title: Transgenerational impaired male fertility with an Igf2 epigenetic defect in the rat are induced by the endocrine disruptor p,p'-DDE.
abstract: OBJECTIVE
  What are the epigenetic mechanisms underlying the transgenerational effect of p,p'-DDE on male fertility?
  
  
  CONCLUSIONS
  Impaired male fertility with an Igf2 epigenetic defect is transgenerationally inherited upon exposure of p,p'-DDE.
  
  
  BACKGROUND
  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.
  
  
  METHODS
  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♀.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
authors.affiliation: Hygiene Institute in Zhejiang Academy of Medical Sciences, 182 Tianmushan Road, Hangzhou 310013, China sygp_0@163.com wunanxiang@hotmail.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.affiliation: Hygiene Institute in Zhejiang Academy of Medical Sciences, 182 Tianmushan Road, Hangzhou 310013, China sygp_0@163.com wunanxiang@hotmail.com.
authors.forename: Nanxiang
authors.initials: N
authors.lastname: Wu
authors.affiliation: Hygiene Institute in Zhejiang Academy of Medical Sciences, 182 Tianmushan Road, Hangzhou 310013, China.
authors.forename: Simeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Hygiene Institute in Zhejiang Academy of Medical Sciences, 182 Tianmushan Road, Hangzhou 310013, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.affiliation: Hygiene Institute in Zhejiang Academy of Medical Sciences, 182 Tianmushan Road, Hangzhou 310013, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Song
authors.affiliation: Hygiene Institute in Zhejiang Academy of Medical Sciences, 182 Tianmushan Road, Hangzhou 310013, China.
authors.forename: Jianlin
authors.initials: J
authors.lastname: Lou
authors.affiliation: Hygiene Institute in Zhejiang Academy of Medical Sciences, 182 Tianmushan Road, Hangzhou 310013, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Hygiene Institute in Zhejiang Academy of Medical Sciences, 182 Tianmushan Road, Hangzhou 310013, China.
authors.forename: Kecheng
authors.initials: K
authors.lastname: Liu
mesh_terms: D000818:Animals; D003633:Dichlorodiphenyl Dichloroethylene / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D007248:Infertility, Male / Q000235:genetics*; D007306:Insecticides / Q000494:pharmacology*; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics; D051381:Rats; D013076:Sperm Count; D013081:Sperm Motility / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects; D013737:Testis / Q000187:drug effects
chemical_list: D007306:Insecticides; D003633:Dichlorodiphenyl Dichloroethylene; D007335:Insulin-Like Growth Factor II
keywords: Igf2; male fertility; methylation; p,p′-DDE; transgeneration