Correspondence/Rebuttal Cite This: Environ. Sci. Technol. XXXX, XXX, XXX−XXX
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Response to Comment on “TBBPA and its alternatives disturb the early stages of neural development by interfering with the NOTCH and WNT pathways” TBBPA “administration to humans··· or rats··· resulted in an inactivated glucuronide within 3 h that was slowly eliminated in urine” and that the “overwhelming scientific evidence indicates that the active parent TBBPA was rapidly conjugated to an inactive form of TBBPA and eliminated, demonstrating that this chemical does not accumulate”. Although TBBPA is metabolized quickly, it can still be detected in the human body unmodified, suggesting we are continuously exposed to it. All the references we cited in our article measured, to the best of our knowledge, the unmodified form of TBBPA in tissues and/ or body fluids. One reference acknowledged that TBBPA was detected in humans, particularly in breast milk (#7, Colnot at al., 20145). That paper was also authored by Dr. Kacew. In addition, in our experiments, we only employed concentrations of TBBPA including the unmodified TBBPA levels detected in humans. Also, we were criticized because the “use of Nakajima et al., (2009)6 as a citation for TBBPA brain accumulation and a neurobehavioral effect is questionable in light of previously published papers”. We just mentioned that study as an additional evidence for TBBPA potential accumulation in the body and not for their neurobehavioral results, since our study does not involve the assessment of TBBPA neurobehavioral effects. Drs. Kacew and Hayes kept claiming we neglected to “cite the preponderance of findings indicating that TBBPA does not reach the brain following oral in vivo administration (Schauer et al., 2006; Colnot et al., 2014; Knudsen et al., 2014)” and that “although Yin et al. (2018) suggest that embryonic stem cells serve as a model for neural developmental toxicity, it is well-established through in vivo studies that TBBPA does not reach the brain; and hence, biological relevance of effects of this chemical in vitro, especially as an inference for behavioral alterations, remain questionable”. Whether TBBPA reaches the brain or not does not change the relevance of our findings since we did not assess, or claimed that we did, the effects of TBBPA on the brain. Furthermore, while we suggested that embryonic stem cells could serve as models for neural developmental toxicity, we did not suggest such models for developmental stages involving the developed brain with a blood-brain barrier, as Drs. Kacew and Hayes claim we did. There are many other neural developmental toxicity studies employing embryonic stem cells-based systems, such as the ones from James Thomson, an eminent stem cell biologist (Schwartz et al., 2015)7, and two broad international collaboration projects, SCR&Tox (http://www.scrtox.eu) and ESNATS (http://www.esnats.eu). In the fourth and following paragraphs of their commentary, Drs. Kacew and Hayes stressed again we did not cite important papers claiming TBBPA was not toxic at all and that we mistakenly cited Fraser at al., 20178. We would like to mention
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irst of all, we are thankful to the eminent toxicologists, Drs. Kacew and Hayes, for constructively criticizing our study. We also thank the ES&T Editorial Board for giving us a chance to further discuss our article (Yin et al., 2018)1. Drs. Kacew and Hayes state that our study "1) fails to recognize and acknowledge scientifically published in vivo data that may be more relevant for risk assessment, especially for human exposure and neurodevelopment; 2) utilizes an embryonic stem cell system that is not representative of neurobehavioral and/or neuronal function, and which lacks the essential components of the functions of a blood-brain barrier which plays a key role in chemical entry into the brain and neurodevelopment; and 3) makes generalizations regarding brominated flame retardants that do not always comport with the science”. We tried our best to cite as many relevant studies as possible and mention in the introduction of our article that there was still controversy about TBBPA being a neurotoxicant at human exposure doses. As point 2) is concerned, we did not claim that our embryonic stem cell system was “representative of neurobehavioral and/or neuronal function” and we agree that such a system “lacks the essential components of the functions of a blood-brain barrier which plays a key role in chemical entry into the brain and neurodevelopment”. Nevertheless, neurodevelopment starts when during very early stages of embryonic development, embryonic stem cells give rise to neuroectoderm, neural epithelium, neural progenitor cells and so on. Those are the developmental stages we were interested in, which occur way before the blood-brain barrier of the developing brain forms. Therefore, even though TBBPA may not penetrate the blood-brain barrier and reach the brain, it could still have neurodevelopmental toxicity if it affects the early neural developmental stages mentioned above. In fact, studies suggest TBBPA can be detected in umbilical cord serum and penetrate the placental barrier (Cariou et al., 2008;2 Kawashiro et al., 20083; Knudsen et al., 20184). For point 3), in our study we employed more than one brominated flame retardant, and not just TBBPA. Moreover, with our “generalizations” (about which we would have been happier if Drs. Kacew and Hayes had mentioned more details) we just wanted to emphasize that we should be careful when considering flame retardants in their common applications, before comprehensively assessing their potential developmental toxicity. A statement that we believe anyone would agree should be applied to any industrial chemical whatsoever. Drs. Kacew and Hayes also state that one of the goals of our study was to “evaluate the cytotoxicity and neural development toxicity of TBBPA, TBBPS, and TCBPA with a mouse embryonic stem cell system” as “high detection rates in human breast milk and umbilical cord serum have raised concerns about the adverse effects on human fetal development”. Moreover, they continued saying we did not consider that © XXXX American Chemical Society
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DOI: 10.1021/acs.est.8b05786 Environ. Sci. Technol. XXXX, XXX, XXX−XXX
Environmental Science & Technology
Correspondence/Rebuttal
(3) Kawashiro, Y.; Fukata, H.; Omori-inoue, M.; Kubonoya, K.; Jotaki, T.; Takigami, H.; Sakai, S.-i.; Mori, C. Perinatal exposure to brominated flame retardants and polychlorinated biphenyls in Japan. Endocr. J. 2008, 55 (6), 1071−1084. (4) Knudsen, G. A.; Hall, S. M.; Richards, A. C.; Birnbaum, L. S. TBBPA disposition and kinetics in pregnant and nursing Wistar Han IGS rats. Chemosphere 2018, 192, 5−13. (5) Colnot, T.; Kacew, S.; Dekant, W. Mammalian toxicology and human exposures to the flame retardant 2,2’,6,6’-tetrabromo-4,4’isopropylidenediphenol (TBBPA): implications for risk assessment. Arch. Toxicol. 2014, 88 (3), 553−73. (6) Nakajima, A.; Saigusa, D.; Tetsu, N.; Yamakuni, T.; Tomioka, Y.; Hishinuma, T. Neurobehavioral effects of tetrabromobisphenol A, a brominated flame retardant, in mice. Toxicol. Lett. 2009, 189 (1), 78− 83. (7) Schwartz, M. P.; Hou, Z.; Propson, N. E.; Zhang, J.; Engstrom, C. J.; Costa, V. S.; Jiang, P.; Bolin, B. K. N. J. M.; Daly, W.; Wang, Y.; Stewart, R.; Page, D.; Murphy, W. L.; Thomson, J. A. Human pluripotent stem cell-derived neural constructs for predicting neural toxicity. Proc. Natl. Acad. Sci. U. S. A. 2015, 112 (40), 12516−12521. (8) Fraser, T. W. K.; Khezri, A.; Jusdado, J. G. H.; LewandowskaSabat, A. M.; Henry, T.; Ropstad, E. Toxicant induced behavioural aberrations in larval zebrafish are dependent on minor methodological alterations. Toxicol. Lett. 2017, 276, 62−68.
one more time that in our article we acknowledged the fact that TBBPA toxicity, particularly neurotoxicity, has not been proved for sure. The other reason we wanted to investigate the potential neurotoxicity of TBBPA was to have a control for TBBPS and TCBPA, for which no much information was available. In addition, we correctly cited Fraser et al., 2017 because that study involved not only BPA but also TBBPA. In conclusion, Drs. Kacew’s and Hayes’ argument illustrates the fact that TBBPA potential developmental toxicity, especially neurotoxicity, is still controversial, as we have stated in our article. While we respect the opinion of the two eminent toxicologists, we feel we cannot disregard studies against our belief/findings as either species-specific or not scientifically sound. Moreover, contrary to what they claim we did, our study was not about neurobehavioral and/or neuronal function. In fact, we investigated the effects of TBBPA (and also TBBPS and TCBPA) on the specification of neural progenitor cells, a process that occurs very early during embryonic development, and before the blood-brain barrier forms. Thus, our findings are still relevant and we are in the process of confirming them with human systems.
Nuoya Yin†,‡,∥ Shaojun Liang†,‡,∥ Shengxian Liang†,‡ Renjun Yang†,‡ Bowen Hu†,‡ Zhanfen Qin†,‡ Aifeng Liu§ Francesco Faiola*,†,‡ †
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State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China ‡ College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, 100049, China § CAS Key Laboratory of Bio-based Materials, Qingdao Institute of Biomass Energy and Bioprocess Technology, Chinese Academy of Science, Qingdao 266101, China
AUTHOR INFORMATION
Corresponding Author
*Phone/fax: 86 10-62917609; e-mail:
[email protected]. ORCID
Zhanfen Qin: 0000-0002-3961-0389 Francesco Faiola: 0000-0002-3512-8253 Author Contributions ∥
Co-first author
Notes
The authors declare no competing financial interest.
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REFERENCES
(1) Yin, N.; Liang, S.; Liang, S.; Yang, R.; Hu, B.; Qin, Z.; Liu, A.; Faiola, F. TBBPA and its alternatives disturb the early stages of neural development by interfering with the NOTCH and WNT pathways. Environ. Sci. Technol. 2018, 52 (9), 5459−5468. (2) Cariou, R.; Antignac, J. P.; Zalko, D.; Berrebi, A.; Cravedi, J. P.; Maume, D.; Marchand, P.; Monteau, F.; Riu, A.; Andre, F.; Le Bizec, B. Exposure assessment of French women and their newborns to tetrabromobisphenol-A: occurrence measurements in maternal adipose tissue, serum, breast milk and cord serum. Chemosphere 2008, 73 (7), 1036−41. B
DOI: 10.1021/acs.est.8b05786 Environ. Sci. Technol. XXXX, XXX, XXX−XXX
