Male offspring of sires exposed to ethanol demonstrate alterations in ethanol sensitivity and drinking behavior
Sunday, Nov 10, 2013, 8:00 AM - 9:00 AM
++C.18.d. Alcohol: Behavioral effects
, G. E. HOMANICS;
Univ. of Pittsburgh, Pittsburgh, PA
BACKGROUND: Emerging evidence indicates that perturbations of the parental environment, including cocaine administration, can affect offspring behavior through inheritance of epigenetic marks. We hypothesize that epigenetic inheritance can explain a portion of the missing heritability of ethanol (EtOH) use disorders. METHODS: Eight-week-old, C57BL/6J male mice were exposed to vapor EtOH (E) or room air (C) for 8 hours/day, 5 days/week for 5 weeks (1 cycle of murine spermatogenesis). Sires were mated to 129Sv/ImJ females, sacrificed, and sperm extracted using a double swim up assay. Bisulfite sequencing was used to assess DNA methylation at paternally imprinted regions in motile sperm. Offspring from matings were reared normally and used for behavioral and molecular experiments starting at 8 weeks of age. RESULTS: The daily blood EtOH concentrations of E-sires were 169 +/- 11.2 mg/dL (mean +/- SEM). E-sires had significantly decreased DNA methylation at the intergenic (IG) differentially methylated region (DMR) but not at the H19 DMR in motile sperm compared to C-sires. In the initial 32 litters (18 C, 14 E) consisting of 158 offspring (88 C, 70 E), E-sired males weighed significantly more than C-sired males. After injection of 1 g/kg EtOH, E-sired males spent more time in open arms on the Elevated Plus Maze and had enhanced performance on an Accelerating Rotarod compared to C-sired males. On a 2 bottle choice drinking assay, E-sired males consumed significantly less EtOH and had significantly decreased EtOH preference compared to C-sired males. E-sired males also had a significant increase in expression of Bdnf in the ventral tegmental area, with no change in expression of the imprinted genes Dlk1 or Igf2. There were no significant differences between E- and C-sired female offspring on these assays. CONCLUSIONS: Paternal exposure to EtOH can alter EtOH sensitivity and preference in male offspring, conceivably via epigenetic mechanisms that lead to gene expression changes. These findings are similar to recently reported effects of paternal cocaine exposure, suggesting sexually dimorphic effects of drugs of abuse on paternal inheritance. Supported by R37AA10422.
NIH Grant R37AA10422
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