GLI3 Links Environmental Arsenic Exposure and Human Fetal Growth.
Although considerable evidence suggests that in utero arsenic exposure affects children's health, these data are mainly from areas of the world where groundwater arsenic levels far exceed the World Health Organization limit of 10 μg/L. We, and others, have found that more common levels of in utero arsenic exposure may also impact children's health. However, the underlying molecular mechanisms are poorly understood. To address this issue, we analyzed the expression of key developmental genes in fetal placenta in a birth cohort of women using unregulated water supplies in a US region with elevated groundwater arsenic. We identified several genes whose expression associated with maternal arsenic exposure in a fetal sex-specific manner. In particular, expression of the HEDGEHOG pathway component, GLI3, in female placentae was both negatively associated with arsenic exposure and positively associated with infant birth weight. This suggests that modulation of GLI3 in the fetal placenta, and perhaps in other fetal tissues, contributes to arsenic's detrimental effects on fetal growth. We showed previously that arsenic-exposed NIH3T3 cells have reduced GLI3 repressor protein. Together, these studies identify GLI3 as a key signaling node that is affected by arsenic, mediating a subset of its effects on developmental signaling and fetal health.
Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Emily F
EF
Winterbottom
Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA ; Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
Dennis L
DL
Fei
Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Devin C
DC
Koestler
Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Camilla
C
Giambelli
Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Eric
E
Wika
Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA ; Molecular Oncology Program, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Anthony J
AJ
Capobianco
Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Ethan
E
Lee
Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA ; Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
Carmen J
CJ
Marsit
Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
Margaret R
MR
Karagas
Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA ; Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA ; Molecular Oncology Program, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
David J
DJ
Robbins
D000293:Adolescent; D000328:Adult; D001151:Arsenic / Q000633:toxicity* / Q000652:urine; D001724:Birth Weight / Q000187:drug effects; D000067576:Child Health; D004781:Environmental Exposure / Q000009:adverse effects*; D005260:Female; D047109:Fetal Development / Q000187:drug effects* / Q000502:physiology; D020869:Gene Expression Profiling; D060587:Groundwater / Q000032:analysis; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D018811:Maternal Exposure; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014874:Water Pollutants, Chemical / Q000633:toxicity; D014876:Water Pollution / Q000009:adverse effects; D055815:Young Adult; D000074290:Zinc Finger Protein Gli3
C065683:GLI3 protein, human; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D014874:Water Pollutants, Chemical; D000074290:Zinc Finger Protein Gli3; D001151:Arsenic
Arsenic; As, arsenic; Birth Weight; CI, confidence interval; Development; GLI3; HH, HEDGEHOG; IQR, interquartile range; MCL, maximum contaminant level; Placenta; Sex; U-As, total urinary arsenic concentration