RESEARCH GROUP: NICHE, Biomedical Sciences
Project Title:
Novel biomarkers of fish consumption: Implications for neurodevelopment
Supervisor(s):
Dr Alison Yeates, Dr Maria Mulhern, Dr Emeir McSorley
Contact Details:
[email protected]; [email protected]; [email protected]
Level: PhD
Background to the project :
Fish are the primary human exposure source of methylmercury (MeHg), to which the developing brain is
especially sensitive. On the basis of limited data, government advisories have cautioned pregnant women
to limit their consumption, especially of fish with high MeHg content. However, fish are a rich source of
nutrients, including long-chain polyunsaturated fatty acids (LCPUFA), which are important for the
developing brain as shown by the Seychelles Child Development Study (SCDS) (1, 2), and therefore
limiting maternal fish intake could pose a threat to optimal neurodevelopment (1).
The SCDS have used hair MeHg and blood LCPUFA as biomarkers of fish consumption, in addition to
dietary data (3,4). However dietary data are associated with reporting error and bias (5) and often do not
correlate well with physiologic biomarkers which can be further impeded by factors such as bioavailability,
physiology and genetics. Uncertainties surrounding the validity of such markers warrant the investigation of
alternative more robust biomarkers of fish consumption which would reflect the proportion of fish
(encompassing both toxin and nutrient components), as well as the average MeHg content of fish,
consumed by the individual. Stable isotope ratios could potentially fulfil these criteria and be used to
improve the accuracy of risk assessment of fish consumption in relation to neurodevelopmental outcomes,
with important ramifications for public health.
Objectives of the research project :
The overall objectives of the research are to explore the use of stable isotope ratios as novel biomarkers of
fish consumption and to test these biomarkers in the SCDS in relation to neurodevelopmental outcomes.
Furthermore, this proposal offers the opportunity to investigate the genetic factors which may influence the
proposed stable isotope biomarkers, with recent work from the SCDS demonstrating that certain genotypes
account for variation in hair MeHg and serum LCPUFA status (6,7).
Study-specific objectives:
STUDY 1
Aim: To evaluate the use of sulphur and nitrogen stable isotopes in conjunction with total MeHg in hair as
novel biomarkers of fish consumption
1. To demonstrate that varying the amount and type (with respect to MeHg content) of fish consumed
results in predictable changes in S34 ratios and MeHg values in hair
2. To demonstrate that the MeHg/ S34 ratio can be used as a novel biomarker for both the amount of
marine fish consumed and the average MeHg content of consumed fish
3. To evaluate the potential modifying influence of genetic polymorphisms related to MeHg kinetics on
the MeHg/ S34 ratio
STUDY 2
Aim: To evaluate the use of nitrogen stable isotopes in hair as a more robust biomarker of LCPUFA status
4. To demonstrate that N15 ratios in hair reflect the red blood cell composition of LCPUFA and may
therefore be an alternative marker of LCPUFA status
5. To evaluate the potential modifying influence of genetic polymorphisms related to LCPUFA
metabolism on the N15 ratio
STUDY 3
Aim: To apply stable isotope ratios in the SCDS to assess the effects of fish consumption, as captured by
above biomarkers, of mothers during pregnancy on child developmental outcomes
6. To determine if the hair MeHg/ S34 ratio is associated with neurodevelopmental outcomes and
whether genetic variation modifies this association
7. To determine if the N15 ratio, as a marker of LCPUFA, modifies the association between MeHg/ δ34S
and neurodevelopmental outcomes
Methods to be used :
Objectives 1 - 5
This project will utilise samples that are currently being collected as part of the iFish study (REC 16/0077).
Hair samples will be analysed for stable isotope ratios (funded by NIH grant) of S34 and N15 and for total
MeHg composition by SCDS collaborators at the University of Rochester.
The student will undertake an analysis of red blood cells (RBC) collected from the iFish study for fatty acid
profile using GC-MS within the Metabolomics and Proteomics Core Facility.
The genotyping of these individuals is already being completed with SCDS collaborators at the Karolinska
Institute, Sweden. Single nucleotide polymorphisms will be examined in the ATP-binding cassette (ABC)
transporter and Fatty Acid Desaturase (FADS) genes which we have previously shown to impact on MeHg
and PUFA kinetics respectively (6,7).
The student will conduct a series of statistical analyses, with assistance of biostatisticians at the University
of Rochester, in order to address Objectives 1-5.
Objectives 6 & 7
The student will have access to the large SCDS Nutrition Cohort 2 database, which will complement the
analysis planned within this study.
Collected hair and blood samples from this cohort will be analysed for the stable isotope ratios above using
SCDS collaborators at the University of Rochester.
The student will validate the stable isotope markers in the SCDS setting and furthermore conduct a series
of statistical analyses, with assistance of biostatistical team at Rochester, in order to determine if: a) the
maternal hair MeHg/ δ34S ratio is associated with neurodevelopmental outcomes of the child, b) the
maternal hair N15 ratio modifies the association between the MeHg/ δ34S ratio and neurodevelopmental
outcomes, c) whether genetic variation in ABC and/or FADS genes modifies the association between the
MeHg/ δ34S ratio and neurodevelopmental outcomes.
Skills required of applicant :
This project would allow the PhD student to undertake a substantial body of work through three interrelated
studies.
The applicant will be required to have the following:
 Sound knowledge of nutrition, biochemistry, epidemiology or related discipline
 Excellent interpersonal skills
 Laboratory experience and willingness to acquire new laboratory skills
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Good oral and written communication skills
Excellent team working skills
Ability to use his/her initiative and work under pressure
High quality level of record keeping
Ability to deal effectively with administrative tasks
References :
1. Strain JJ, Davidson PW, Bonham MP, Duffy EM, Stokes-Riner A, Thurston SW, Wallace JM,
Robson PJ, Shamlaye CF, Georger LA, et al: Associations of maternal long-chain
polyunsaturated fatty acids, methyl mercury, and infant development in the Seychelles Child
Development Nutrition Study. Neurotoxicology 2008, 29:776-782.
2. Strain J, Yeates AJ, van Wijngaarden E, Thurston SW, Mulhern MS, McSorley EM, Watson G, Love
T, Smith TH, Harrington D, et al: Prenatal exposure to methyl mercury from fish consumption
and polyunsaturated fatty acids: associations with child development at 20 mo of age in an
observational study in the Republic of Seychelles. Am J Clin Nutr 2015.
3. Davidson PW, Strain JJ, Myers GJ, Thurston SW, Bonham MP, Shamlaye CF, Stokes-Riner A,
Wallace JM, Robson PJ, Duffy EM, et al: Neurodevelopmental effects of maternal nutritional
status and exposure to methylmercury from eating fish during pregnancy. Neurotoxicology
2008, 29:767-775.
4. Bonham MP, Duffy EM, Robson PJ, Wallace JM, Myers GJ, Davidson PW, Clarkson TW, Shamlaye
CF, Strain JJ, Livingstone MB: Contribution of fish to intakes of micronutrients important for
fetal development: a dietary survey of pregnant women in the Republic of Seychelles. Public
Health Nutr 2009, 12:1312-1320.
5. Natarajan L, Pu M, Fan J, Levine RA, Patterson RE, Thomson CA, Rock CL, Pierce JP:
Measurement error of dietary self-report in intervention trials. Am J Epidemiol 2010, 172:819827.
6. Engström K, Love TM, Watson GE, Zareba G, Yeates A, Wahlberg K, Alhamdow A, Thurston SW,
Mulhern M, McSorley EM, et al: Polymorphisms in ATP-binding cassette transporters
associated with maternal methylmercury disposition and infant neurodevelopment in
mother-child pairs in the Seychelles Child Development Study. Environ Int 2016, 94:224-9.
7. Yeates AJ, Love TM, Engström K, Mulhern MS, McSorley EM, Grzesik K, Alhamdow A, Wahlberg
K, Thurston SW, Davidson PW, et al: Genetic variation in FADS genes in associated with
maternal long-chain PUFA status but not with cognitive development of infants in a high
fish-eating observational study. Prostaglandins Leukot Essent Fatty Acids 2015, 102-103:13-20.