Association Is Not Causation

Association Is Not Causation TOXICOLOGICAL SCIENCES, 164(1), 2018, 3–4 Letter to the Editor “The first study to explain the metabolic variation caused by Letter to the Editor BPA in amino acid.” The BPA field is controversial enough without introduction of a “mechanism of action” for BPA in children that may or may The study by Khan et al. (2017) is an extremely interesting study not exist. on the association of bisphenol A (BPA) levels in children with metabolomic profiles, especially as related to steroidogenesis REFERENCE and amino acid metabolism pathways. However, over 20 times throughout the manuscript the Khan, A., Park, H., Lee, H. A., Park, B., Gwak, H. S., Lee, H. R., Jee, S. authors use language of causation rather than association. H., and Park, Y. H. (2017). Elevated metabolites of steroido- Below are examples from different sections of the paper. genesis and amino acid metabolism in preadolescent female Abstract: “Are the main targets of perturbation by BPA.” children with high urinary bisphenol A levels: A high resolu- Introduction: “Understand the mechanistic aspects behind tion metabolomics study.Toxicol. Sci. 160:371–385. the effects generated by BPA exposure.” Materials and Methods: “Potential biomarkers related to David E. Williams metabolic effects caused by BPA.” Results: “To observe the metabolic alterations caused by BPA Linus Pauling Institute, Environmental and Molecular in male or female.” Toxicology, Oregon State University, Corvallis, Oregon 97331 “To confirm our hypothesis of sex-related metabolic distur- To whom correspondence should be addressed. bance caused by BPA.” E-mail: david.williams@oregonstate.edu. “Similar to the significant effect caused by high or low BPA in children.” doi: 10.1093/toxsci/kfy095 “. that sex-related metabolic disturbance caused by BPA.” Advance Access Publication Date: April 18, 2018 “. we decided to further investigate additional BPA-induced metabolic.” V The Author(s) 2018. Published by Oxford University Press on Discussion: “Clarify the possible sex-related metabolic behalf of the Society of Toxicology. effects caused by BPA exposure.” All rights reserved. For permissions, please e-mail: “The sensitivity of reproductive development to minute journals.permissions@oup.com changes caused by BPA exposure.” Response Letter to the Editor allow unparalleled opportunity to query the molecular mecha- Metabolomics on Preadolescent Children With High nisms of BPA-related gender-specific health risks in children. Urinary Bisphenol A: Response to Dr Williams We investigated the potential correlation of BPA exposure with alteration both in urine and serum metabolites among male We appreciate Dr Williams comments on our recently published and female children and showed steroidogenesis pathway and article (Khan et al., 2017). We thank Dr Williams for appreciating amino acid metabolism as the main targets of perturbation by our data and interpretation and we are very grateful to the edi- BPA in preadolescent girls. tors for providing the opportunity to clarify the points raised by Considering the BPA concentration and BMI of subjects, we Dr Williams related to our work. performed a very careful selection of children for proceeding High-resolution metabolomics is a promising tool to aid in analysis. A total of 414 children participated in the pre- providing insight to answer a biological question, by document- adolescence period from 2010 to 2013 (Total number of partici- ing a set of affected endogenous metabolites (end products of pants by age: 7 years:50; 8 years:215; 9 years of age: 49). A total cellular processes) due to the relevance of affected metabolic of 67 subjects who were not detected for BPA concentration pathways varying according to the physiology, developmental among the participants were excluded. A total of 347 children or pathological state (Deidda et al., 2015; Dias and Koal, 2016). with detectable BPA levels were further divided into quartiles; Metabolomics uses principal component analysis (PCA) and par- first quartile (BPA: <6.593 lg/g_cr), second quartile (BPA: 6.593– tial least squares-discriminant analysis (PLS-DA), hierarchical 12.341 lg/g_cr), third quartile (BPA: 12.342–28.407 lg/g_cr), and clustering analysis (HCA), Heatmaps, and pairwise t test, as fourth quartile (BPA: >28.408 lg/g_cr). Subjects with the lowest tools to identify the differences between the sample groups and quartile (BPA: <6.593 lg/g_cr, n ¼ 87) and the highest quartile the relevant altered metabolites connected with each group. (BPA: >28.408 lg/g_cr n ¼ 86) were selected. Then, each quartile The underlying mechanism for the health risks associated group was divided into 3 groups according to BMI status, and 9 with bisphenol A (BPA) exposure are completely undefined and/ subjects were selected for low or high BMI group considering their or controversial, which leads to delays in identifying the poten- BPA concentrations. In short, even though a total of 414 urine and tial role of BPA in pathophysiological conditions. Our work was serum samples were collected, only 18 children were finally in- an attempt to the use the power of metabolomics which can cluded in this study. Of these 9 children were with high Downloaded from https://academic.oup.com/toxsci/article-abstract/164/1/3/4975769 by Ed 'DeepDyve' Gillespie user on 26 June 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Toxicological Sciences Oxford University Press

Association Is Not Causation

Toxicological Sciences , Volume Advance Article (1) – Apr 18, 2018
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© The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
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1096-6080
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1096-0929
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10.1093/toxsci/kfy095
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Abstract

TOXICOLOGICAL SCIENCES, 164(1), 2018, 3–4 Letter to the Editor “The first study to explain the metabolic variation caused by Letter to the Editor BPA in amino acid.” The BPA field is controversial enough without introduction of a “mechanism of action” for BPA in children that may or may The study by Khan et al. (2017) is an extremely interesting study not exist. on the association of bisphenol A (BPA) levels in children with metabolomic profiles, especially as related to steroidogenesis REFERENCE and amino acid metabolism pathways. However, over 20 times throughout the manuscript the Khan, A., Park, H., Lee, H. A., Park, B., Gwak, H. S., Lee, H. R., Jee, S. authors use language of causation rather than association. H., and Park, Y. H. (2017). Elevated metabolites of steroido- Below are examples from different sections of the paper. genesis and amino acid metabolism in preadolescent female Abstract: “Are the main targets of perturbation by BPA.” children with high urinary bisphenol A levels: A high resolu- Introduction: “Understand the mechanistic aspects behind tion metabolomics study.Toxicol. Sci. 160:371–385. the effects generated by BPA exposure.” Materials and Methods: “Potential biomarkers related to David E. Williams metabolic effects caused by BPA.” Results: “To observe the metabolic alterations caused by BPA Linus Pauling Institute, Environmental and Molecular in male or female.” Toxicology, Oregon State University, Corvallis, Oregon 97331 “To confirm our hypothesis of sex-related metabolic distur- To whom correspondence should be addressed. bance caused by BPA.” E-mail: david.williams@oregonstate.edu. “Similar to the significant effect caused by high or low BPA in children.” doi: 10.1093/toxsci/kfy095 “. that sex-related metabolic disturbance caused by BPA.” Advance Access Publication Date: April 18, 2018 “. we decided to further investigate additional BPA-induced metabolic.” V The Author(s) 2018. Published by Oxford University Press on Discussion: “Clarify the possible sex-related metabolic behalf of the Society of Toxicology. effects caused by BPA exposure.” All rights reserved. For permissions, please e-mail: “The sensitivity of reproductive development to minute journals.permissions@oup.com changes caused by BPA exposure.” Response Letter to the Editor allow unparalleled opportunity to query the molecular mecha- Metabolomics on Preadolescent Children With High nisms of BPA-related gender-specific health risks in children. Urinary Bisphenol A: Response to Dr Williams We investigated the potential correlation of BPA exposure with alteration both in urine and serum metabolites among male We appreciate Dr Williams comments on our recently published and female children and showed steroidogenesis pathway and article (Khan et al., 2017). We thank Dr Williams for appreciating amino acid metabolism as the main targets of perturbation by our data and interpretation and we are very grateful to the edi- BPA in preadolescent girls. tors for providing the opportunity to clarify the points raised by Considering the BPA concentration and BMI of subjects, we Dr Williams related to our work. performed a very careful selection of children for proceeding High-resolution metabolomics is a promising tool to aid in analysis. A total of 414 children participated in the pre- providing insight to answer a biological question, by document- adolescence period from 2010 to 2013 (Total number of partici- ing a set of affected endogenous metabolites (end products of pants by age: 7 years:50; 8 years:215; 9 years of age: 49). A total cellular processes) due to the relevance of affected metabolic of 67 subjects who were not detected for BPA concentration pathways varying according to the physiology, developmental among the participants were excluded. A total of 347 children or pathological state (Deidda et al., 2015; Dias and Koal, 2016). with detectable BPA levels were further divided into quartiles; Metabolomics uses principal component analysis (PCA) and par- first quartile (BPA: <6.593 lg/g_cr), second quartile (BPA: 6.593– tial least squares-discriminant analysis (PLS-DA), hierarchical 12.341 lg/g_cr), third quartile (BPA: 12.342–28.407 lg/g_cr), and clustering analysis (HCA), Heatmaps, and pairwise t test, as fourth quartile (BPA: >28.408 lg/g_cr). Subjects with the lowest tools to identify the differences between the sample groups and quartile (BPA: <6.593 lg/g_cr, n ¼ 87) and the highest quartile the relevant altered metabolites connected with each group. (BPA: >28.408 lg/g_cr n ¼ 86) were selected. Then, each quartile The underlying mechanism for the health risks associated group was divided into 3 groups according to BMI status, and 9 with bisphenol A (BPA) exposure are completely undefined and/ subjects were selected for low or high BMI group considering their or controversial, which leads to delays in identifying the poten- BPA concentrations. In short, even though a total of 414 urine and tial role of BPA in pathophysiological conditions. Our work was serum samples were collected, only 18 children were finally in- an attempt to the use the power of metabolomics which can cluded in this study. Of these 9 children were with high Downloaded from https://academic.oup.com/toxsci/article-abstract/164/1/3/4975769 by Ed 'DeepDyve' Gillespie user on 26 June 2018

Journal

Toxicological SciencesOxford University Press

Published: Apr 18, 2018

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