Abstract
Young adult wild-type and aryl hydrocarbon receptor knockout (AHRKO) mice of both sexes and the C57BL/6J background were exposed to 10 weekly oral doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; total dose of 200 μg/kg bw) to further characterize the observed impacts of AHR as well as TCDD on the retinoid system. Unexposed AHRKO mice harboured heavier kidneys, lighter livers and lower serum all-trans retinoic acid (ATRA) and retinol (REOH) concentrations than wild-type mice. Results from the present study also point to a role for the murine AHR in the control of circulating REOH and ATRA concentrations. In wild-type mice, TCDD elevated liver weight and reduced thymus weight, and drastically reduced the hepatic concentrations of 9-cis-4-oxo-13,14-dihydro-retinoic acid (CORA) and retinyl palmitate (REPA). In female wild-type mice, TCDD increased the hepatic concentration of ATRA as well as the renal and circulating REOH concentrations. Renal CORA concentrations were substantially diminished in wild-type male mice exclusively following TCDD-exposure, with a similar tendency in serum. In contrast, TCDD did not affect any of these toxicity or retinoid system parameters in AHRKO mice. Finally, a distinct sex difference occurred in kidney concentrations of all the analysed retinoid forms. Together, these results strengthen the evidence of a mandatory role of AHR in TCDD-induced retinoid disruption, and suggest that the previously reported accumulation of several retinoid forms in the liver of AHRKO mice is a line-specific phenomenon. Our data further support participation of AHR in the control of liver and kidney development in mice.
Highlights
He patic vitamin A reduction was later included as an effect-biomarker for retinoid disruption in the World Health Organization (WHO) Toxic Equivalency Factor (TEF) system developed for the assessment of mixtures of persistent organic pollutants whose mode of action is based on aryl hydrocarbon receptor (AHR) activation [85,86,87]
We have demonstrated that AHR is necessary for normal concentrations of REOH and all-trans retinoic acid (ATRA) in the circulation of adult mice
Hepatic and renal retinoid concentrations were not influenced by AHR deficiency, and the elevated hepatic retinoid concentrations reported in another aryl hydrocarbon receptor knockout (AHRKO) mouse line [1,2,3] were not confirmed in this study
Summary
An important intention of this study is to support ongoing reg ulatory initiatives dedicated to science-based incorporation of the reti noid system into test programs for chemical safety evaluations in the many different domains of human and wildlife health as recently reviewed [6,7,169]. To this end, the obtained original retinoid data from the experimental part of this study were further evaluated in relation to previously published data and by the use of mode-of-action and weight-of-evidence types of analytical approaches to derive additional regulatory-relevant insights. The experimental study background, design, and results are embedded and evaluated in compre hensive, yet narrative, and review-style Introduction and Discussion sections of this article, with the aim to provide, in parallel, a broader context of both AHR and retinoid biology as a common background to the interpretation and conclusions of the presented original data
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