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Genetic Resistance to DEHP-Induced Transgenerational

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Genetic Resistance to DEHP-Induced Transgenerational bioRxiv preprint doi: https://doi.org/10.1101/474155; this version posted November 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Genetic resistance to DEHP-induced 2 transgenerational endocrine disruption 3 Ludwig Stenz1*, Rita Rahban1, Julien Prados2,3, Serge Nef1, Ariane Paoloni- 4 Giacobino1 5 1 Department of Genetic Medicine and Development, 6 2 Department of Microbiology and Molecular Medicine, 7 3 Department of Neuroscience, 8 University of Geneva Faculty of Medicine, Geneva, Switzerland 9 Short title: Transgenerational endocrine disruption 10 11 *Corresponding author: 12 E-mail: [email protected] (LS) 13 14 1 bioRxiv preprint doi: https://doi.org/10.1101/474155; this version posted November 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 15 Abstract 16 Di(2-ethylhexyl)phthalate (DEHP) interferes with sex hormones signaling pathways 17 (SHP). C57BL/6J mice prenatally exposed to DEHP develop a testicular dysgenesis 18 syndrome (TDS) at adulthood, but similarly-exposed FVB/N mice are not affected. 19 Here we aim to understand the reasons behind this drastic difference that should 20 depend on the genome of the strain. In both backgrounds, pregnant female mice 21 received per os either DEHP or corn oil vehicle and the male filiations were 22 examined. Computer-assisted sperm analysis showed a DEHP-induced decreased 23 sperm count and velocities in C57BL/6J. Sperm RNA sequencing experiments 24 resulted in the identification of the 62 most differentially expressed RNAs. These 25 RNAs, mainly regulated by hormones, produced strain-specific transcriptional 26 responses to prenatal exposure to DEHP; a pool of RNAs was increased in FVB, 27 another pool of RNAs was decreased in C57BL/6J. In FVB/N, analysis of non- 28 synonymous SNP impacting SHP identified rs387782768 and rs387782768 29 respectively associated with absence of the Forkhead Box A3 (Foxa3) RNA and 30 increased expression of estrogen receptor 1 variant 4 (NM_001302533) RNA. 31 Analysis of the role of SNPs modifying SHP binding sites in function of strain-specific 32 responses to DEHP revealed a DEHP-resistance allele in FVB/N containing an 33 additional FOXA1-3 binding site at rs30973633 and four DEHP-induced beta- 34 defensins (Defb42, Defb30, Defb47 and Defb48). A DEHP-susceptibility allele in 35 C57BL/6J contained five SNPs (rs28279710, rs32977910, rs46648903, rs46677594 36 and rs48287999) affecting SHP and six genes (Svs2, Svs3b, Svs4, Svs3a, Svs6 and 37 Svs5) epigenetically silenced by DEHP. Finally, targeted experiments confirmed 38 increased methylation in the Svs3ab promoter with decreased SEMG2 persisting 2 bioRxiv preprint doi: https://doi.org/10.1101/474155; this version posted November 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 39 across generations, providing a molecular explanation for the transgenerational 40 sperm velocity decrease found in C57BL/6J after DEHP exposure. We conclude that 41 the existence of SNP-dependent mechanisms in inbred mice may confer resistance 42 to transgenerational endocrine disruption. 43 Keywords: Endocrine, disruption, transgenerational, motility, sperm, RNA, DEHP, 44 beta-defensins, semenogelin 45 3 bioRxiv preprint doi: https://doi.org/10.1101/474155; this version posted November 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 46 Introduction 47 Genetic factors combined with epigenetic mechanisms disrupting androgen actions 48 during fetal life may result in testicular dysgenesis syndrome (TDS) at adulthood. 49 TDS is characterized by poor semen quality, urogenital malformations and testicular 50 cancers [1]. Phthalate plasticizers are well-described detrimental environmental 51 factors interfering with androgen actions and considered as repro-toxic. Both di-(2- 52 ethylhexyl) phthalate (DEHP; CAS No. 117-81-7) and its principal metabolite, mono- 53 (2-ethylhexyl) phthalate (MEHP; CAS No. 4376-20-9) interact with the androgen 54 (AR), estrogen (ER) and peroxisome proliferator-activated receptors (PPARs), with a 55 negative impact on testosterone production [2, 3]. Multiple direct effects at the 56 molecular level of both DEHP and its metabolite were observed in vitro by using a 57 reporter assay with human cell lines on the estrogen receptor (ESR1) and on AR [2]. 58 Accumulated data thus demonstrate that DEHP interferes with sex steroid hormone 59 signaling pathways (SHP). 60 The impact of prenatal exposure to DEHP on human reproductive health at 61 adulthood remains largely unknown as human prospective studies testing such 62 associations are lacking. However, an increasing body of evidence shows that 63 prenatal exposure to DEHP may cause androgen deficiency during embryogenesis, 64 with effects in animal models reproducing those observed in humans. First, a direct 65 negative impact of DEHP on testosterone production was reported in the rat fetal 66 testis after prenatal exposure to DEHP, as well as in human testis explants cultured 67 with DEHP or MEHP [4, 5]. Second, meta-analyses in human studies resulted in a 68 statistically significant association between maternal urinary concentrations of DEHP 69 metabolites and a shortened anogenital distance (AGD) in boys, consistent with the 4 bioRxiv preprint doi: https://doi.org/10.1101/474155; this version posted November 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 70 statistically significant association obtained between DEHP treatment and reduced 71 AGD in animal meta-analysis [6]. Currently, AGD remains the best marker of fetal 72 androgen exposure in humans [7]. DEHP and MEHP concentrations in maternal 73 urine during pregnancy, as well as in umbilical cords, were associated with a reduced 74 AGD in male newborns, but also with a shortened gestation period [8, 9]. 75 Interestingly, a dose-response gradient and heterogeneity explained by strains were 76 observed in animal studies [6]. Our previous studies in mice suggest that genetic 77 variations may explain a strain-dependent alteration in adult sperm induced by 78 prenatal exposure to DEHP, probably causing an endocrine disruption during the 79 development of the embryo. We administered DEHP to pregnant C57BL/6J and 80 FVB/N inbred mice strains to evaluate the impact of prenatal exposure to DEHP on 81 sperm counts, as well as on the epigenetic status of the male gametes produced at 82 adulthood by the first filial generation of exposed animals (F1) [10]. DEHP was 83 injected per os to pregnant mice at the dose of 300 mg/kg/day and during embryonic 84 (E) days (E9-19). The dose was chosen from a previous study and appears to be 85 relevant for extreme human exposure, corresponding to 16 mg/kg/day of direct 86 exposure in preterm infants treated in neonatal intensive care units, when taking into 87 account all maternal barriers existing between the injection site and the embryos in 88 the mice model [11]. The exposure time frame extends from the primordial germ cell 89 (PGC) migration period (~E10.5) and covers the gonadal differentiation period 90 initiated between E11 and E12 in the developing mice embryos, representing a 91 susceptible time window for androgen interference. In our previous study, a 92 decreased sperm count was observed in the C57BL/6J strain, but not in FVB/N mice, 93 indicating that the latter seem to be resistant and the former sensitive to DEHP [10]. 5 bioRxiv preprint doi: https://doi.org/10.1101/474155; this version posted November 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 94 Thus, we postulated that genomic variations should be responsible for strain-specific 95 impacts. 96 Both DNA methylation and RNA expression may be affected in the sperm of mice 97 prenatally exposed to DEHP. We showed that PGCs were present at the time of 98 DEHP exposure. PGCs are characterized by a specific pattern of DNA methylation 99 and transcription controlling the cell fate in the lineage and involving notably genes 100 required for pluripotency, as well as germline-specific genes. PGCs differentiate 101 themselves in male germ cells during the fetal androgen-dependent sexual 102 differentiation of the somatic gonads to testis. At puberty, a peak of testosterone 103 triggers the spermatogenesis process starting from the spermatogonia. The latter is 104 derived from the male fetal germ cell by mechanisms still poorly understood. The 105 spermatogenesis involves transcriptional patterns specific to the successive 106 developmental stages from spermatogonia to spermatozoa [12]. Spermatogonia 107 undergo mitotic divisions with incomplete cytokinesis in the testis, producing 108 spermatids in the lumen of the seminiferous tubule, then maturing in spermatozoa in 109 the epididymis. Mature spermatozoa located in the cauda epididymis are those with 110 the ability to fertilize an egg naturally after ejaculation. In mature sperm, RNAs 111 remain present despite inactive transcription, with some deeply embedded in the 112 sperm nucleus.
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