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Mol Autism. 2018 Aug 2;9:43. doi: 10.1186/s13229-018-0225-5. eCollection 2018.

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

Author information

1
1Institute 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
3Department of Pediatrics, Hainan Maternal and Child Health Hospital, Haikou, 570206 People's Republic of China.
#
Contributed equally

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.

KEYWORDS:

Autism spectrum disorder; Estrogen receptor β; Lipid metabolism; Mitochondria; Oxidative stress; Progestin; Resveratrol

PMID:
30123446
PMCID:
PMC6090838
DOI:
10.1186/s13229-018-0225-5
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The animal protocol conformed to the US NIH guidelines (Guide for the Care and Use of Laboratory Animals, No. 85–23, revised 1996) and was reviewed and approved by the Institutional Animal Care and Use Committee from Wuhan University. Not applicable. Authors including Drs Xiaohu Ge, Xiaoyan Wang, Yifei Wang, and Haijia Chen, were employed by the company Guangzhou SALIAI Stem Cell Science and Technology Co. LTD. All other authors declare that they have no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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