Perinatal nicotine exposure‐induced transgenerational asthma: Effects of reexposure in F1 gestation

Liu, Jie; Yu, Celia; Doherty, Terence M.; Akbari, Omid; Allard, Patrick; Rehan, Virender K.

doi:10.1096/fj.201902386r

Cited by 14 publications

(21 citation statements)

References 38 publications

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“…In the same animal model and study design, we have previously reported that DNA methylation of the whole testicular tissue is increased at the global level in nicotine‐exposed F1 offspring 6,23 . Here, we show that perinatal nicotine exposure did not change global DNA methylation in spermatozoa from F1 animals.…”

Section: Discussionsupporting

confidence: 61%

“…In the same animal model and study design, we have previously reported that DNA methylation of the whole testicular tissue is increased at the global level in nicotine-exposed F1 offspring. 6,23 Here, we show that perinatal nicotine exposure did not change global DNA methylation in spermatozoa from F1 animals. This discrepancy may be due to DNA methylation changes in a non-germ cell(s) in the testis or may be due to the difference in the assays performed between the studies.…”

Section: Discussionmentioning

confidence: 61%

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Perinatal exposure to nicotine alters spermatozoal DNA methylation near genes controlling nicotine action

et al. 2021

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Perinatal smoke/nicotine exposure alters lung development and causes asthma in exposed offspring, transmitted transgenerationally. The mechanism underlying the transgenerational inheritance of perinatal smoke/nicotine‐induced asthma remains unknown, but germline epigenetic modulations may play a role. Using a well‐established rat model of perinatal nicotine‐induced asthma, we determined the DNA methylation pattern of spermatozoa of F1 rats exposed perinatally to nicotine in F0 gestation. To identify differentially methylated regions (DMRs), reduced representation bisulfite sequencing was performed on spermatozoa of F1 litters. The top regulated gene body and promoter DMRs were tested for lung gene expression levels, and key proteins involved in lung development and repair were determined. The overall CpG methylation in F1 sperms across gene bodies, promoters, 5′‐UTRs, exons, introns, and 3′‐UTRs was not affected by nicotine exposure. However, the methylation levels were different between the different genomic regions. Eighty one CpG sites, 16 gene bodies, and 3 promoter regions were differentially methylated. Gene enrichment analysis of DMRs revealed pathways involved in oxidative stress, nicotine response, alveolar and brain development, and cellular signaling. Among the DMRs, Dio1 and Nmu were the most hypermethylated and hypomethylated genes, respectively. Gene expression analysis showed that the mRNA expression and DNA methylation were incongruous. Key proteins involved in lung development and repair were significantly different (FDR < 0.05) between the nicotine and placebo‐treated groups. Our data show that DNA methylation is remodeled in offspring spermatozoa upon perinatal nicotine exposure. These epigenetic alterations may play a role in transgenerational inheritance of perinatal smoke/nicotine induced asthma.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 61%

Perinatal exposure to nicotine alters spermatozoal DNA methylation near genes controlling nicotine action

et al. 2021

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“…Interestingly, several studies have shown that sperm total or small RNAs from male mice with an epigenetic phenotype (e.g., metabolic disorders induced by HFD and the whitetail tips caused by Kit paramutation), seem capable of inducing a similar phenotype in offspring derived from zygotes injected with either total or small RNAs isolated from the sperm, suggesting that sperm RNAs may function as the epigenetic codes responsible for the paternal transmission of certain acquired traits ( 19 – 21 ). Our previous studies have shown that the sperm 5mC profiles and histone marks are altered in the male rats with perinatal exposure to nicotine ( 11 , 22 ). Given that both DNA methylation and histone marks in sperm are largely established during testicular development and spermatogenesis ( 23 , 24 ), it is plausible to hypothesize that both large and small sperm-borne RNAs may also be altered in the male rats of our perinatal nicotine rat models.…”

Section: Introductionmentioning

confidence: 99%

“…Given that the childhood asthma induced by perinatal exposure to nicotine arises in one generation and the distribution of this disease phenotype in subsequent generations never follows Mendel’s Law ( 11 – 14 ), it is highly unlikely that the asthma phenotype results from genetic mutations caused by nicotine exposure. Instead, transgenerational inheritance of the phenotype is most probably mediated by an epigenetic mechanism.…”

Section: Introductionmentioning

confidence: 99%

Perinatal Exposure to Nicotine Alters Sperm RNA Profiles in Rats

et al. 2022

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Perinatal exposure to smoking has been associated with childhood asthma, one of the most common pediatric conditions affecting millions of children globally. Of great interest, this disease phenotype appears heritable as it can persist across multiple generations even in the absence of persistent exposure to smoking in subsequent generations. Although the molecular mechanisms underlying childhood asthma induced by perinatal exposure to smoking or nicotine remain elusive, an epigenetic mechanism has been proposed, which is supported by the data from our earlier analyses on germline DNA methylation (5mC) and histone marks (H3 and H4 acetylation). To further investigate the potential epigenetic inheritance of childhood asthma induced by perinatal nicotine exposure, we profiled both large and small RNAs in the sperm of F1 male rats. Our data revealed that perinatal exposure to nicotine leads to alterations in the profiles of sperm-borne RNAs, including mRNAs and small RNAs, and that rosiglitazone, a PPARγ agonist, can attenuate the effect of nicotine and reverse the sperm-borne RNA profiles of F1 male rats to close to placebo control levels.

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“…A limited number of animal studies have evaluated the transgenerational transmission of the airway asthmatic phenotype from perinatal nicotine exposure. Epigenetic inheritance of the asthmatic phenotype in a rat model was observed in the F1 and F2 generations after gestational nicotine exposure in the F0 generation (Liu et al, 2020). DNA methylation changes environmentally induced from nicotine exposure increased with the asthmatic phenotype progressively more severe in the F2 offspring compared to the preceding generations.…”

Section: Evidence Of Transgenerational Epigenetic Phenotype Inheritancementioning

confidence: 95%

Maternal electronic cigarettes (e-cigs) and offspring asthma

Kraus¹,

Havaldar

Chiu

et al. 2021

J Stud Res

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Given that the rise of electronic cigarettes (e-cigs) has become increasingly relevant to the younger generations of today’s society, this paper investigates the impact of e-cig components, specifically nicotine and various e-cig flavoring chemicals, to fetal exposure during pregnancy on offspring respiratory outcomes. Previous animal studies primarily document the fetal side effects attributed to nicotine, including impaired lung development, with a model of direct chemical exposure, but we have hypothesized that in e-cig users, such phenotypes could result from and be exacerbated by the additional amalgam of chemicals that are responsible for the flavoring of e-cigs. Therefore, we have examined the harmful effects of nicotine and flavoring chemicals used in e-cigs in defense of the hypothesis that perinatal inhaled nicotine and e-cig flavoring exposure in vivo results in an airway asthmatic phenotype in offspring, which is transmitted transgenerationally, is characterized by Th2 polarization, and is more severe with combined exposure than with either constituent alone. The findings of this review support the hypothesis of this paper in regard to the potential detrimental respiratory effects of combined constituent exposure and indicate the need for the testing of further experimental animal models to better understand the foreseeable health implications of a rising e-cig use.

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Perinatal nicotine exposure‐induced transgenerational asthma: Effects of reexposure in F1 gestation

Cited by 14 publications

References 38 publications

Perinatal exposure to nicotine alters spermatozoal DNA methylation near genes controlling nicotine action

Perinatal exposure to nicotine alters spermatozoal DNA methylation near genes controlling nicotine action

Perinatal Exposure to Nicotine Alters Sperm RNA Profiles in Rats

Maternal electronic cigarettes (e-cigs) and offspring asthma

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