Abstract
The results of the present work show that the exposure of pregnant rats to low doses of all-trans-retinoic acid (ATRA) (2.5 mg/kg body weight) results in postnatal dysfunction of complex I of the respiratory chain in the cerebellum of the offspring. ATRA had no effect on the postnatal expression of complex I and did not exert any direct inhibitory effect on the enzymatic activity of the complex. The ATRA embryonic exposure resulted, however, in a marked increase in the level of carbonylated proteins in the mitochondrial fraction of the cerebellum, in particular of complex I subunits. The postnatal increase of the carbonylated proteins correlated directly with the inhibition of the activity of complex I. ATRA had, on the other hand, no effect on oxygen free-radical scavengers. It is proposed that embryonic exposure to ATRA results in impairment of protein surveillance in the cerebellum, which persists after birth and results in accumulation of oxidatively damaged complex I.
Footnotes
This work was supported by National Project “Progetto FIRB Rete Nazionale per lo Studio della Proteomica Umana (Italian Human ProteomeNet),” Ministero dell'Istruzione, dell'Università e della Ricerca [Grant RBRN07BMCT_014, 2009]; Progetto FIRB futuro in ricerca, Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR), [Grant RBFR0813Z5, 2008]; and Progetto Strategico Ric.002 [Cip PS 101, POR 2000/06].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.111.073353.
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ABBREVIATIONS:
- ATRA
- all-trans-retinoic acid
- ADU
- arbitrary densitometric unit
- RA
- retinoic acid
- DNPH
- dinitrophenyl-hydrazine
- ECL
- enhanced chemiluminescence
- GD
- gestational day
- NHEK
- normal human epidermal keratinocyte
- KB
- human mouth epidermoid cells carcinoma
- PBS
- phosphate-buffered saline
- PND
- postnatal day
- POD
- horseradish peroxidase
- ROS
- reactive oxygen species
- SOD
- superoxide dismutase
- TTBS
- Tris-buffered saline/Tween 20
- GSH
- glutathione
- G + M
- glutamate plus malate
- PAGE
- polyacrylamide gel electrophoresis
- DCFH
- dichlorofluorescein
- TCA
- trichloroacetic acid
- GSSG
- oxidized glutathione.
- Received May 3, 2011.
- Accepted July 13, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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