PROJECT SUMMARY: Childhood obesity is a major public health risk in critical need of novel prevention and
therapeutic efforts. Environmental exposures may promote the onset of childhood obesity through altered
developmental programming. Poly-brominated diphenyl ether (PBDE) flame-retardants can bioaccumulate in
utero resulting in elevated prenatal exposure. Experimental evidence suggests that PBDEs are adipogenic,
however, studies in human populations are limited and the mechanisms remain unclear. PBDEs may induce
mitochondrial dysfunction, which is further implicated in obesity, reflecting the key role of mitochondria in energy
consumption. We propose to investigate associations of prenatal PBDE exposure with childhood adiposity,
examining mitochondrial DNA (mtDNA) content, oxidative damage, and mutations as potential mechanisms of
exposure and effect. In this K99/R00, Dr. Allison Kupsco will complement her skills in experimental toxicology
with training in human population studies, specifically in mitochondriomics, environmental health, epidemiology,
and statistics. As persistent, endocrine disrupting chemicals, PBDEs are an excellent paradigm exposure for this
research/training program. In this proposal, we will leverage a longitudinal birth cohort, the Columbia Center for
Children’s Environmental Health (CCCEH) with cord blood PBDE data, longitudinal data on adiposity (BMI and
fat mass) from 5 to 18 years of age, and innovative abdominal magnetic resonance imaging (MRI) at 18 years
to identify adipose sub-depots. In the K99 phase, existing adiposity data will provide precise information on
longitudinal and adipose-tissue specific effects of PBDEs, individually and in mixtures (Aim 1), and we will
generate longitudinal markers of mtDNA content, an excellent general indicator of mitochondrial health (Aim 2).
In the R00 phase, Dr. Kupsco will complete mtDNA content data analysis and initiate a new investigation of
mtDNA oxidative damage and mutations (heteroplasmy) with a novel deep-sequencing method, to assess
specific effects of PBDEs on mtDNA and elucidate the mitochondrial basis of adiposity (Aim 3). These endpoints
may serve as early biomarkers to identify children with high obesity risk, which would be critical to prevention
efforts. To complete these aims, Dr. Kupsco will undergo training as a mix of formal coursework and expert
guidance from her renowned mentoring team of Drs. Andrea Baccarelli, Julie Herbstman, Andrew Rundle, Jeff
Goldsmith and Dympna Gallagher. Specifically, Dr. Kupsco will receive training in; 1) Mitochondrial markers with
Dr. Baccarelli; 2) Prenatal exposure and children’s environmental health with Dr. Herbstman; 3) Methods in
environmental epidemiology and causal mediation with Dr. Rundle; 4) Advanced longitudinal data analysis with
Dr. Goldsmith; and 5) Clinical markers of adiposity/MRI with Dr. Gallagher. This will prepare Dr. Kupsco for a
career as an independent molecular environmental epidemiologist, investigating prenatal exposures,
mitochondrial toxicity and child obesity. Results from this work will advance the field of children’s environmental
health and contribute to new hypotheses on drivers and mechanisms of adiposity.