Bhattacharya, Siladitya

Drake, Amanda J.

Feldmann, Jorg

Fowler, Paul A.

Meharg, Andrew A.

O'Shaughnessy, Peter J.

Raab, Andrea

Sinclair, Kevin D.

Environmental Health Perspectives

English

PubMed

Aberdeen University Research

Environmental Health Perspectives • volume 124 | number 6 | June 2016 A 99Perspectives | CorrespondenceComment on “Effects of Arsenite during Fetal Development on Energy Metabolism and Susceptibility to Diet-Induced Fatty Liver Diseases in Male Mice” and “Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Trends and Scientific Gaps”http://dx.doi.org/10.1289/ehp.1611345Refers to http://dx.doi.org/10.1289/ehp.1409501 and http://dx.doi.org/10.1289/ehp.1409360 We were very interested to read the  excellent article and commentary on arsenic and health, with respect to prenatal exposures, metabolic health, and underlying mecha-nisms, by Ditzel et al. and Bailey et al. For many years there have been growing concerns as knowledge accumulates about the long-term consequences of early-life influences on adult health (Fleming et al. 2015), including environmental programming resulting from prenatal exposure to arsenic (Farzan et al. 2013). These concerns rightly extend to metabolic consequences for the offspring (Ashley-Martin et al. 2015) and also encom-pass epigenetic modifications as a result of developmental exposures to arsenic and other metals (Bailey and Fry 2014).The elephant in the room, however, is the paucity of knowledge about what is happening to the human fetus early in gestation. A great deal of emphasis is placed on levels of toxicants in maternal urine or plasma, and on levels in the offspring at term (usually in cord blood), which is then often mislabeled as “fetal.” Last year we published a study of 55 normally progressing, electively termi-nated second-trimester human fetuses where changes in fetal hepatic cobalt levels were traced through vitamin B12 to changes in one-carbon metabolism and alterations in DNA methylation (Drake et al. 2015). We also characterized hepatic concentrations of essential and nonessential elements. Maternal smoking was validated by measuring circu-lating fetal cotinine, and we were surprised to find no increase in the number of fetal livers with cadmium levels above limits of detection when the mother smoked (only 5 of 55 fetuses had hepatic levels of cadmium above limits of detection, irrespective of smoke exposure) (Drake et al. 2015), despite a known increase in maternal cadmium levels with smoking (Sikorski et al. 1988). This clearly demonstrates the importance of studying fetal toxicant burden in our own species rather than simply making  assumptions from animal models. Relevant to Ditzel et al. and Bailey et al., we also published fetal hepatic arsenic concentrations and found levels above limits of detection in 39 of 55 fetuses, with a median arsenic concentration of 39.8 ng/g dry liver weight (Drake et al. 2015). As with cadmium, maternal smoking did not signifi-cantly alter fetal hepatic levels of arsenic, and arsenic concentrations did not change between 11 and 21 weeks of gestation. These kinds of “real-life” human fetal data are essential to improve our understanding of the risks to the developing human, the points during gestation when those risks are most acute, and the key underlying mechanisms.Editor’s note: In accordance with journal policy, Ditzel et al. and Fry et al. were asked whether they wanted to respond to this letter. Neither group chose to do so.The authors declare they have no actual or potential competing financial interests.Paul A. Fowler,1 Amanda J. Drake,2 Peter J. O’Shaughnessy,3 Siladitya Bhattacharya,4 Andrea Raab,5 Kevin D. Sinclair,6 Jörg Feldmann,5 and Andrew A. Meharg71Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom; 2University/BHF Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, United Kingdom; 3Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; 4Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, United Kingdom; 5TESLA (Trace Element Speciation Laboratory) and Marine Biodiscovery Laboratory, University of Aberdeen, Aberdeen, United Kingdom; 6School of Biosciences, Sutton Bonington Campus, University of Nottingham, Loughborough, United Kingdom; 7Institute for Global Food Security, Queen’s University Belfast, Belfast, United KingdomAddress correspondence to P.A. Fowler, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom. E-mail: p.a.fowler@abdn.ac.ukRefeRencesAshley-Martin J, Dodds L, Arbuckle TE, Ettinger AS, Shapiro GD, Fisher M, et al. 2015. Maternal blood metal levels and fetal markers of metabolic function. Environ Res 136:27–34, doi:10.1016/j.envres.2014.10.024.Bailey KA, Fry RC. 2014. Arsenic-associated changes to the epigenome: what are the functional consequences? Curr Environ Health Rep 1:22–34, doi:10.1007/s40572-013-0002-8. Drake AJ, O’Shaughnessy PJ, Bhattacharya S, Monteiro A, Kerrigan D, Goetz S, et al. 2015. In utero exposure to ciga-rette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver. BMC Med 13:18, doi: 10.1186/s12916-014-0251-x.Farzan SF, Karagas MR, Chen Y. 2013. In utero and early life arsenic exposure in relation to long-term health and disease. Toxicol Appl Pharmacol 272(2):384–390, doi:10.1016/j.taap.2013.06.030.Fleming TP, Velazquez MA, Eckert JJ. 2015. Embryos, DOHaD and David Barker. J Dev Orig Health Dis 6(5):377–383, doi:10.1017/S2040174415001105.Sikorski R, Radomański T, Paszkowski T, Skoda J. 1988. Smoking during pregnancy and the perinatal cadmium burden. J Perinat Med 16(3):225–231, PMID:3210108.The Correspondence section is not peer-reviewed. Personal opinions expressed herein are the sole responsibility of the authors.  EHP neither endorses nor disputes the content of the letters it publishes.A Section 508–conformant HTML version of this article is available at http://dx.doi.org/10.1289/ehp.1611345. 

Comment on “Effects of Arsenite during Fetal Development on Energy Metabolism and Susceptibility to Diet-Induced Fatty Liver Diseases in Male Mice” and “Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Trends and Scientific Gaps”

Feldmann, Jörg

Enlighten

Comment on “Effects of arsenite during fetal development on energy metabolism and susceptibility to diet-induced fatty liver diseases in male mice” and “Mechanisms underlying latent disease risk associated with early-life arsenic exposure: current trends and scientific gaps”

Enlighten: Publications

Environmental Health Perspectives • volume 124 | number 6 | June 2016 A 99
Perspectives | Correspondence
Comment on “Effects of Arsenite 
during Fetal Development 
on Energy Metabolism and 
Susceptibility to Diet-Induced Fatty 
Liver Diseases in Male Mice” and 
“Mechanisms Underlying Latent 
Disease Risk Associated with Early-
Life Arsenic Exposure: Current 
Trends and Scientific Gaps”
http://dx.doi.org/10.1289/ehp.1611345
Refers to http://dx.doi.org/10.1289/ehp.1409501 
and http://dx.doi.org/10.1289/ehp.1409360 
We were very interested to read the  excellent 
article and commentary on arsenic and 
health, with respect to prenatal exposures, 
metabolic health, and underlying mecha-
nisms, by Ditzel et al. and Bailey et al. For 
many years there have been growing concerns 
as knowledge accumulates about the long-
term consequences of early-life influences on 
adult health (Fleming et al. 2015), including 
environmental programming resulting 
from prenatal exposure to arsenic (Farzan 
et al. 2013). These concerns rightly extend 
to metabolic consequences for the offspring 
(Ashley-Martin et al. 2015) and also encom-
pass epigenetic modifications as a result of 
developmental exposures to arsenic and other 
metals (Bailey and Fry 2014).
The elephant in the room, however, 
is the paucity of knowledge about what 
is happening to the human fetus early in 
gestation. A great deal of emphasis is placed 
on levels of toxicants in maternal urine or 
plasma, and on levels in the offspring at term 
(usually in cord blood), which is then often 
mislabeled as “fetal.” 
Last year we published a study of 
55 normally progressing, electively termi-
nated second-trimester human fetuses where 
changes in fetal hepatic cobalt levels were 
traced through vitamin B12 to changes in 
one-carbon metabolism and alterations in 
DNA methylation (Drake et al. 2015). We 
also characterized hepatic concentrations of 
essential and nonessential elements. Maternal 
smoking was validated by measuring circu-
lating fetal cotinine, and we were surprised 
to find no increase in the number of fetal 
livers with cadmium levels above limits of 
detection when the mother smoked (only 
5 of 55 fetuses had hepatic levels of cadmium 
above limits of detection, irrespective of 
smoke exposure) (Drake et al. 2015), despite 
a known increase in maternal cadmium 
levels with smoking (Sikorski et al. 1988). 
This clearly demonstrates the importance 
of studying fetal toxicant burden in our 
own species rather than simply making 
 assumptions from animal models. 
Relevant to Ditzel et al. and Bailey 
et al., we also published fetal hepatic arsenic 
concentrations and found levels above limits 
of detection in 39 of 55 fetuses, with a 
median arsenic concentration of 39.8 ng/g 
dry liver weight (Drake et al. 2015). As with 
cadmium, maternal smoking did not signifi-
cantly alter fetal hepatic levels of arsenic, 
and arsenic concentrations did not change 
between 11 and 21 weeks of gestation. 
These kinds of “real-life” human fetal data 
are essential to improve our understanding 
of the risks to the developing human, the 
points during gestation when those risks 
are most acute, and the key underlying 
mechanisms.
Editor’s note: In accordance with journal policy, 
Ditzel et al. and Fry et al. were asked whether they 
wanted to respond to this letter. Neither group 
chose to do so.
The authors declare they have no actual or 
potential competing financial interests.
Paul A. Fowler,1 Amanda J. Drake,2 
Peter J. O’Shaughnessy,3 
Siladitya Bhattacharya,4 Andrea Raab,5 
Kevin D. Sinclair,6 Jörg Feldmann,5 and 
Andrew A. Meharg7
1Institute of Medical Sciences, University of 
Aberdeen, Aberdeen, United Kingdom; 2University/
BHF Centre for Cardiovascular Science, University 
of Edinburgh, Queen’s Medical Research Institute, 
Edinburgh, United Kingdom; 3Institute of Biodiversity, 
Animal Health and Comparative Medicine, College 
of Medical, Veterinary and Life Sciences, University 
of Glasgow, Glasgow, United Kingdom; 4Institute 
of Applied Health Sciences, University of Aberdeen, 
Aberdeen, United Kingdom; 5TESLA (Trace Element 
Speciation Laboratory) and Marine Biodiscovery 
Laboratory, University of Aberdeen, Aberdeen, United 
Kingdom; 6School of Biosciences, Sutton Bonington 
Campus, University of Nottingham, Loughborough, 
United Kingdom; 7Institute for Global Food Security, 
Queen’s University Belfast, Belfast, United Kingdom
Address correspondence to P.A. Fowler, Institute 
of Medical Sciences, University of Aberdeen, 
Foresterhill, Aberdeen, AB25 2ZD, United Kingdom. 
E-mail: p.a.fowler@abdn.ac.uk
RefeRences
Ashley-Martin J, Dodds L, Arbuckle TE, Ettinger AS, 
Shapiro GD, Fisher M, et al. 2015. Maternal blood metal 
levels and fetal markers of metabolic function. Environ 
Res 136:27–34, doi:10.1016/j.envres.2014.10.024.
Bailey KA, Fry RC. 2014. Arsenic-associated changes to the 
epigenome: what are the functional consequences? Curr 
Environ Health Rep 1:22–34, doi:10.1007/s40572-013-0002-8. 
Drake AJ, O’Shaughnessy PJ, Bhattacharya S, Monteiro A, 
Kerrigan D, Goetz S, et al. 2015. In utero exposure to ciga-
rette chemicals induces sex-specific disruption of one-
carbon metabolism and DNA methylation in the human 
fetal liver. BMC Med 13:18, doi: 10.1186/s12916-014-0251-x.
Farzan SF, Karagas MR, Chen Y. 2013. In utero and early 
life arsenic exposure in relation to long-term health 
and disease. Toxicol Appl Pharmacol 272(2):384–390, 
doi:10.1016/j.taap.2013.06.030.
Fleming TP, Velazquez MA, Eckert JJ. 2015. Embryos, DOHaD 
and David Barker. J Dev Orig Health Dis 6(5):377–383, 
doi:10.1017/S2040174415001105.
Sikorski R, Radomański T, Paszkowski T, Skoda J. 1988. 
Smoking during pregnancy and the perinatal cadmium 
burden. J Perinat Med 16(3):225–231, PMID:3210108.
The Correspondence section is not peer-reviewed. Personal opinions expressed herein are the sole responsibility 
of the authors.  EHP neither endorses nor disputes the content of the letters it publishes.
A Section 508–conformant HTML version of this article 
is available at http://dx.doi.org/10.1289/ehp.1611345. 


Fowler, Paul A

Drake, Amanda J

O'Shaughnessy, Peter J

Sinclair, Kevin D

Meharg, Andrew A

Queen's University Belfast Research Portal

Comment on "Effects of Arsenite during Fetal Development onEnergy Metabolism and Susceptibility to Diet-Induced Fatty LiverDiseases in Male Mice" and "Mechanisms Underlying LatentDisease Risk Associated with Early-Life Arsenic Exposure:Current Trends and Scientific Gaps"Fowler, P. A., Drake, A. J., O'Shaughnessy, P. J., Bhattacharya, S., Raab, A., Sinclair, K. D., ... Meharg, A. A.(2016). Comment on "Effects of Arsenite during Fetal Development on Energy Metabolism and Susceptibility toDiet-Induced Fatty Liver Diseases in Male Mice" and "Mechanisms Underlying Latent Disease Risk Associatedwith Early-Life Arsenic Exposure: Current Trends and Scientific Gaps". Environmental Health Perspectives,124(6), [A99]. DOI: 10.1289/ehp.1611345Published in:Environmental Health PerspectivesDocument Version:Publisher's PDF, also known as Version of recordQueen's University Belfast - Research Portal:Link to publication record in Queen's University Belfast Research PortalPublisher rightsContent lies in the public domain. No permission is required to reuse EHP content. However, use of materials published in EHP should beacknowledged.General rightsCopyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or othercopyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associatedwith these rights.Take down policyThe Research Portal is Queen's institutional repository that provides access to Queen's research output. Every effort has been made toensure that content in the Research Portal does not infringe any person's rights, or applicable UK laws. If you discover content in theResearch Portal that you believe breaches copyright or violates any law, please contact openaccess@qub.ac.uk.Download date:15. Feb. 2017Environmental Health Perspectives • volume 124 | number 6 | June 2016 A 99Perspectives | CorrespondenceComment on “Effects of Arsenite during Fetal Development on Energy Metabolism and Susceptibility to Diet-Induced Fatty Liver Diseases in Male Mice” and “Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Trends and Scientific Gaps”http://dx.doi.org/10.1289/ehp.1611345Refers to http://dx.doi.org/10.1289/ehp.1409501 and http://dx.doi.org/10.1289/ehp.1409360 We were very interested to read the  excellent article and commentary on arsenic and health, with respect to prenatal exposures, metabolic health, and underlying mecha-nisms, by Ditzel et al. and Bailey et al. For many years there have been growing concerns as knowledge accumulates about the long-term consequences of early-life influences on adult health (Fleming et al. 2015), including environmental programming resulting from prenatal exposure to arsenic (Farzan et al. 2013). These concerns rightly extend to metabolic consequences for the offspring (Ashley-Martin et al. 2015) and also encom-pass epigenetic modifications as a result of developmental exposures to arsenic and other metals (Bailey and Fry 2014).The elephant in the room, however, is the paucity of knowledge about what is happening to the human fetus early in gestation. A great deal of emphasis is placed on levels of toxicants in maternal urine or plasma, and on levels in the offspring at term (usually in cord blood), which is then often mislabeled as “fetal.” Last year we published a study of 55 normally progressing, electively termi-nated second-trimester human fetuses where changes in fetal hepatic cobalt levels were traced through vitamin B12 to changes in one-carbon metabolism and alterations in DNA methylation (Drake et al. 2015). We also characterized hepatic concentrations of essential and nonessential elements. Maternal smoking was validated by measuring circu-lating fetal cotinine, and we were surprised to find no increase in the number of fetal livers with cadmium levels above limits of detection when the mother smoked (only 5 of 55 fetuses had hepatic levels of cadmium above limits of detection, irrespective of smoke exposure) (Drake et al. 2015), despite a known increase in maternal cadmium levels with smoking (Sikorski et al. 1988). This clearly demonstrates the importance of studying fetal toxicant burden in our own species rather than simply making  assumptions from animal models. Relevant to Ditzel et al. and Bailey et al., we also published fetal hepatic arsenic concentrations and found levels above limits of detection in 39 of 55 fetuses, with a median arsenic concentration of 39.8 ng/g dry liver weight (Drake et al. 2015). As with cadmium, maternal smoking did not signifi-cantly alter fetal hepatic levels of arsenic, and arsenic concentrations did not change between 11 and 21 weeks of gestation. These kinds of “real-life” human fetal data are essential to improve our understanding of the risks to the developing human, the points during gestation when those risks are most acute, and the key underlying mechanisms.Editor’s note: In accordance with journal policy, Ditzel et al. and Fry et al. were asked whether they wanted to respond to this letter. Neither group chose to do so.The authors declare they have no actual or potential competing financial interests.Paul A. Fowler,1 Amanda J. Drake,2 Peter J. O’Shaughnessy,3 Siladitya Bhattacharya,4 Andrea Raab,5 Kevin D. Sinclair,6 Jörg Feldmann,5 and Andrew A. Meharg71Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom; 2University/BHF Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, United Kingdom; 3Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; 4Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, United Kingdom; 5TESLA (Trace Element Speciation Laboratory) and Marine Biodiscovery Laboratory, University of Aberdeen, Aberdeen, United Kingdom; 6School of Biosciences, Sutton Bonington Campus, University of Nottingham, Loughborough, United Kingdom; 7Institute for Global Food Security, Queen’s University Belfast, Belfast, United KingdomAddress correspondence to P.A. Fowler, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom. E-mail: p.a.fowler@abdn.ac.ukRefeRencesAshley-Martin J, Dodds L, Arbuckle TE, Ettinger AS, Shapiro GD, Fisher M, et al. 2015. Maternal blood metal levels and fetal markers of metabolic function. Environ Res 136:27–34, doi:10.1016/j.envres.2014.10.024.Bailey KA, Fry RC. 2014. Arsenic-associated changes to the epigenome: what are the functional consequences? Curr Environ Health Rep 1:22–34, doi:10.1007/s40572-013-0002-8. Drake AJ, O’Shaughnessy PJ, Bhattacharya S, Monteiro A, Kerrigan D, Goetz S, et al. 2015. In utero exposure to ciga-rette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver. BMC Med 13:18, doi: 10.1186/s12916-014-0251-x.Farzan SF, Karagas MR, Chen Y. 2013. In utero and early life arsenic exposure in relation to long-term health and disease. Toxicol Appl Pharmacol 272(2):384–390, doi:10.1016/j.taap.2013.06.030.Fleming TP, Velazquez MA, Eckert JJ. 2015. Embryos, DOHaD and David Barker. J Dev Orig Health Dis 6(5):377–383, doi:10.1017/S2040174415001105.Sikorski R, Radomański T, Paszkowski T, Skoda J. 1988. Smoking during pregnancy and the perinatal cadmium burden. J Perinat Med 16(3):225–231, PMID:3210108.The Correspondence section is not peer-reviewed. Personal opinions expressed herein are the sole responsibility of the authors.  EHP neither endorses nor disputes the content of the letters it publishes.A Section 508–conformant HTML version of this article is available at http://dx.doi.org/10.1289/ehp.1611345. 

Comment on "Effects of Arsenite during Fetal Development on Energy Metabolism and Susceptibility to Diet-Induced Fatty Liver Diseases in Male Mice" and "Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Trends and Scientific Gaps"

Paul A. Fowler

Amanda J. Drake

Peter J. O’Shaughnessy

Siladitya Bhattacharya

Andrea Raab

Kevin D. Sinclair

Jörg Feldmann

Andrew A. Meharg

Crossref

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Comment on "effects of arsenite during fetal development on energy metabolism and susceptibility to diet-induced fatty liver diseases in male mice" and "mechanisms underlying latent disease risk associated with early-life arsenic exposure: current trends and scientific gaps"

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Comment on “Effects of Arsenite during Fetal Development on Energy Metabolism and Susceptibility to Diet-Induced Fatty Liver Diseases in Male Mice” and “Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Trends and Scientific Gaps”

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