Regulatory mechanism of perinatal nonylphenol exposure on cardiac mitochondrial autophagy and the PINK1/Parkin signaling pathway in male offspring rats

Feb 17, 2024Phytomedicine : international journal of phytotherapy and phytopharmacology

How early-life nonylphenol exposure affects heart cell cleanup and energy recycling pathways in male rat offspring

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Abstract

Perinatal exposure to nonylphenol (NP) at 100 mg/kg resulted in increased apoptosis and mitochondrial damage in neonatal rat cardiomyocytes.

Mitochondrial swelling and autophagosome-like structures were observed in neonatal rat cardiomyocytes exposed to NP.
Elevated serum myocardial enzyme levels and disorganized fiber arrangement were noted with higher NP dosages.
Increased levels of oxidative stress markers, such as malondialdehyde (MDA), and decreased antioxidant activity (SOD) were found in myocardial tissue.
In vitro exposure to NP was associated with increased reactive oxygen species (ROS) and lactate dehydrogenase (LDH) release, along with decreased ATP levels.
The inhibition of the PINK1/Parkin signaling pathway reduced the expression of key proteins linked to mitochondrial autophagy and apoptosis.

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OBJECTIVE: This study investigated whether perinatal exposure to nonylphenol (NP) induces mitochondrial autophagy (i.e., mitophagy) damage in neonatal rat cardiomyocytes (NRCMs) and whether the PINK1/Parkin signaling pathway is involved in NP-induced primary cardiomyocyte injury.

METHODS AND RESULTS: In vivo: Perinatal NP exposure increased apoptosis and mitochondrial damage in NRCMs. Mitochondrial swelling and autophagosome-like structures with multiple concentric membranes were observed in the 100 mg/kg NP group, with an increase in the number of autophagosomes. Disorganized fiber arrangement and elevated serum myocardial enzyme levels were observed with increasing NP dosage. Additionally, NP exposure led to increased MDA levels and decreased SOD activity and ATP levels in myocardial tissue. The mRNA expression levels of autophagy-related genes, including Beclin-1, p62, and LC3B, as well as the expression of mitochondrial autophagy-related proteins (PINK1, p-Parkin, Parkin, Beclin-1, p62, LC3-I, LC3-II, and LC3-II/I) and apoptosis-related proteins (Bax and caspase-3), increased, whereas the expression levels of the mitochondrial membrane protein TOMM20 and the anti-apoptotic protein Bcl-2 decreased. In vitro: NP increased ROS levels, LDH release, and decreased ATP levels in NRCMs. CsA treatment significantly inhibited the expression of autophagy-related proteins (Beclin-1, LC3-II/I, and p62) and apoptosis-related proteins (caspase-3 and Bax), increased the expression levels of TOMM20 and Bcl-2 proteins, increased cellular ATP levels, and inhibited LDH release. The inhibition of the PINK1/Parkin signaling pathway suppressed the expression of mitochondrial autophagy-related proteins (PINK1, p-Parkin, Parkin, Beclin-1, LC3-II/I, and p62) and apoptosis-related proteins (caspase-3 and Bax), increased TOMM20 and Bcl-2 protein expression, increased ATP levels, and decreased LDH levels in NRCMs.

CONCLUSIONS: This study is novel in reporting that perinatal NP exposure induced myocardial injury in male neonatal rats, thereby inducing mitophagy. The PINK1/Parkin signaling pathway was involved in this injury by regulating mitophagy.

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Regulatory mechanism of perinatal nonylphenol exposure on cardiac mitochondrial autophagy and the PINK1/Parkin signaling pathway in male offspring rats

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