Perinatal exposure to low dose 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) alters sperm DNA methylation in adult rats

Suvorov, Alexander; Shershebnev, Alex; Wu, Haotian; Medvedeva, Yulia A.; Sergeyev, Oleg; Pilsner, J. Richard

doi:10.1016/j.reprotox.2017.10.009

Cited by 37 publications

(14 citation statements)

References 67 publications

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“…Collectively, our findings demonstrate that two common endocrine disruptors are capable of causing aberrant DNA methylation of CpG islands in sperm and the brain and that a few of these sites are faithfully transmitted for multiple generations. EDC exposure has been shown to be associated with altered DNA methylation in humans for dioxins [78], flame retardants like organophosphates [44] and polybrominated diphenyl ethers [79], phthalates [80], and PCBs [81]. To our knowledge, a similar study has not been performed for VIN in humans.…”

Section: Discussionmentioning

confidence: 84%

Passing experiences on to future generations: endocrine disruptors and transgenerational inheritance of epimutations in brain and sperm

et al. 2018

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All animals have body burdens of polychlorinated biphenyls (PCBs) despite their ban decades ago. These and modern endocrine-disrupting chemicals (EDCs) such as the fungicide vinclozolin (VIN) perturb hormone signaling and lead to dysfunctions following prenatal exposures. Beyond direct exposures, transgenerational disease phenotypes can persist for multiple generations without subsequent exposure. The mechanisms of action of these EDCs differ: VIN is anti-androgenic while the PCB mixture Aroclor 1221 (A1221) is weakly estrogenic. Based on limited evidence for the inheritance of epimutations in germline, we measured DNA methylation in brain and sperm of rats. Pregnant dams were exposed from day 8-18 of gestation to low dosages of VIN, A1221, or the vehicle. To produce paternal lineages, exposed F1 males were bred with untreated females, creating the F2 and subsequently F3 generations. In adult F1 and F3 males, mature sperm was collected, and brain nuclei involved in anxiety and social behaviors (CA3 of the hippocampus; central amygdala) were selected for assays of epimutations in CpG islands using reduced representation bisulfite sequencing. In F1 sperm, VIN and PCBs induced differential methylation in 215 and 284 CpG islands, respectively, compared to vehicle. The majority of effects were associated with hypermethylation. Fewer epimutations were detected in the brain. A subset of differentially methylated regions were retained from the F1 to the F3 generation, suggesting a common mechanism of EDC and germline epigenome interaction. Thus, EDCs can cause heritable epimutations in the sperm that may embody the future phenotype of brain-behavior disorders caused by direct or transgenerational exposures. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 84%

Passing experiences on to future generations: endocrine disruptors and transgenerational inheritance of epimutations in brain and sperm

et al. 2018

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“…For example, Pb exposure altered DNA methylation in both the present generation [36] and the offspring [37]. The PBDE exposure formed DNA adducts [38] and disturbed the microRNA profiling [39] in the present generation and altered the DNA methylation and histone-protamine exchange in offspring adults [15,16]. The epigenetic changes underlying the transgenerational effects might also contribute to the interactions.…”

Section: Transgenerational Effects Between Individual and Sequential mentioning

confidence: 99%

“…Regarding the persistence, PBDE and Pb showed long-term influences over generations. Perinatal exposure to 2,2′,4,4′-tetra-brominated diphenyl ether (BDE47) significantly damaged the normal spermatogenesis of adult rats [15,16]. Lead (Pb) inhibited the growth of daughters (F1) of Caenorhabditis elegans more than that of parents (F0) [17].…”

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confidence: 99%

Transgenerational effects of different sequential exposure to 2,2′,4,4′-tetra-brominated diphenyl ether (BDE47) and lead (Pb) on Caenorhabditis elegans

Zhang

2020

Environ Sci Eur

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Background: Poly-brominated diphenyl ethers (PBDEs) and heavy metals are persistent pollutants in Yangtze River basin, China and also around the globe. In the exposure reality, they may have sequential exposures and long-term outcomes. Yet, the effects combining these two aspects remained largely unexplored. At present, the effects of 2,2′,4,4′-tetra-brominated diphenyl ether (BDE47) and lead (Pb) on Caenorhabditis elegans were studied with two sequential arrangements. One was first exposure to BDE47 and then to Pb (or vice versa) in one generation, and the other one was an early exposure to BDE47 in the parent generation (F0) and then a later exposure to Pb in the offspring (F1) (or vice versa). Results: On growth, sequential Pb-BDE47 exposure caused inhibition in exposure but stimulation in recovery, showing similarity to individual Pb results. Meanwhile, the opposite sequential BDE47-Pb exposure showed inhibition in both exposure and recovery, similar to those of individual BDE47 results. On behavior, the effects of sequential exposure were significantly different from individual results without any similarity. In transgenerational effects, F0 Pb exposure with F1 BDE47 exposure (Pb-F1-BDE47) inhibited growth, similar to the transgenerational results of individual Pb exposure. Meanwhile, the recovery effects were similar to the transgenerational results of individual BDE47. At the same time, Pb-F1-BDE47 exposure significantly hindered the recovery of behavior while the opposite BDE47-F1-Pb exposure resulted in different results. The behavioral effects in F1 showed negative correlation with the contents of γ-aminobutyric acid (GABA), while those in F1 were positively correlated with the activities of acetylcholine esterase (AChE). Conclusions: Sequential exposure to BDE47 and Pb within one generation or over generations showed significant different effects from individual results. Further studies are still needed to investigate the toxicity patterns and underlying mechanisms.

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“…With existing trend for delayed parenthood and ever expanding preconception period of paternal exposure to environmental stressors it is important to understand effects of age and environmental factors on the sperm epigenome. Therefore, we utilized existing data from our previous study that examined the effects of perinatal exposure to 2,2',4,4'tetrabromodiphenylether (BDE-47), the most ubiquitous congener of polybrominated diphenyl ethers (PBDE), on the sperm methylome in adult rat offspring (Suvorov et al, 2018). In this study, perinatal BDE-47 exposure resulted in 21 and 9 differentially methylated regions (DMRs) in sperm collected on postnatal day (PND) 65 and PND120, respectively (Suvorov et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Aging-induced Changes in Sperm DNA Methylation are Modified by Low Dose of Perinatal Flame retardants

Pilsner

Shershebnev

et al. 2020

Preprint

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Advanced paternal age at fertilization has been suggested to be a risk factor for neurodevelopmental, psychiatric and other disorders in offspring. One emerging hypothesis suggests that altered offspring phenotype is linked with age-related accumulation of epigenetic changes in the sperm of fathers. Given that paternal age is increasing in the developed world, understanding aging-related epigenetic changes in sperm is needed as well as environmental factors that modify such changes. In this study, we characterize age-dependent changes in sperm DNA methylation profiles between young pubertal (postnatal day (PNDs) 65) and mature (PND120) Wistar rats. We also analyze these changes in rats exposed perinatally to 0.2 mg/kg of ubiquitous environmental xenobiotic 2,2’,4,4’-tetrabromodiphenyl ether (BDE-47). Reduced representation bisulfite sequencing (RRBS) libraries were prepared from caudal epididymal sperm DNA and differentially methylated regions (DMRs; ≥ 10x coverage depth, ≥ 3 CpGs per cluster, ≥ 5% methylation change, q < 0.05) were identified via MethPipe package. In control animals, 5,319 age-dependent DMRs were identified, with 99.3% DMRs hypermethylated in mature animals compared to young pubertal rats. These age-related DMRs were enriched for functional categories essential for embryonic development, such as pattern specification, forebrain and sensory organ development, Hippo and Wnt pathways. Age-related changes in sncRNA, reported in different study, target similar list of genes and biological categories.In BDE-47 exposed rats, sperm DNA methylation was higher in young pubertal and lower in mature animals when compared to controls, which resulted in a significant attenuation in the number of age-dependent DMRs (N = 189) identified in the exposed group. In conclusion, our results indicate that the natural aging process has profound effects on sperm methylation levels and this effect may be modified by environmental exposures. Moreover, our results further support the role of epigenetic mechanisms as a likely link betwen paternal age and offspring health and development.

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Perinatal exposure to low dose 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) alters sperm DNA methylation in adult rats

Cited by 37 publications

References 67 publications

Passing experiences on to future generations: endocrine disruptors and transgenerational inheritance of epimutations in brain and sperm

Passing experiences on to future generations: endocrine disruptors and transgenerational inheritance of epimutations in brain and sperm

Transgenerational effects of different sequential exposure to 2,2′,4,4′-tetra-brominated diphenyl ether (BDE47) and lead (Pb) on Caenorhabditis elegans

Aging-induced Changes in Sperm DNA Methylation are Modified by Low Dose of Perinatal Flame retardants

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