title: Toxicological responses of environmental mixtures: Environmental metal mixtures display synergistic induction of metal-responsive and oxidative stress genes in placental cells.
abstract: Exposure to elevated levels of the toxic metals inorganic arsenic (iAs) and cadmium (Cd) represents a major global health problem. These metals often occur as mixtures in the environment, creating the potential for interactive or synergistic biological effects different from those observed in single exposure conditions. In the present study, environmental mixtures collected from two waste sites in China and comparable mixtures prepared in the laboratory were tested for toxicogenomic response in placental JEG-3 cells. These cells serve as a model for evaluating cellular responses to exposures during pregnancy. One of the mixtures was predominated by iAs and one by Cd. Six gene biomarkers were measured in order to evaluate the effects from the metal mixtures using dose and time-course experiments including: heme oxygenase 1 (HO-1) and metallothionein isoforms (MT1A, MT1F and MT1G) previously shown to be preferentially induced by exposure to either iAs or Cd, and metal transporter genes aquaporin-9 (AQP9) and ATPase, Cu(2+) transporting, beta polypeptide (ATP7B). There was a significant increase in the mRNA expression levels of ATP7B, HO-1, MT1A, MT1F, and MT1G in mixture-treated cells compared to the iAs or Cd only-treated cells. Notably, the genomic responses were observed at concentrations significantly lower than levels found at the environmental collection sites. These data demonstrate that metal mixtures increase the expression of gene biomarkers in placental JEG-3 cells in a synergistic manner. Taken together, the data suggest that toxic metals that co-occur may induce detrimental health effects that are currently underestimated when analyzed as single metals.
authors.affiliation: Department of Biological Sciences, North Carolina State University, United States.
authors.forename: Oluwadamilare A
authors.initials: OA
authors.lastname: Adebambo
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, United States.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Ray
authors.affiliation: Department of Biological Sciences, North Carolina State University, United States.
authors.forename: Damian
authors.initials: D
authors.lastname: Shea
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, United States. Electronic address: rfry@unc.edu.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fry
mesh_terms: D001151:Arsenic / Q000633:toxicity; D002104:Cadmium / Q000633:toxicity; D045744:Cell Line, Tumor; D002681:China; D004305:Dose-Response Relationship, Drug; D005260:Female; D000075322:Heavy Metal Poisoning; D006801:Humans; D008668:Metallothionein / Q000378:metabolism; D019216:Metals, Heavy / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics*; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011041:Poisoning; D011247:Pregnancy; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D019216:Metals, Heavy; D014874:Water Pollutants, Chemical; D002104:Cadmium; D008668:Metallothionein; D001151:Arsenic
keywords: Biomarkers; Gene expression; Real-world mixtures; Synergism; Toxicogenomics; mRNA