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 Unpublished data.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