Responsive genes for fish embryos have been identified so far for some endocrine pathways but not for androgens. Using transcriptome analysis and multiple concentration-response modeling, we identified putative androgen-responsive genes in zebrafish embryos exposed to 0.05-5000 nM 11-ketotestosterone for 24 h. Four selected genes with sigmoidal concentration-dependent expression profiles (EC50 = 6.5-30.0 nM) were characterized in detail. The expression of cyp2k22 and slco1f4 was demonstrated in the pronephros; lipca was detected in the liver, and sult2st3 was found in the olfactory organs and choroid plexus. Their expression domains, the function of human orthologs, and a pathway analysis suggested a role of these genes in the metabolism of hormones. Hence, it was hypothesized that they were induced to compensate for elevated hormone levels. The induction of sult2st3 and cyp2k22 by 11-ketotestosterone was repressed by co-exposure to the androgen receptor antagonist nilutamide supporting a potential androgen receptor mediated regulation. Sensitivity (expressed as EC50 values) of sult2st3 and cyp2k22 gene expression induction after exposure to other steroidal hormones (11-ketotestosterone ∼ testosterone > progesterone > cortisol > ethinylestradiol) correlated with their known binding affinities to zebrafish androgen receptor. Hence, these genes might represent potential markers for screening of androgenic compounds in the zebrafish embryo.

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Disturbed iron (Fe) ion homeostasis and mitochondrial dysfunction have been implicated in neurodegeneration. Both processes are related, because central Fe ion consuming biogenetic pathways take place in mitochondria and affect their oxidative energy metabolism. Iron is imported into mitochondria by the two homologous Fe ion importers mitoferrin-1 and mitoferrin-2. To elucidate more specifically the role of mitochondrial Fe ions for brain energy metabolism and for proper neuronal function, we generated mice with a neuron-specific knockout of mitoferrin-1 (Slc25a37 −/− or mfrn-1 −/−) and compared them with corresponding control littermates (mfrn-1 flox/flox). Mice lacking neuronal mfrn-1 exhibited no obvious anatomical or behavioral abnormalities as neonates, young or adult animals. However, they exhibited a moderate decrease in brain mitochondrial O 2-consumption with complex-I substrates of the electron transport chain (p < 0.05), indicating a moderate suppression of electron transport. While these mice did not exhibit altered basal fear levels, inquisitiveness or motor skills in specific neurobiological test batteries, they clearly exhibited decreased spatial learning skills and missing establishment of stable spatial memory in Morris water maze, as compared to floxed controls (p < 0.05). We thus conclude that mitochondrial Fe ion supply is an important player in neuronal energy metabolism and proper brain function and that the carrier mitoferrin-1 cannot be completely replaced by mitoferrin-2 or other as yet unknown Fe ion carriers.