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Prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERbeta suppression in the amygdala in Molecular Autism, 8 (2017)
[article]
Titre : Prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERbeta suppression in the amygdala Type de document : Texte imprimé et/ou numérique Article en page(s) : 46p. Langues : Anglais (eng) Mots-clés : Amygdala Autism-like behavior Estrogen receptor beta Oral contraceptives Oxidative stress Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is characterized by impairments in social communication and restricted or repetitive behaviors or interests. ASD is now diagnosed in more than one out of 100 children and is biased towards males by a ratio of at least 4:1. Many possible explanations and potential causative factors have been reported, such as genetics, sex, and environmental factors, although the detailed mechanisms of ASD remain unclear. METHODS: The dams were exposed through oral contraceptives to either vehicle control (VEH) alone, levonorgestrel (LNG) alone, ethinyl estradiol (EE) alone, or a combination of LNG/EE for 21 days during their pregnancy. The subsequent 10-week-old offspring were used for autism-like behavior testing, and the limbic tissues were isolated for analysis. In another experimental group, 8-week-old male offspring were treated by infusion of ERbeta overexpression/knockdown lentivirus in the amygdala, and the offspring were analyzed after 2 weeks. RESULTS: We show that prenatal exposure of either LNG alone or a LNG/EE combination, but not EE alone, results in suppression of ERbeta (estrogen receptor beta) and its target genes in the amygdala with autism-like behavior in male offspring, while there is a much smaller effect on female offspring. However, we find that there is no effect on the hippocampus and hypothalamus. Further investigation shows that ERbeta suppression is due to LNG-mediated altered methylation on the ERbeta promoter and results in tissue damage with oxidative stress and the dysfunction of mitochondria and fatty acid metabolism, which subsequently triggers autism-like behavior. Overexpression of ERbeta in the amygdala completely restores LNG-induced ERbeta suppression and autism-like behaviors in offspring, while ERbeta knockdown mimics this effect, indicating that ERbeta expression in the amygdala plays an important role in autism-like behavior development. CONCLUSIONS: We conclude that prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERbeta suppression in the amygdala. To our knowledge, this is the first time the potential effect of oral contraceptives on the contribution of autism-like behavior in offspring has been discovered. En ligne : http://dx.doi.org/10.1186/s13229-017-0159-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331
in Molecular Autism > 8 (2017) . - 46p.[article] Prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERbeta suppression in the amygdala [Texte imprimé et/ou numérique] . - 46p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 46p.
Mots-clés : Amygdala Autism-like behavior Estrogen receptor beta Oral contraceptives Oxidative stress Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is characterized by impairments in social communication and restricted or repetitive behaviors or interests. ASD is now diagnosed in more than one out of 100 children and is biased towards males by a ratio of at least 4:1. Many possible explanations and potential causative factors have been reported, such as genetics, sex, and environmental factors, although the detailed mechanisms of ASD remain unclear. METHODS: The dams were exposed through oral contraceptives to either vehicle control (VEH) alone, levonorgestrel (LNG) alone, ethinyl estradiol (EE) alone, or a combination of LNG/EE for 21 days during their pregnancy. The subsequent 10-week-old offspring were used for autism-like behavior testing, and the limbic tissues were isolated for analysis. In another experimental group, 8-week-old male offspring were treated by infusion of ERbeta overexpression/knockdown lentivirus in the amygdala, and the offspring were analyzed after 2 weeks. RESULTS: We show that prenatal exposure of either LNG alone or a LNG/EE combination, but not EE alone, results in suppression of ERbeta (estrogen receptor beta) and its target genes in the amygdala with autism-like behavior in male offspring, while there is a much smaller effect on female offspring. However, we find that there is no effect on the hippocampus and hypothalamus. Further investigation shows that ERbeta suppression is due to LNG-mediated altered methylation on the ERbeta promoter and results in tissue damage with oxidative stress and the dysfunction of mitochondria and fatty acid metabolism, which subsequently triggers autism-like behavior. Overexpression of ERbeta in the amygdala completely restores LNG-induced ERbeta suppression and autism-like behaviors in offspring, while ERbeta knockdown mimics this effect, indicating that ERbeta expression in the amygdala plays an important role in autism-like behavior development. CONCLUSIONS: We conclude that prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERbeta suppression in the amygdala. To our knowledge, this is the first time the potential effect of oral contraceptives on the contribution of autism-like behavior in offspring has been discovered. En ligne : http://dx.doi.org/10.1186/s13229-017-0159-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation / W. XIE in Molecular Autism, 9 (2018)
[article]
Titre : Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation Type de document : Texte imprimé et/ou numérique Auteurs : W. XIE, Auteur ; X. GE, Auteur ; L. LI, Auteur ; A. YAO, Auteur ; X. WANG, Auteur ; M. LI, Auteur ; X. GONG, Auteur ; Z. CHU, Auteur ; Z. LU, Auteur ; X. HUANG, Auteur ; Y. JIAO, Auteur ; Y. WANG, Auteur ; M. XIAO, Auteur ; H. CHEN, Auteur ; W. XIANG, Auteur ; P. YAO, Auteur Article en page(s) : 43p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder Estrogen receptor beta Lipid metabolism Mitochondria Oxidative stress Progestin Resveratrol Index. décimale : PER Périodiques Résumé : Background: Recent literatures indicate that maternal hormone exposure is a risk factor for autism spectrum disorder (ASD). We hypothesize that prenatal progestin exposure may counteract the neuroprotective effect of estrogen and contribute to ASD development, and we aim to develop a method to ameliorate prenatal progestin exposure-induced autism-like behavior. Methods: Experiment 1: Prenatal progestin exposure-induced offspring are treated with resveratrol (RSV) through either prenatal or postnatal exposure and then used for autism-like behavior testing and other biomedical analyses. Experiment 2: Prenatal norethindrone (NET) exposure-induced offspring are treated with ERbeta knockdown lentivirus together with RSV for further testing. Experiment 3: Pregnant dams are treated with prenatal NET exposure together with RSV, and the offspring are used for further testing. Results: Eight kinds of clinically relevant progestins were used for prenatal exposure in pregnant dams, and the offspring showed decreased ERbeta expression in the amygdala with autism-like behavior. Oral administration of either postnatal or prenatal RSV treatment significantly reversed this effect with ERbeta activation and ameliorated autism-like behavior. Further investigation showed that RSV activates ERbeta and its target genes by demethylation of DNA and histone on the ERbeta promoter, and then minimizes progestin-induced oxidative stress as well as the dysfunction of mitochondria and lipid metabolism in the brain, subsequently ameliorating autism-like behavior. Conclusions: We conclude that resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation. Our data suggest that prenatal progestin exposure is a strong risk factor for autism-like behavior. Many potential clinical progestin applications, including oral contraceptive pills, preterm birth drugs, and progestin-contaminated drinking water or seafood, may be risk factors for ASD. In addition, RSV may be a good candidate for clinically rescuing or preventing ASD symptoms in humans, while high doses of resveratrol used in the animals may be a potential limitation for human application. En ligne : https://dx.doi.org/10.1186/s13229-018-0225-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371
in Molecular Autism > 9 (2018) . - 43p.[article] Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation [Texte imprimé et/ou numérique] / W. XIE, Auteur ; X. GE, Auteur ; L. LI, Auteur ; A. YAO, Auteur ; X. WANG, Auteur ; M. LI, Auteur ; X. GONG, Auteur ; Z. CHU, Auteur ; Z. LU, Auteur ; X. HUANG, Auteur ; Y. JIAO, Auteur ; Y. WANG, Auteur ; M. XIAO, Auteur ; H. CHEN, Auteur ; W. XIANG, Auteur ; P. YAO, Auteur . - 43p.
Langues : Anglais (eng)
in Molecular Autism > 9 (2018) . - 43p.
Mots-clés : Autism spectrum disorder Estrogen receptor beta Lipid metabolism Mitochondria Oxidative stress Progestin Resveratrol Index. décimale : PER Périodiques Résumé : Background: Recent literatures indicate that maternal hormone exposure is a risk factor for autism spectrum disorder (ASD). We hypothesize that prenatal progestin exposure may counteract the neuroprotective effect of estrogen and contribute to ASD development, and we aim to develop a method to ameliorate prenatal progestin exposure-induced autism-like behavior. Methods: Experiment 1: Prenatal progestin exposure-induced offspring are treated with resveratrol (RSV) through either prenatal or postnatal exposure and then used for autism-like behavior testing and other biomedical analyses. Experiment 2: Prenatal norethindrone (NET) exposure-induced offspring are treated with ERbeta knockdown lentivirus together with RSV for further testing. Experiment 3: Pregnant dams are treated with prenatal NET exposure together with RSV, and the offspring are used for further testing. Results: Eight kinds of clinically relevant progestins were used for prenatal exposure in pregnant dams, and the offspring showed decreased ERbeta expression in the amygdala with autism-like behavior. Oral administration of either postnatal or prenatal RSV treatment significantly reversed this effect with ERbeta activation and ameliorated autism-like behavior. Further investigation showed that RSV activates ERbeta and its target genes by demethylation of DNA and histone on the ERbeta promoter, and then minimizes progestin-induced oxidative stress as well as the dysfunction of mitochondria and lipid metabolism in the brain, subsequently ameliorating autism-like behavior. Conclusions: We conclude that resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation. Our data suggest that prenatal progestin exposure is a strong risk factor for autism-like behavior. Many potential clinical progestin applications, including oral contraceptive pills, preterm birth drugs, and progestin-contaminated drinking water or seafood, may be risk factors for ASD. In addition, RSV may be a good candidate for clinically rescuing or preventing ASD symptoms in humans, while high doses of resveratrol used in the animals may be a potential limitation for human application. En ligne : https://dx.doi.org/10.1186/s13229-018-0225-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371