Molecular and organismal changes in offspring of male mice treated with chemical stressors.
Both gene methylation changes and genetic instability have been noted in offspring of male rodents exposed to radiation or chemicals, but few specific gene targets have been established. Previously, we identified the gene for ribosomal RNA, rDNA, as showing methylation change in sperm of mice treated with the preconceptional carcinogen, chromium(III) chloride. rDNA is a critical cell growth regulator. Here, we investigated the effects of paternal treatments on rDNA in offspring tissue. A total of 93 litters and 758 offspring were obtained, permitting rigorous mixed-effects models statistical analysis of the results. We show that the offspring of male mice treated with Cr(III) presented increased methylation in a promoter sequence of the rDNA gene, specifically in lung. Furthermore polymorphic variants of the multi-copy rDNA genes displayed altered frequencies indicative of structural changes, as a function of both tissue type and paternal treatments. Organismal effects also occurred: some groups of offspring of male mice treated with either Cr(III) or its vehicle, acidic saline, compared with those of untreated mice, had altered average body and liver weights and levels of serum glucose and leptin. Males treated directly with Cr(III) or acidic saline presented serum hormone changes consistent with a stress response. These results establish for the first time epigenetic and genetic instability effects in a gene of central physiological importance, in offspring of male mice exposed preconceptionally to chemicals, possibly related to a stress response in these males.
Laboratory of Comparative Carcinogenesis, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Yih-Horng
YH
Shiao
Robert M
RM
Leighty
Cuiju
C
Wang
Xin
X
Ge
Erik B
EB
Crawford
Joshua M
JM
Spurrier
Sean D
SD
McCann
Janet R
JR
Fields
Laura
L
Fornwald
Lisa
L
Riffle
Craig
C
Driver
Kazimierz S
KS
Kasprzak
Octavio A
OA
Quiñones
Ralph E
RE
Wilson
Gregory S
GS
Travlos
W Gregory
WG
Alvord
Lucy M
LM
Anderson
D000818:Animals; D019175:DNA Methylation; D004275:DNA, Ribosomal / Q000235:genetics; D005838:Genotype; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008297:Male; D051379:Mice; D012045:Regulatory Sequences, Nucleic Acid; D013312:Stress, Physiological / Q000187:drug effects*
D004275:DNA, Ribosomal; D007334:Insulin-Like Growth Factor I