Editor's Highlight: Screening ToxCast Prioritized Chemicals for PPARG Function in a Human Adipose-Derived Stem Cell Model of Adipogenesis.
The developmental origins of obesity hypothesis posits a multifaceted contribution of factors to the fetal origins of obesity and metabolic disease. Adipocyte hyperplasia in gestation and early childhood may result in predisposition for obesity later in life. Rodent in vitro and in vivo studies indicate that some chemicals may directly affect adipose progenitor cell differentiation, but the human relevance of these findings is unclear. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARG) is the master regulator of adipogenesis. Human adipose-derived stem cells (hASC) isolated from adipose tissue express endogenous isoforms of PPARG and represent a biologically relevant cell-type for evaluating activity of PPARG ligands. Here, a multi-endpoint approach based on a phenotypic adipogenesis assay was applied to screen a set of 60 chemical compounds identified in ToxCast Phase I as PPARG active (49) or inactive (11). Chemicals showing activity in the adipogenesis screen were further evaluated in a series of 4 orthogonal assays representing 7 different key events in PPARG-dependent adipogenesis, including gene transcription, protein expression, and adipokine secretion. An siRNA screen was also used to evaluate PPARG-dependence of the adipogenesis phenotype. A universal concentration-response design enabled inter-assay comparability and implementation of a weight-of-evidence approach for bioactivity classification. Collectively, a total of 14/49 (29%) prioritized chemicals were identified with moderate-to-strong activity for human adipogenesis. These results provide the first integrated screening approach of prioritized ToxCast chemicals in a human stem cell model of adipogenesis and provide insight into the capacity of PPARG-activating chemicals to modulate early life programming of adipose tissue.
The Hamner Institutes for Health Sciences, Institute for Chemical Safety Sciences, 6 Davis Drive, Research Triangle Park, North Carolina 27709.
Briana
B
Foley
The Hamner Institutes for Health Sciences, Institute for Chemical Safety Sciences, 6 Davis Drive, Research Triangle Park, North Carolina 27709.|ScitoVation, LLC, 6 Davis Drive, Research Triangle Park, North Carolina 27709.
Daniel L
DL
Doheny
The Hamner Institutes for Health Sciences, Institute for Chemical Safety Sciences, 6 Davis Drive, Research Triangle Park, North Carolina 27709.|ScitoVation, LLC, 6 Davis Drive, Research Triangle Park, North Carolina 27709.
Michael B
MB
Black
The Hamner Institutes for Health Sciences, Institute for Chemical Safety Sciences, 6 Davis Drive, Research Triangle Park, North Carolina 27709.|ScitoVation, LLC, 6 Davis Drive, Research Triangle Park, North Carolina 27709.
Salil N
SN
Pendse
The Hamner Institutes for Health Sciences, Institute for Chemical Safety Sciences, 6 Davis Drive, Research Triangle Park, North Carolina 27709.|ScitoVation, LLC, 6 Davis Drive, Research Triangle Park, North Carolina 27709.
Barbara A
BA
Wetmore
The Hamner Institutes for Health Sciences, Institute for Chemical Safety Sciences, 6 Davis Drive, Research Triangle Park, North Carolina 27709.|ScitoVation, LLC, 6 Davis Drive, Research Triangle Park, North Carolina 27709.
Rebecca A
RA
Clewell
The Hamner Institutes for Health Sciences, Institute for Chemical Safety Sciences, 6 Davis Drive, Research Triangle Park, North Carolina 27709.|ScitoVation, LLC, 6 Davis Drive, Research Triangle Park, North Carolina 27709.
Melvin E
ME
Andersen
The Hamner Institutes for Health Sciences, Institute for Chemical Safety Sciences, 6 Davis Drive, Research Triangle Park, North Carolina 27709 deisenroth.chad@epa.gov.|ScitoVation, LLC, 6 Davis Drive, Research Triangle Park, North Carolina 27709.
Chad
C
Deisenroth
D050156:Adipogenesis; D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects*; D000328:Adult; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D047495:PPAR gamma / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D013234:Stem Cells / Q000166:cytology*
D052242:Adiponectin; D047495:PPAR gamma; D034741:RNA, Small Interfering
PPARG; ToxCast; adipogenesis; adipose-derived stem cell; endocrine disrupting chemicals; obesogens
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