Transgenerational impaired male fertility with an Igf2 epigenetic defect in the rat are induced by the endocrine disruptor p,p'-DDE.

STUDY QUESTION: What are the epigenetic mechanisms underlying the transgenerational effect of p,p'-DDE on male fertility? SUMMARY ANSWER: Impaired male fertility with an Igf2 epigenetic defect is transgenerationally inherited upon exposure of p,p'-DDE. WHAT IS KNOWN ALREADY: p,p'-Dichlorodiphenoxydichloroethylene (p,p'-DDE) is one of the primary metabolite products of the ancestral organochlorine pesticide dichlorodiphenoxytrichloroethane. As it is a known anti-androgen endocrine disruptor, it could cause harmful effects on the male reproductive system. STUDY DESIGN, SIZE, DURATION: Pregnant rats (F0) were administered with p,p'-DDE or corn oil at the critical time of testis development, i.e. from gestation days 8 to 15. Male and female rats of the F1 generation were mated with each other to produce F2 progeny. To reveal whether the transgenerational phenotype is produced by the maternal or paternal line, F3 progeny were generated by intercrossing control (C) and treated (DDE) males and females of the F2 generation according to the following groups: (i) C♂-C♀, (ii) DDE♂-DDE♀, (iii) DDE♂-C♀ and (iv) C♂-DDE♀. PARTICIPANTS/MATERIALS, SETTING,
METHODS: Mature sperm and testes were collected from male offspring of the F1-F3 generations for the examination of male fertility parameters, i.e. sperm count and motility, testis histology and apoptosis. Expression of the imprinted genes, H19 and Igf2, was detected by real-time PCR. Igf2 DMR2 methylation was analyzed by bisulfite genomic sequencing. MAIN RESULTS AND THE ROLE OF CHANCE: Upon exposure of p,p'-DDE, the male F1 generation showed impaired male fertility and altered imprinted gene expression caused by Igf2 DMR2 hypomethylation. These defects were transferred to the F3 generation through the male germline. LIMITATIONS, REASONS FOR CAUTION: This study has examined the effect of p,p'-DDE only on the sperm number and motility and the possible mechanism of Igf2 DMR2 methylation in vivo and thus has some limitations. Further investigation is necessary to focus on the epigenetic effects of p,p'-DDE at the genome level and to include a more detailed semen quality analysis including sperm morphology assessment. WIDER IMPLICATIONS OF THE
FINDINGS: Impaired male fertility with epigenetic alterations is transgenerationally inherited after environmental exposure of p,p'-DDE, posing significant implications in the etiology of male infertility. STUDY FUNDING/COMPETING INTERESTS: The present research was supported by National Natural Science Fund for Young Scholar (81102161), the Natural Science Fund of Zhejiang Province (LY14H260004) and funding from the Health Department of Zhejiang Province (201475777). No competing interests are declared.