Cadmium exposure alters metabolomics of sulfur-containing amino acids in rat testes.
This study aimed to examine distribution of cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE), the hydrogen sulfide (H(2)S)-generating enzymes, and metabolomic alterations in sulfur-containing amino acids in rat testes exposed to stressors. Immunohistochemistry revealed distinct distribution of the two enzymes: CBS occurred mainly in Leydig cells and was also detectable in Sertoli cells and germ cells, whereas CSE was evident in Sertoli cells and immature germ cells involving spermatogonia. The amounts of CSE and CBS in testes did not alter in response to administration of cadmium chloride, an antispermatogenic stressor leading to apoptosis. Metabolome analyses assisted by liquid chromatography equipped with mass spectrometry revealed marked alterations in sulfur-containing amino acid metabolism: amounts of methionine and cysteine were significantly elevated concurrently with a decrease in the ratio between S-adenosylhomocysteine and Sadenosylmethionine, suggesting expansion of the remethylation cycle and acceleration of methyl donation. Despite a marked increase in cysteine, amounts of H(2)S were unchanged, leading to a remarkable decline of the H(2)S/cysteine ratio in the cadmium-treated rats. Under such circumstances, oxidized glutathione (GSSG) was significantly reduced, whereas reduced glutathione (GSH) was well maintained, and the GSH/GSSG ratio was consequently elevated. These results collectively showed that cadmium induces metabolomic remodeling of sulfur-containing amino acids even when the protein expression of CBS or CSE is not evident. Although detailed mechanisms for such a remodeling event remain unknown, our study suggests that metabolomic analyses serve as a powerful tool to pinpoint a critical enzymatic reaction that regulates metabolic systems as a whole.
Sugiura
Yasoo
Y
Department of Biochemistry and Integrative Medical Biology, School of Medicine, Keio University, Tokyo, Japan.
Kashiba
Misato
M
Maruyama
Kayo
K
Hoshikawa
Koichi
K
Sasaki
Ryoko
R
Saito
Kazuyoshi
K
Kimura
Hideo
H
Goda
Nobuhito
N
Suematsu
Makoto
M
D000603:Amino Acids, Sulfur / Q000378:metabolism*; D000818:Animals; D002104:Cadmium / Q000494:pharmacology*; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013737:Testis / Q000187:drug effects* / Q000378:metabolism*
D000603:Amino Acids, Sulfur; D002104:Cadmium; D006710:Homocysteine; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D005978:Glutathione; D003545:Cysteine; D006862:Hydrogen Sulfide