EFFECTS OF MIXTURES OF CHEMICALS ON BIOMARKER RESPONSES IN RAINBOW TROUT (ONCORHYNCHUS MYKISS).

• Aquatic organisms reside and reproduce in an environment where they are exposed to mixtures of pollutants in their natural habitat. The CYP3A enzyme and the P-glycoprotein (Pgp) transporter are important for clearance of lipophilic compounds. In mammals, both CYP3A and Pgp are regulated by the pregnane X receptor (PXR) and a number of adverse drug-interactions have been associated either with activation of PXR or inhibition of CYP3A/Pgp activities. The PXR from rainbow trout was cloned and a reporter assay, using the human CYP3A4 promotor, showed that rainbow trout PXR was less responsive to PXR agonists compared to the mammalian PXRs. To further address species differences in PXR-CYP3A signaling, we have cloned a part (650 base pairs) of the rainbow trout CYP3A27 promotor. Prototypical PXR agonists have no or little effect on CYP3A/Pgp induction in rainbow trout. Therefore, activation of PXR in fish exposed to mixtures of pollutants may be of less importance compared to that in mammals. In contrast, inhibition of CYP3A activities in situations of mixed exposure seems to have a more profound adverse effect on detoxification in rainbow trout and also to interfere with biomarker responses. For example, azole fungicides efficiently inhibited CYP1A and CYP3A enzyme activities in juvenile rainbow trout, which resulted in up to 9-times increased response to estrogenic exposure. Hence, in situations of exposure to mixtures of azoles and estrogens there is a risk for overestimation of the estrogenic exposure. Inhibiting receptor crosstalks can also interfere with biomarker responses. For example, activation of the arylhydrocarbon receptor (AhR) resulted in decreased estrogen receptor (ER) signaling in primary cultures of hepatocytes from rainbow trout. Thus, in situations of exposure to mixtures of aromatic hydrocarbons and estrogens there is a risk for underestimation of the estrogenic exposure as a result of inhibiting AhR-ER crosstalk (FORMAS 2009-1362-13695-62).

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)

NATURVETENSKAP  -- Biologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences (hsv//eng)

Keyword

mechanisms of toxicity

induction

inhibition

crosstalk

Publication and Content Type

ref (subject category)

kon (subject category)