# Melatonin Ameliorates decaBDE-Induced Autism-Relevant Behaviors Through Promoting SIRT1/SIRT3/FOXO3a-Dependent Mitochondrial Quality Control

## TL;DR

Melatonin helps reduce autism-like behaviors in rats exposed to a harmful chemical by improving mitochondrial health through specific molecular pathways.

## Contribution

This study reveals a novel role of melatonin in mitigating PBDE-induced neurodevelopmental issues via the SIRT1/SIRT3/FOXO3a pathway.

## Key findings

- Melatonin improved social and cognitive abilities impaired by BDE-209 exposure in rats.
- Mitochondrial dysfunction caused by BDE-209 was partially reversed by melatonin through SIRT1-dependent pathways.
- Melatonin's protective effects were blocked by the SIRT1 inhibitor EX527, confirming the pathway's involvement.

## Abstract

The etiology of autism spectrum disorder (ASD) implicates genetic predispositions and environmental chemicals, such as polybrominated diphenyl ethers (PBDEs). We aimed to identify whether mitochondrial quality control (MQC) was involved in ASD-relevant behavioral changes induced by decabromodiphenyl ether (deca-BDE, BDE-209) and the alleviation by melatonin. Pregnant rats exposed to BDE-209 (50 mg/kg i.g.) were administrated melatonin through drinking water (0.2 mg/mL) during gestation and lactation. Behavioral assessments integrated open-field test, three-chamber social test, and Morris water maze; mitochondrial detections took transmission electron microscopy, immunofluorescence, and homeostasis together; hippocampal molecular network was identified through transcriptomics profiles, combining dendritic morphology analysis after Golgi-Cox staining. Melatonin supplementation attenuated BDE-209-reduced social and cognitive ability, accompanied by improvements in hippocampal synaptic plasticity (dendritic spines, PSD95, SNAP25). Mitochondrial dysfunctions, shown as decreases in complex IV activity, ATP content, and mtDNA copies, plus redox imbalance (ROS/SOD2) and resultant mitochondrial membrane potential disruption and apoptosis, together with fusion/fission dynamic (MFN2/DRP1), biogenesis (SIRT1-PGC1α-TFAM), and mitophagy (SIRT3-FOXO3-PINK1) suppression, were reversed by melatonin partially through SIRT1 (Sirtuin-1)-dependent pathways, as these protections were abolished by inhibitor EX527. This study highlighted the SIRT1–SIRT3 axis in MQC and behavioral effects, providing novel intervention for PBDEs’ neurodevelopmental impairment.