α7 nAChR mediated Fas demethylation contributes to prenatal nicotine exposure-induced programmed thymocyte apoptosis in mice

Abstract

This study aimed to investigate the effects of prenatal nicotine exposure (PNE) on thymocyte apoptosis and postnatal immune impairments in vivo and further explore the epigenetic mechanisms of the pro-apoptotic effect of nicotine in vitro. The results showed that PNE caused immune impairments in offspring on postnatal day 49, manifested as increased IL-4 production and an increased IgG1/IgG2a ratio in serum. Enhanced apoptosis of total and CD4+SP thymocytes was observed both in fetus and in offspring. Further, by exposing thymocytes to 0–100 μM of nicotine in vitro for 48 h, we found that nicotine increased α7 nicotinic acetylcholine receptor (nAChR) expression, activated the Fas apoptotic pathway, and promoted thymocyte apoptosis in concentration-dependent manners. In addition, nicotine could induce Tet methylcytosine dioxygenase (TET) 2 expression and Fas promoter demethylation, which can be abolished by TET2 siRNA transfection. Moreover, the α7 nAChR specific antagonist α-bungarotoxin can abrogate nicotine-induced TET2 increase, and the following Fas demethylation and Fas-mediated apoptosis. In conclusion, our findings showed, for the first time, that α7 nAChR activation could induce TET2-mediated Fas demethylation in thymocytes and results in the upregulation of Fas apoptotic pathway, which provide evidence for elucidating the PNE-induced programmed thymocyte apoptosis.

Developmental nicotine exposure engenders intergenerational downregulation and aberrant posttranslational modification of cardinal epigenetic factors in the frontal cortices, striata, and hippocampi of adolescent mice

“…Congruent with the putative role of DNMT3A downregulation in neurodevelopmental disorder-associated and DNE-evoked DNA methylome deficits, contemporary rodent research demonstrates deregulation of TET2, an enzyme which catalyzes DNA demethylation, accompanied by global DNA hypomethylation in peripheral tissues of first-generation DNE offspring [72]. However, the present study indicates that DNE does not impact frontal cortical, striatal, or hippocampal TET2 expression in either first-or second-generation DNE progeny.…”

“…The DNA demethylase TET2 is dysregulated in first-generation DNE rodents, and TET2 dysfunction is broadly linked to myriad epigenetic and phenotypic alterations which mirror those observed in neurodevelopmental disorders as well as first-and second-generation DNE offspring [39,40,72,[77][78][79]. Accordingly, we reasoned that DNE may elicit multigenerational overexpression of TET2 which could contribute to the multigenerational global DNA hypomethylation which we previously reported in DNE mice [39].…”

“…Contemporary research indicates that DNE alters the transcription and expression of the epigenetic factors DNA methyltransferase 3A (DNMT3A) and ten-eleven translocase methylcytosine dioxygenase 2 (TET2) in rodent offspring [59,71,72]. Given that DNMT3A and TET2 reciprocally regulate DNA methylation via catalysis of de novo DNA methylation and demethylation, respectively, downregulation of DNMT3A and/or upregulation of TET2 could mediate the multigenerational global DNA methylome deficits and associated neurobehavioral phenotypes that we have previously identified in adolescent DNE mice [39,40,73,74].…”

Immunotoxicity evaluation by subchronic oral administration of clothianidin in Sprague-Dawley rats

“…Nicotine, which is an agonist of nAChRs, can activate the α7 nAChR on thymocytes and induce upregulation of the Fas apoptotic pathway [36]. It has been demonstrated that nicotine can induce cell-cycle progression mainly through the α7 nAChRs [54].…”

Tomorou attenuates progression of rheumatoid arthritis through alteration in ULK-1 independent autophagy pathway in collagen induced arthritis mice model

“…RNA was quantified on NanoDrop (Thermofisher Scientific) and cDNA was synthesized using Oligo dT. ULK-1, Caspase 3, and GAPDH, as housekeeping gene, were quantified using primers reported in Lenhare et al 66 , Lui et al 67 , and Ren et al 68 in order to monitor alterations in the expression of autophagy and apoptotic markers. Real-time PCR was performed on 7300 Real-Time PCR System (Applied Biosystems).…”