Perfluorononanoic acid in combination with 14 chemicals exerts low-dose mixture effects in rats

Niels Hadrup, Mikael Pedersen, Kasper Skov, Niels Lund Hansen, Line Olrik Berthelsen, Kristine Grønning Kongsbak, Julie Boberg, Marianne Dybdahl, Ulla Hass, Henrik Lauritz Frandsen, Anne Marie Vinggaard

Research output: Contribution to journalJournal articleResearchpeer-review

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.
Original languageEnglish
JournalArchives of Toxicology
Volume90
Issue number3
Pages (from-to)661-675
ISSN0340-5761
DOIs
Publication statusPublished - 2016

Keywords

  • Mixture toxicology
  • Steroidogenesis
  • Testosterone
  • Corticosterone
  • Pituitary hormones
  • Perfluorononanoic acid (PFNA)

Cite this

Hadrup, Niels ; Pedersen, Mikael ; Skov, Kasper ; Hansen, Niels Lund ; Berthelsen, Line Olrik ; Kongsbak, Kristine Grønning ; Boberg, Julie ; Dybdahl, Marianne ; Hass, Ulla ; Frandsen, Henrik Lauritz ; Vinggaard, Anne Marie. / Perfluorononanoic acid in combination with 14 chemicals exerts low-dose mixture effects in rats. In: Archives of Toxicology. 2016 ; Vol. 90, No. 3. pp. 661-675.
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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.",
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language = "English",
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Perfluorononanoic acid in combination with 14 chemicals exerts low-dose mixture effects in rats. / Hadrup, Niels; Pedersen, Mikael; Skov, Kasper; Hansen, Niels Lund; Berthelsen, Line Olrik; Kongsbak, Kristine Grønning; Boberg, Julie; Dybdahl, Marianne; Hass, Ulla; Frandsen, Henrik Lauritz; Vinggaard, Anne Marie.

In: Archives of Toxicology, Vol. 90, No. 3, 2016, p. 661-675.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Perfluorononanoic acid in combination with 14 chemicals exerts low-dose mixture effects in rats

AU - Hadrup, Niels

AU - Pedersen, Mikael

AU - Skov, Kasper

AU - Hansen, Niels Lund

AU - Berthelsen, Line Olrik

AU - Kongsbak, Kristine Grønning

AU - Boberg, Julie

AU - Dybdahl, Marianne

AU - Hass, Ulla

AU - Frandsen, Henrik Lauritz

AU - Vinggaard, Anne Marie

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Mixture toxicology

KW - Steroidogenesis

KW - Testosterone

KW - Corticosterone

KW - Pituitary hormones

KW - Perfluorononanoic acid (PFNA)

U2 - 10.1007/s00204-015-1452-6

DO - 10.1007/s00204-015-1452-6

M3 - Journal article

VL - 90

SP - 661

EP - 675

JO - Archives of Toxicology

JF - Archives of Toxicology

SN - 0340-5761

IS - 3

ER -