Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERβ activation

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Abstract

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 ERβ 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 ERβ expression in the amygdala with autism-like behavior. Oral administration of either postnatal or prenatal RSV treatment significantly reversed this effect with ERβ activation and ameliorated autism-like behavior. Further investigation showed that RSV activates ERβ and its target genes by demethylation of DNA and histone on the ERβ 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 ERβ 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.

Electronic supplementary material

The online version of this article (10.1186/s13229-018-0225-5) contains supplementary material, which is available to authorized users.

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Most cited references 46

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Advances in autism genetics: on the threshold of a new neurobiology.

Brett Abrahams, Daniel Geschwind (2008)

Autism is a heterogeneous syndrome defined by impairments in three core domains: social interaction, language and range of interests. Recent work has led to the identification of several autism susceptibility genes and an increased appreciation of the contribution of de novo and inherited copy number variation. Promising strategies are also being applied to identify common genetic risk variants. Systems biology approaches, including array-based expression profiling, are poised to provide additional insights into this group of disorders, in which heterogeneity, both genetic and phenotypic, is emerging as a dominant theme.

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A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures

D Rossignol, R Frye (2011)

Recent studies have implicated physiological and metabolic abnormalities in autism spectrum disorders (ASD) and other psychiatric disorders, particularly immune dysregulation or inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures (‘four major areas'). The aim of this study was to determine trends in the literature on these topics with respect to ASD. A comprehensive literature search from 1971 to 2010 was performed in these four major areas in ASD with three objectives. First, publications were divided by several criteria, including whether or not they implicated an association between the physiological abnormality and ASD. A large percentage of publications implicated an association between ASD and immune dysregulation/inflammation (416 out of 437 publications, 95%), oxidative stress (all 115), mitochondrial dysfunction (145 of 153, 95%) and toxicant exposures (170 of 190, 89%). Second, the strength of evidence for publications in each area was computed using a validated scale. The strongest evidence was for immune dysregulation/inflammation and oxidative stress, followed by toxicant exposures and mitochondrial dysfunction. In all areas, at least 45% of the publications were rated as providing strong evidence for an association between the physiological abnormalities and ASD. Third, the time trends in the four major areas were compared with trends in neuroimaging, neuropathology, theory of mind and genetics (‘four comparison areas'). The number of publications per 5-year block in all eight areas was calculated in order to identify significant changes in trends. Prior to 1986, only 12 publications were identified in the four major areas and 51 in the four comparison areas (42 for genetics). For each 5-year period, the total number of publications in the eight combined areas increased progressively. Most publications (552 of 895, 62%) in the four major areas were published in the last 5 years (2006–2010). Evaluation of trends between the four major areas and the four comparison areas demonstrated that the largest relative growth was in immune dysregulation/inflammation, oxidative stress, toxicant exposures, genetics and neuroimaging. Research on mitochondrial dysfunction started growing in the last 5 years. Theory of mind and neuropathology research has declined in recent years. Although most publications implicated an association between the four major areas and ASD, publication bias may have led to an overestimation of this association. Further research into these physiological areas may provide insight into general or subset-specific processes that could contribute to the development of ASD and other psychiatric disorders.

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Resveratrol stimulates AMP kinase activity in neurons.

Biplab Dasgupta, Jeffrey Milbrandt (2007)

Resveratrol is a polyphenol produced by plants that has multiple beneficial activities similar to those associated with caloric restriction (CR), such as increased life span and delay in the onset of diseases associated with aging. CR improves neuronal health, and the global beneficial effects of CR have been postulated to be mediated by the nervous system. One key enzyme thought to be activated during CR is the AMP-activated kinase (AMPK), a sensor of cellular energy levels. AMPK is activated by increases in the cellular AMP:ATP ratio, whereupon it functions to help preserve cellular energy. In this regard, the regulation of dietary food intake by hypothalamic neurons is mediated by AMPK. The suppression of nonessential energy expenditure by activated AMPK along with the CR mimetic and neuroprotective properties of resveratrol led us to hypothesize that neuronal activation of AMPK could be an important component of resveratrol activity. Here, we show that resveratrol activated AMPK in Neuro2a cells and primary neurons in vitro as well as in the brain. Resveratrol and the AMPK-activating compound 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) promoted robust neurite outgrowth in Neuro2a cells, which was blocked by genetic and pharmacologic inhibition of AMPK. Resveratrol also stimulated mitochondrial biogenesis in an AMPK-dependent manner. Resveratrol-stimulated AMPK activity in neurons depended on LKB1 activity but did not require the NAD-dependent protein deacetylase SIRT1 during this time frame. These findings suggest that neuronal activation of AMPK by resveratrol could affect neuronal energy homeostasis and contribute to the neuroprotective effects of resveratrol.

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Author and article information

Contributors

Haijia Chen: +86-13922736688 , chenhaijia@saliai.com

Wei Xiang: +86-18608981299 , xiangwei8@163.com

Paul Yao:

ORCID: http://orcid.org/0000-0001-9407-0779

+86-13049687987 , vasilis112@yahoo.com

Journal

Journal ID (nlm-ta): Mol Autism

Journal ID (iso-abbrev): Mol Autism

Title: Molecular Autism

Publisher: BioMed Central (London )

ISSN (Electronic): 2040-2392

Publication date (Electronic): 2 August 2018

Publication date PMC-release: 2 August 2018

Publication date Collection: 2018

Volume: 9

Electronic Location Identifier: 43

Affiliations

[1 ]ISNI 0000 0001 2331 6153, GRID grid.49470.3e, Institute of Rehabilitation Center, , Tongren Hospital of Wuhan University, ; Wuhan, 430060 People’s Republic of China

[2 ]SALIAI Stem Cell Institute of Guangdong, Guangzhou SALIAI Stem Cell Science and Technology Co. LTD, Guangzhou, 510055 People’s Republic of China

[3 ]GRID grid.459758.2, Department of Pediatrics, , Hainan Maternal and Child Health Hospital, ; Haikou, 570206 People’s Republic of China

Author information

Paul Yao http://orcid.org/0000-0001-9407-0779

Article

Publisher ID: 225

DOI: 10.1186/s13229-018-0225-5

PMC ID: 6090838

PubMed ID: 30123446

SO-VID: 70c15d77-ce3b-4265-b750-1fb867c2531d

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 5 February 2018

Date accepted : 19 July 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81772097

Custom metadata

ScienceOpen disciplines: Neurosciences

Keywords: autism spectrum disorder,estrogen receptor β,lipid metabolism,mitochondria,oxidative stress,progestin,resveratrol

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ScienceOpen disciplines: Neurosciences

Keywords: autism spectrum disorder, estrogen receptor β, lipid metabolism, mitochondria, oxidative stress, progestin, resveratrol

Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERβ activation

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Most cited references 46

Advances in autism genetics: on the threshold of a new neurobiology.

A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures

Resveratrol stimulates AMP kinase activity in neurons.

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