title: Perfluorononanoic acid in combination with 14 chemicals exerts low-dose mixture effects in rats.
abstract: Humans are simultaneously exposed to several chemicals that act jointly to induce mixture effects. At doses close to or higher than no-observed adverse effect levels, chemicals usually act additively in experimental studies. However, we are lacking knowledge on the importance of exposure to complex real-world mixtures at more relevant human exposure levels. We hypothesised that adverse mixture effects occur at doses approaching high-end human exposure levels. A mixture (Mix) of 14 chemicals at a combined dose of 2.5 mg/kg bw/day was tested in combination with perfluorononanoic acid (PFNA) at doses of 0.0125 (Low PFNA), 0.25 (Mid PFNA) and 5 (High PFNA) mg/kg bw/day by oral administration for 14 days in juvenile male rats. Indication of a toxicokinetic interaction was found, as simultaneous exposure to PFNA and the Mix caused a 2.8-fold increase in plasma PFNA concentrations at Low PFNA. An increase in testosterone and dihydrotestosterone plasma concentrations was observed for Low PFNA + Mix. This effect was considered non-monotonic, as higher doses did not cause this effect. Reduced LH plasma concentrations together with increased androgen concentrations indicate a disturbed pituitary-testis axis caused by the 15-chemical mixture. Low PFNA by itself increased the corticosterone plasma concentration, an effect which was normalised after simultaneous exposure to Mix. This combined with affected ACTH plasma concentrations and down-regulation of 11β HSD mRNA in livers indicates a disturbed pituitary-adrenal axis. In conclusion, our data suggest that mixtures of environmental chemicals at doses approaching high-end human exposure levels can cause a hormonal imbalance and disturb steroid hormones and their regulation. These effects may be non-monotonic and were observed at low doses. Whether this reflects a more general phenomenon that should be taken into consideration when predicting human mixture effects or represents a rarer phenomenon remains to be shown.
authors.affiliation: Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, 2860, Søborg, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Hadrup
authors.affiliation: Division of Food Chemistry, National Food Institute, Technical University of Denmark, Søborg, Denmark.
authors.forename: Mikael
authors.initials: M
authors.lastname: Pedersen
authors.affiliation: Division of Food Chemistry, National Food Institute, Technical University of Denmark, Søborg, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Skov
authors.affiliation: Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, 2860, Søborg, Denmark.
authors.forename: Niels Lund
authors.initials: NL
authors.lastname: Hansen
authors.affiliation: Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, 2860, Søborg, Denmark.
authors.forename: Line Olrik
authors.initials: LO
authors.lastname: Berthelsen
authors.affiliation: Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, 2860, Søborg, Denmark.
authors.forename: Kristine
authors.initials: K
authors.lastname: Kongsbak
authors.affiliation: Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, 2860, Søborg, Denmark.
authors.forename: Julie
authors.initials: J
authors.lastname: Boberg
authors.affiliation: Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, 2860, Søborg, Denmark.
authors.forename: Marianne
authors.initials: M
authors.lastname: Dybdahl
authors.affiliation: Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, 2860, Søborg, Denmark.
authors.forename: Ulla
authors.initials: U
authors.lastname: Hass
authors.affiliation: Division of Food Chemistry, National Food Institute, Technical University of Denmark, Søborg, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Frandsen
authors.affiliation: Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, 2860, Søborg, Denmark. annv@food.dtu.dk.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Vinggaard
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics; D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005227:Fatty Acids; D005466:Fluorocarbons / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity*; D006728:Hormones / Q000097:blood; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D017208:Rats, Wistar; D013737:Testis / Q000187:drug effects
chemical_list: D005227:Fatty Acids; D005466:Fluorocarbons; D006728:Hormones; D027362:Organic Anion Transport Protein 1; C421043:Slc22a6 protein, rat; C101816:perfluoro-n-nonanoic acid; D015067:17-Hydroxysteroid Dehydrogenases; D003345:Corticosterone
keywords: Corticosterone; Mixture toxicology; Perfluorononanoic acid (PFNA); Pituitary hormones; Steroidogenesis; Testosterone