uncovering early life metal exposures using …...uncovering early life metal exposures using...
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Uncovering early life metal exposures using elemental bio-imaging of teeth
Manish Arora
Environmental and Occupational Medicine and Epidemiology Harvard School of Public Health
n = 311
r = 0.68
0
2
4
6
8
10
12
0 2 4 6 8 10 12 14 16
Maternal blood lead (µg/dL)
Cord blood lead (µg/dL)
Arora et al. Unpublished data.
Prenatal development – a critical window
Difficulties in estimating prenatal exposure
• Variable partitioning across placenta
• Maternal biomarkers may not reflect fetal exposure
• Not feasible to obtain fetal tissue during pregnancy
Challenges of exposure assessment
Critical window of exposure?
time Cases
Controls
Why teeth?
• Commence development prenatally
• Non-invasive collection from 6 to 13 years of age
• Hydroxyapatite incorporates many metals
Mn – essential nutrient and toxicant
• Mn excess and deficiency linked to adverse health outcomes (Takser et al. 2003; Claus Henn et al. 2010; Zota et al. 2009)
• Perinatal development represents period of increased susceptibility
• Uncertainty over most suitable biomarker of Mn exposure (Smith et al. 2007)
Primary dentine and enamel completion
Dentine extension
Dentine layers
Dentine
Enamel
NL NL
Overview of tooth development
Gestational week 13-16 Birth
Postnatal months 2-11
Dentine and enamel extension
Calcification starts
Neonatal line appears at birth
Daily growth rings in teeth
Study populations
1.CHAMACOS Study, UC-Berkeley
2.PHIME Study, University of Brescia , UC-Santa Cruz
CHAMACOS cohort
Incisor mantle dentine mineralization
Study start
Maternal blood and urine; House dust
Cord blood
Maternal, child urine
Child urine and blood collected between 1-5 years – data not
used in this study
Teeth
6 m wk 26 3 m BIRTH wk 13 7 y
2nd trimester dentine vs house dust Mn loading
0 2 4 6 8 10
rspearman=0.40
p=0.005
n=72
6.6
7.6
8.6
9.6
Loge(dentine2nd trimester Mn)
Loge(house dust Mn loading)
RESULTS: Cord blood Mn
All prenatal dentine
Loge(prenatal dentine Mn)
9.5
10.5
11.5
12.5
2.5 3.0 3.5 4.0 4.5
Loge(cord blood Mn)
rspearman = -0.01; p=0.99
Dentine formed at birth
Loge(dentinebirth Mn)
rs pearman= 0.70; p=0.003
4.5 0
1
2
3
4
5
2.5 3.0 3.5 4.0 0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
Loge (cord blood Mn)
PHIME Cohort
0.00
0.50
1.00
1.50
2.00
2.50
55Mn:43Ca AUC prenatal dentine
Valcamonica Bagnolo Mella Garda Lake
Prenatal 106 d 267 d
Low Pb High Pb
Primate model of Pb exposure
• Exposure assessment is the “Achilles Heel” of case-control studies
• Objectively reconstruct exposure during critical perinatal developmental windows with samples collected later in life
• Can be applied to other metals and non-metals
Implications for environmental epidemiology
Future Directions - Organics
Reference Substance
Cattaneo, C., et al. Morphine, Codeine (forensic tox)
Pellegrini, M. et al. Opiates and cocaine
Jan, J. et al. Organochlorines
Jan, J. and Vrbic V. Polychlorinated Biphenyls (PCBs)
I/S group Nicotine, cotinine
McGrath, K.K. et al. Drugs in bone
Camann et al. Organics in teeth (in press)
Acknowledgements
Robert Wright
Brenda Eskenazi, Roberto Lucchini, Don Smith
CHAMACOS and PHIME teams
NIEHS grants to B. Eskenazi, R. Lucchini, D. Smith, M. Arora
Carol Shreffler, Kimberly Gray, Cindy Lawler