Background

Paternal alcohol abuse is a well-recognized risk factor for the development of an alcohol use disorder (AUD). In addition to genetic and environmental risk factors, heritable epigenetic factors also have been proposed to play a key role in the development of AUD. However, it is not clear whether epigenetic factors contribute to the genetic inheritance in families affected by AUD. We used reciprocal crosses of the alcohol-preferring (P) and -nonpreferring (NP) rat lines to test whether epigenetic factors also impacted alcohol drinking in up to two generations of offspring.

Methods

F1 offspring derived by reciprocal breeding of P and NP rats were tested for differences in alcohol consumption using a free-choice protocol of 10% ethanol, 20% ethanol, and water that were available concurrently. In a separate experiment, an F2 population was tested for alcohol consumption not only due to genetic differences. These rats were generated from inbred P (iP) and iNP rat lines that were reciprocally bred to produce genetically identical F1 offspring that remained alcohol-naïve. Intercrosses of the F1 generation animals produced the F2 generation. Alcohol consumption was then assessed in the F2 generation using a standard two-bottle choice protocol, and was analyzed using genome-wide linkage analysis. Alcohol consumption measures were also analyzed for sex differences.

Results

Average alcohol consumption was higher in the F1 offspring of P vs. NP sires and in the F2 offspring of F0 iP vs. iNP grandsires. Linkage analyses showed the maximum LOD scores for alcohol consumption in both male and female offspring were on chromosome 4 (Chr 4). The LOD score for both sexes considered together was higher when the grandsire was iP vs. iNP (5.0 vs. 3.35, respectively). Furthermore, the F2 population displayed enhanced alcohol consumption when the P alleles from the F0 sire were present.

Conclusions

These results demonstrate that epigenetic and/or non-genetic factors mapping to rat chromosome 4 contribute to a transgenerational paternal effect on alcohol consumption in the P and NP rat model of AUD.

中文翻译：

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大鼠 4 号染色体上的表观遗传变化导致嗜酒和不嗜酒大鼠的不同饮酒行为。

 背景

父亲酗​​酒是公认的酒精使用障碍 (AUD) 的危险因素。除了遗传和环境风险因素外，遗传性表观遗传因素也被认为在 AUD 的发展中发挥着关键作用。然而，尚不清楚表观遗传因素是否有助于受 AUD 影响的家庭的遗传。我们使用嗜酒 (P) 和不嗜酒 (NP) 大鼠品系的相互杂交来测试表观遗传因素是否也会影响最多两代后代的饮酒。

 方法

使用同时提供的 10% 乙醇、20% 乙醇和水的自由选择方案，测试 P 和 NP 大鼠相互繁殖产生的 F1 后代的酒精消耗差异。在一项单独的实验中，对 F2 群体的饮酒量进行了测试，这不仅是由于遗传差异。这些大鼠是由近交 P (iP) 和 iNP 大鼠品系产生的，这些大鼠品系相互交配，产生基因相同但仍不酗酒的 F1 后代。 F1代动物的杂交产生了F2代。然后使用标准两瓶选择方案评估 F2 代的酒精消耗量，并使用全基因组连锁分析进行分析。还分析了饮酒量的性别差异。

 结果

P 与 NP 公牛的 F1 后代以及 F0 iP 与 iNP 祖父的 F2 后代的平均酒精消耗量较高。连锁分析显示，雄性和雌性后代的饮酒量最高 LOD 得分均位于 4 号染色体 (Chr 4) 上。当祖父是 iP 与 iNP 时，两性的 LOD 分数一起考虑较高（分别为 5.0 与 3.35）。此外，当 F0 父系的 P 等位基因存在时，F2 群体表现出饮酒量增加。

 结论

这些结果表明，映射到大鼠 4 号染色体的表观遗传和/或非遗传因素有助于 AUD 的 P 和 NP 大鼠模型中酒精消耗的跨代父系效应。