Perfluorononanoic acid in combination with 14 chemicals exerts low-dose mixture effects in rats
Hadrup, N; Pedersen, M; Skov, K; Hansen, NL; Berthelsen, LO; Kongsbak, K; Boberg, J; Dybdahl, M; Hass, U; Frandsen, H; Vinggaard, AM
HERO ID
2851018
Reference Type
Journal Article
Year
2016
Language
English
PMID
| HERO ID | 2851018 |
|---|---|
| In Press | No |
| Year | 2016 |
| Title | Perfluorononanoic acid in combination with 14 chemicals exerts low-dose mixture effects in rats |
| Authors | Hadrup, N; Pedersen, M; Skov, K; Hansen, NL; Berthelsen, LO; Kongsbak, K; Boberg, J; Dybdahl, M; Hass, U; Frandsen, H; Vinggaard, AM |
| Journal | Archives of Toxicology |
| Volume | 90 |
| Issue | 3 |
| Page Numbers | 661-675 |
| 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. |
| Doi | 10.1007/s00204-015-1452-6 |
| Pmid | 25588985 |
| Wosid | WOS:000370343000013 |
| Url | https://search.proquest.com/docview/1765262418?accountid=171501 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |
| Keyword | Mixture toxicology; Steroidogenesis; Testosterone; Corticosterone; Pituitary hormones; Perfluorononanoic acid (PFNA) |
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