title: Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice.
abstract: The epigenetic events imposed during germline reprogramming and affected by harmful exposure can be inherited and transferred to subsequent generations via gametes inheritance. In this study, we examine the transgenerational effects promoted by widely used herbicide atrazine (ATZ). We exposed pregnant outbred CD1 female mice and the male progeny was crossed for three generations with untreated females. We demonstrate here that exposure to ATZ affects meiosis, spermiogenesis and reduces the spermatozoa number in the third generation (F3) male mice. We suggest that changes in testis cell types originate from modified transcriptional network in undifferentiated spermatogonia. Importantly, exposure to ATZ dramatically increases the number of transcripts with novel transcription initiation sites, spliced variants and alternative polyadenylation sites. We found the global decrease in H3K4me3 occupancy in the third generation males. The regions with altered H3K4me3 occupancy in F3 ATZ-derived males correspond to altered H3K4me3 occupancy of F1 generation and 74% of changed peaks in F3 generation are associated with enhancers. The regions with altered H3K4me3 occupancy are enriched in SP family and WT1 transcription factor binding sites. Our data suggest that the embryonic exposure to ATZ affects the development and the changes induced by ATZ are transferred up to three generations.
authors.affiliation: Inserm U1085 IRSET, 9 Avenue du Professeur Léon-Bernard, 35000 Rennes, France.
authors.forename: Chunxiang
authors.initials: C
authors.lastname: Hao
authors.affiliation: Inserm U1085 IRSET, 9 Avenue du Professeur Léon-Bernard, 35000 Rennes, France.|EHESP, 2 Avenue du Professeur Léon-Bernard, 35000 Rennes, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Gely-Pernot
authors.affiliation: Inserm U1085 IRSET, 9 Avenue du Professeur Léon-Bernard, 35000 Rennes, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Kervarrec
authors.affiliation: Inserm U1085 IRSET, 9 Avenue du Professeur Léon-Bernard, 35000 Rennes, France.
authors.forename: Melissa
authors.initials: M
authors.lastname: Boudjema
authors.affiliation: Inserm U1085 IRSET, 9 Avenue du Professeur Léon-Bernard, 35000 Rennes, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Becker
authors.affiliation: Clinical Center, National Institute of Health, Bethesda, MD 20892, USA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Khil
authors.affiliation: University of Florida, Department of Physiological Sciences, Box 100144, 1333 Center Drive, 32610 Gainesville, FL, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Tevosian
authors.affiliation: Inserm U1085 IRSET, 9 Avenue du Professeur Léon-Bernard, 35000 Rennes, France.|EHESP, 2 Avenue du Professeur Léon-Bernard, 35000 Rennes, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Jégou
authors.affiliation: Inserm U1085 IRSET, 9 Avenue du Professeur Léon-Bernard, 35000 Rennes, France fatima.smagulova@inserm.fr.
authors.forename: Fatima
authors.initials: F
authors.lastname: Smagulova
mesh_terms: D000818:Animals; D001280:Atrazine / Q000009:adverse effects*; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D004781:Environmental Exposure / Q000009:adverse effects*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D020869:Gene Expression Profiling; D006540:Herbicides / Q000009:adverse effects*; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000378:metabolism*; D008297:Male; D018811:Maternal Exposure; D008540:Meiosis / Q000187:drug effects; D008745:Methylation / Q000187:drug effects; D051379:Mice; D059372:Nucleotide Motifs; D009928:Organ Specificity / Q000235:genetics; D056510:Position-Specific Scoring Matrices; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011485:Protein Binding; D062085:RNA, Long Noncoding / Q000235:genetics; D013091:Spermatogenesis / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects / Q000378:metabolism; D013737:Testis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D006540:Herbicides; D006657:Histones; D062085:RNA, Long Noncoding; D001280:Atrazine