct the data errors, unify the ethical approval numbers, and correct "MBaP" in Table 3. Provide an explanation for handling multicollinearity, clearly explain how QGC reduces the influence of multicollinearity (such as quantile transformation), or provide a VIF analysis in the supplementary material.

Minor concerns:

1. Chart optimization: Table 1: Add units (such as blood lead μg/dL) and provide a footnote stating "median [IQR]" or "mean (SD)". Figure S4: Simplify the correlation coefficient graph, highlighting the high correlations with |ρ| > 0.7.

2. Discussion Extension: Analyze the potential mechanisms underlying the significant effect of MBzP in girls and the lack of such effect in boys (such as differences in sex hormone pathways). Refer to the latest literature to support the discussion on the urban-rural disparity.

3. Terminology Consistency: The term "phthalate metabolites" (instead of "phthalates") is uniformly used throughout the text to avoid confusion between the parent compound and its metabolites.

==============================

Please submit your revised manuscript by Aug 13 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Li Yang, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments:

Please further address editor comments.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #3: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #3: Yes

**********

Reviewer #1:  (No Response)

Reviewer #3:  (No Response)

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #1: No

Reviewer #3: No

**********

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Dear Dr. Ha,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Dec 13 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Li Yang, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

1. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

Additional Editor Comments:

Thanks for submitting your revised paper to PLOS ONE. Your manuscript has now been assessed by our editorial team and external peer experts. Although the study is of potential significance, some additional problems were proposed. Please further address the reviewers' concerns.

[Note: HTML markup is below. Please do not edit.]

Reviewer's Responses to Questions

Comments to the Author

Reviewer #4: All comments have been addressed

Reviewer #5: All comments have been addressed

Reviewer #6: (No Response)

Reviewer #7: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #4: Partly

Reviewer #5: Partly

Reviewer #6: Yes

Reviewer #7: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #4: No

Reviewer #5: Yes

Reviewer #6: Yes

Reviewer #7: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

Reviewer #7: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #4: Yes

Reviewer #5: (No Response)

Reviewer #6: (No Response)

Reviewer #7: Yes

**********

Reviewer #4: The present study includes an overall adequate sample size and has applied sound analytical methods. However, the way results are presented, together with certain limitations—some of which were already acknowledged in the manuscript—makes the findings less interpretable and difficult to draw valid inferences from:

The sample size in the groups with precocious or delayed puberty is very small, especially when analyses are stratified by sex. There were 50 children with precocious puberty (38 girls and 12 boys) and 54 children with delayed puberty, of whom only 12 were girls. This limited subgroup size substantially reduces the robustness of the statistical analyses.

Regarding the inclusion of “having siblings” in the DAG, the rationale for its relationship with the level of exposure to heavy metals, is unclear. Further clarification is needed on how this variable may confound or mediate the associations under study.

Among boys, because pubertal status was defined based on the current questionnaire, boys aged 9–13 years were excluded from the study. However, a similar exclusion was not applied to the girls. The justification for this difference between sexes is not provided.

The manuscript reports that 874 girls were included in the study, yet Table 1 indicates that 771 girls were included in the total cohort and 387 in the delayed puberty cohort. This discrepancy needs to be clarified.

In lines 184–188, the authors make comparisons that are statistically invalid. For example, they state that more girls were in the precocious puberty group (38 of 50). Since the number of boys and girls in the cohort is not equal, such a comparison is not appropriate. Instead, the correct approach would be to compare the proportion of children experiencing precocious puberty within each sex cohort (i.e., the percentage of girls versus the percentage of boys)

The definition of precocious and delayed puberty in your study is inherently age-dependent, as early puberty is only detectable in younger children and delayed puberty only in older children. Consequently, age is strongly collinear with the outcome. Entering age directly into the regression model may therefore lead to problems such as overadjustment or complete separation, making the estimates unstable or difficult to interpret. A more appropriate strategy would be to restrict the analysis to an age window where both exposed and unexposed children with and without the outcome are observed or..

Reviewer #5: "Our findings contribute to the growing body of evidence implicating environmental chemicals that have

lifelong health impacts on pubertal development."

The current study did not focus on all the environmental chemicals so it should be recommended not to say environmental chemicals rather sharing in a more specific way regarding heavy metals and other chemicals included in the study. Longitudinal study should be needed to say the lifelong impact.

Reviewer #6: The author has addressed the reviewers' comments, implemented appropriate revisions, and incorporated additional content that enhances the overall completeness and scholarly rigor of the manuscript. The study demonstrates a degree of innovation and holds academic significance within the relevant field. It is therefore recommended for acceptance.

Reviewer #7: Using data from the Korea Environmental Exposure and Health Survey in Children and Adolescents, the authors conducted a cross-sectional study to look at the associations between exposure to heavy metals, bisphenol A, and phthalates and precocious or delayed puberty. The authors reported that a higher mono-benzyl phthalate concentration was associated with a higher risk of delayed puberty in girls in single-exposure models, concluding that exposure to environmental chemicals may contribute to delayed puberty.

Overall, if the research questions examined in this study were to be replicated in numerous robust studies, the findings could inform public health interventions aimed at reducing the impact of modifiable environmental pollutants on puberty.

With that in mind, this reviewer has the following to remark:

1. The authors have made substantial modifications to their manuscript, improving clarity and overall quality. This is evident from the detailed feedback provided by the editor and reviewers.

2. However, a major concern with this study is statistical power. When interpreting the results, it’s crucial to assess whether statistical power was sufficient to detect at least moderate-effect sizes to answer the research questions raised.

While the authors, as recommended by the editor, have acknowledged the potential risks of overfitting and unstable estimates in their multi-exposure model, the paper could guide future studies on how to proceed. In their discussion section, the authors could suggest strategies, apart from increasing the sample size (which is a given), to improve the likelihood of detecting a true effect, if one exists.

I hope this review is helpful and wish the authors the very best with their research!

**********

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Reviewer #4: Yes:  Mohammad Aghaali

Reviewer #5: Yes:  Muhammed Ashraful Alam

Reviewer #6: No

Reviewer #7: Yes:  Dr. Widad Akreyi

**********

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Attachments

Attachment

Submitted filename: Comments.docx

Exposure to heavy metals, bisphenol A, and phthalates: Implications for precocious or delayed puberty

PONE-D-25-12742R3

Dear Dr. Ha,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Li Yang, M.D.

Academic Editor

PLOS One

Additional Editor Comments (optional):

Thanks for the authors' efforts to comprehensively improve your manuscript according to editor's and reviewers' comments. I am pleased to inform you that your paper can be accepted for publication now. Thanks for the chance to assess your important work. Additionally, many thanks for all the reviewers' precious inputs.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #4: All comments have been addressed

Reviewer #7: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #4: Yes

Reviewer #7: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #4: Yes

Reviewer #7: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #4: Yes

Reviewer #7: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #4: Yes

Reviewer #7: (No Response)

**********

Reviewer #4: (No Response)

Reviewer #7: (No Response)

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #4: Yes:  Mohammad Aghaali

Reviewer #7: Yes:  Dr. Widad Akreyi

**********