Paternal nicotine exposure defines different behavior in subsequent generation via hyper-methylation of mmu-miR-15b

Abstract

The neurobehavioral effects of paternal smoking and nicotine use have not been widely reported. In the present study, nicotine exposure induced depression in the paternal generation, but reduced depression and promoted hyperactivity in F1 offspring. While this intergenerational effect was not passed down to the F2 generation. Further studies revealed that nicotine induced the down-regulation of mmu-miR-15b expression due to hyper-methylation in the CpG island shore region of mmu-miR-15b in both the spermatozoa of F0 mice and the brains of F1 mice. As the target gene of mmu-miR-15b, Wnt4 expression was elevated in the thalamus of F1 mice due to the inheritance of DNA methylation patterns from the paternal generation. Furthermore, the increased expression of Wnt4 elevated the phosphorylation level of its downstream protein GSK-3 through the canonical WNT4 pathway which involved in the behavioral alterations observed in F1 mice. Moreover, in vivo stereotaxic brain injections were used to induce the overexpression of mmu-miR-15b and WNT4 and confirm the neurobehavioral effects in vitro. The behavioral phenotype of the F1 mice resulting from paternal nicotine exposure could be attenuated by viral manipulation of mmu-miR-15b in the thalamus.

Multigenerational and transgenerational effects of paternal exposure to drugs of abuse on behavioral and neural function

“…In addition to basal locomotor activity, anxiety and depressive‐like phenotypes have been assessed in F1 offspring of F0 fathers exposed to nicotine. No differences were observed between nicotine‐sired and control‐sired offspring in anxiety‐like behavior, as assessed by elevated plus maze (Dai et al ., ; Vallaster et al ., ). However, offspring from both chronic nicotine injections (F1‐nic) and chronic tobacco smoke (F1‐smo) displayed reduced depressive‐like behaviors, as assessed by the forced swim test (Dai et al ., ).…”

“…No differences were observed between nicotine‐sired and control‐sired offspring in anxiety‐like behavior, as assessed by elevated plus maze (Dai et al ., ; Vallaster et al ., ). However, offspring from both chronic nicotine injections (F1‐nic) and chronic tobacco smoke (F1‐smo) displayed reduced depressive‐like behaviors, as assessed by the forced swim test (Dai et al ., ). Decreased depressive‐like behavior suggests alterations in neurotransmitter systems, possibly including dopaminergic and serotoninergic systems (Zangen et al ., ).…”

“…In contrast, a study by Dai et al . () utilized two alternate nicotine exposure paradigms and identified differences in baseline activity in the open field. In the study by Dai et al .…”

“…In the study by Dai et al . (), C57BL6/J mice were exposed to either chronic nicotine injections (F1‐nic; 0.05 mg/100 g free‐base nicotine, i.p., 4x daily for 5 weeks) or chronic tobacco smoke (F1‐smo; 2x daily for 1 h for 5 weeks). One criticism of an oral nicotine paradigm, as used in Vallaster et al .…”

Chromatin modifications in metabolic disease: Potential mediators of long‐term disease risk

“…For example, the expression of sRNAs is drastically altered in response to high fat diet and caloric restriction, resulting in an aging phenotype (Green et al, 2017). PiRNAs can also be deregulated in response to high-fat diet, leading to altered DNA methylation in spermatozoa, altered DNA imprinting, and the potential for epigenetic inheritance of metabolic phenotypes (Dai et al, 2017; Kumar, Kuscu, & Dutta, 2016). The tRFs are another type of sRNA with altered expression in response to diet.…”