Suppression of radiation-induced testicular germ cell apoptosis by 2,5-hexanedione pretreatment. II. Gene array analysis reveals adaptive changes in cell cycle and cell death pathways.
Sertoli cells are essential for testicular germ cell maintenance and survival. We made the unexpected observation that x-radiation (x-ray)-induced germ cell loss is attenuated by co-exposure with the Sertoli cell toxicant 2,5-hexanedione (HD). The mechanisms underlying this attenuation of germ cell apoptosis with reduced Sertoli cell support are unknown. The current study was performed to examine alterations in testicular gene expression with co-exposure to HD and x-ray. Adult male rats were exposed to HD (0.33 or 1%) in the drinking water for 18 days followed by x-ray (2 or 5 Gy), resulting in nine treatment groups. Testis samples were collected after 3 h and total messenger RNA was analyzed using Affymetrix Rat Genome 230 2.0 arrays. Normalized log2-expression values were analyzed using LIMMA and summarized using linear contrasts designed to summarize the aggregated effect, in excess of x-ray alteration, of HD across all treatment groups. These contrasts were compared with the overall linear trend expression for x-ray, to determine whether HD effects were agonistic or antagonistic with respect to x-ray damage. Overrepresentation analysis to identify biological pathways where HD modification of gene expression was the greatest was performed. HD exerted a significant influence on genes involved in cell cycle and cell death/apoptosis. The results of this study provide insight into the mechanisms underlying attenuated germ cell toxicity following HD and x-ray co-exposure through the analysis of co-exposure effects on gene expression, and suggest that HD pre-exposure reduces Sertoli cell supported germ cell proliferation thereby reducing germ cell vulnerability to x-rays.
Campion
Sarah N
SN
Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912, USA.
Houseman
E Andres
EA
Sandrof
Moses A
MA
Hensley
Janan B
JB
Sui
Yunxia
Y
Gaido
Kevin W
KW
Wu
Zhijin
Z
Boekelheide
Kim
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000528:radiation effects; D018816:Genes, cdc; D006588:Hexanones / Q000494:pharmacology*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D012671:Seminiferous Tubules / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D013094:Spermatozoa / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects
D006588:Hexanones; D011837:Radiation-Protective Agents; C011269:2,5-hexanedione