Prenatal Trimethyltin Exposure Induces Long-Term DNA Methylation Changes in the Male Mouse Hippocampus.

Soon-Ae Kim,Eun-Hye Jang,Jung-Hoon Chai

doi:10.3390/ijms22158009

Soon-Ae Kim, Eun-Hye Jang + Show 1 more

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https://doi.org/10.3390/ijms22158009

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Abstract

Trimethyltin (TMT) is an irreversible neurotoxicant. Because prenatal TMT exposure has been reported to induce behavioral changes, this study was conducted to observe gender differences and epigenetic changes using a mouse model. In behavioral testing of offspring at 5 weeks of age, the total times spent in the center, corner, or border zones in the male prenatal TMT-exposed mice were less than those of control unexposed mice in the open-field test. Female TMT-exposed mice scored lower on total numbers of arm entries and percentages of alternations than controls in the Y-maze test with lower body weight. We found that only TMT-exposed males had fewer copies of mtDNA in the hippocampus and prefrontal cortex region than controls. Additional epigenetic changes, including increased 5-methyl cytosine/5-hydroxymethyl cytosine levels in the male TMT hippocampus, were observed. After methylation binding domain (MBD) sequencing, multiple signaling pathways related to metabolism and neurodevelopment, including FoxO signaling, were identified by pathway analysis for differentially methylated regions (DMRs). Increased FOXO3 and decreased ASCL1 expression were also observed in male TMT hippocampi. This study suggests that sex differences and epigenetics should be more carefully considered in prenatal toxicology studies.

Highlights

Trimethyltin (TMT) accumulates in the body after acute exposure [1]
Others have reported that several human neurodevelopmental disorders, including autism spectrum disorder and attention deficit hyperactivity disorder, show changes in peripheral mitochondrial DNA
The distances traveled by TMT females were significantly less than those of the CON group (p = 0.049), but there were no differences in time spent in the center, along the borders, or the corners

Summary

Introduction

Stannin (Snn) is a highly conserved 88-residue protein that is localized to mitochondria and may mediate the selective toxicity of TMT [2]. TMT exhibits neurotoxic effects that are localized in the limbic system, in the hippocampus, in both experimental animals and accidentally exposed humans [3,4]. Behavioral tests have demonstrated that TMT exposure damages the hippocampus, resulting in memory and learning deficits [5,6]. TMT-exposed rats showed postnatal toxicity and decreased birth weights [7]. Several animal models involving prenatal chemical exposure to substances including valproic acid and TMT for neurodevelopmental disorders have been suggested [8,9]. Others have reported that several human neurodevelopmental disorders, including autism spectrum disorder and attention deficit hyperactivity disorder, show changes in peripheral mitochondrial DNA copy number, which may be related to mitochondrial dysfunction [10,11,12]

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