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Environmentally Relevant Doses of Bisphenol A and S Exposure In Utero Disrupt Germ Cell Programming across Generations Resolved by Single Nucleus Multiomics.

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Title: Environmentally Relevant Doses of Bisphenol A and S Exposure In Utero Disrupt Germ Cell Programming across Generations Resolved by Single Nucleus Multiomics.
Authors: Liang Zhao1,2, Mingxin Shi1, Winuthayanon, Sarayut3, MacLean II, James A.1, Law, Nathan C.1, Kanako Hayashi1 k.hayashi@wsu.edu
Source: Environmental Health Perspectives. Jun2026, Vol. 134 Issue 2, p210-226. 17p.
Subject Terms: *Phenols, *Animal experimentation, Maternal exposure, Germ cells, Prenatal exposure delayed effects, Data analysis, Research funding, Multiomics, Epigenomics, Polymerase chain reaction, Mann Whitney U Test, Descriptive statistics, Mice, Experimental design, Immunohistochemistry, One-way analysis of variance, Statistics, Sperm motility, Comparative studies, Stains & staining (Microscopy), Data analysis software, Sperm count, Sequence analysis, Fetus, Pregnancy
Abstract: BACKGROUND: Exposure to endocrine-disrupting chemicals (EDCs), such as bisphenol (BP) A, disrupts reproduction across generations. Germ cell epigenetic alterations are proposed to mediate these transgenerational defects. Previously, we have shown that prenatal exposure to environmentally relevant doses of BPA or its substitute, BPS, caused transgenerationally maintained reproductive impairments associated with neonatal spermatogonial epigenetic changes in male mice. However, the mechanisms sustaining these changes across generations remain unclear. OBJECTIVES: This study aimed to systematically elucidate the mechanism of transgenerational inherence by prenatal BPA and BPS exposure in the murine germline from F1 to F3 generations at both transcriptomic and epigenetic levels. METHODS: Pregnant CD-1 females (F0) were orally administered BPA or BPS at doses of 0 (vehicle control), 0.5, 50, or 1000 μg/kg/b.w./day from gestational day 7 to birth. Sperm counts and motility were examined in F1, F2, and F3 adult males. THY1+ germ cells on postnatal day 6 from F1, F2, and F3 males at a dose of 50 μg/kg/b.w./day were used for analysis by single-nucleus (sn) multiomics (paired snRNA-seq and snATAC-seq on the same nucleus). RESULTS: Prenatal exposure to BPA and BPS with 0.5, 50, and 1000 μg/kg/b.w./day reduced sperm counts in mice across F1 to F3 generations. In the F1 generation, BPA or BPS exposure with 50 μg/kg/b.w./day disrupted the balance between maintaining the undifferentiated and differentiating spermatogonial populations. Differentially accessible peaks (DAPs) by snATACseq were primarily located in the promoter regions, with elevated activity of key transcription factors, including SP1, SP4, and DMRT1. Notably, similar gene expression and chromatin changes were observed in directly exposed F1 and F2 generations but differed in the indirectly exposed F3 generation. Approximately 80% of DAPs in F1 and F2 spermatogonia overlapped with histone post-translational modifications linked to transcription activation (e.g., H3K4me1/2/3 and H3K27ac). Across F1 to F3 generations, although BPA exerted more potent effects on gene expression in F1 spermatogonia, BPS induced longer-lasting effects. Interestingly, DMRT1 motif activity was persistently elevated in all three generations following ancestral BPA or BPS exposure. DISCUSSION: Our work provides the first systematic analyses of transgenerational gene and chromatin dynamics following prenatal exposure to BPA or BPS. These results suggest that prenatal exposure to environmentally relevant doses of BPA or BPS alters chromatin accessibility and transcription factor motif activities, consequently contributing to disrupted transcriptional levels in neonatal spermatogonia, and some are sustained to F3 generations, ultimately leading to the reduction of sperm counts in adults. [ABSTRACT FROM AUTHOR]
Copyright of Environmental Health Perspectives is the property of National Institute of Environmental Health Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Environmentally Relevant Doses of Bisphenol A and S Exposure In Utero Disrupt Germ Cell Programming across Generations Resolved by Single Nucleus Multiomics.
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  Data: <searchLink fieldCode="AR" term="%22Liang+Zhao%22">Liang Zhao</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Mingxin+Shi%22">Mingxin Shi</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Winuthayanon%2C+Sarayut%22">Winuthayanon, Sarayut</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22MacLean+II%2C+James+A%2E%22">MacLean II, James A.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Law%2C+Nathan+C%2E%22">Law, Nathan C.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Kanako+Hayashi%22">Kanako Hayashi</searchLink><relatesTo>1</relatesTo><i> k.hayashi@wsu.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Environmental+Health+Perspectives%22">Environmental Health Perspectives</searchLink>. Jun2026, Vol. 134 Issue 2, p210-226. 17p.
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  Data: *<searchLink fieldCode="DE" term="%22Phenols%22">Phenols</searchLink><br />*<searchLink fieldCode="DE" term="%22Animal+experimentation%22">Animal experimentation</searchLink><br /><searchLink fieldCode="DE" term="%22Maternal+exposure%22">Maternal exposure</searchLink><br /><searchLink fieldCode="DE" term="%22Germ+cells%22">Germ cells</searchLink><br /><searchLink fieldCode="DE" term="%22Prenatal+exposure+delayed+effects%22">Prenatal exposure delayed effects</searchLink><br /><searchLink fieldCode="DE" term="%22Data+analysis%22">Data analysis</searchLink><br /><searchLink fieldCode="DE" term="%22Research+funding%22">Research funding</searchLink><br /><searchLink fieldCode="DE" term="%22Multiomics%22">Multiomics</searchLink><br /><searchLink fieldCode="DE" term="%22Epigenomics%22">Epigenomics</searchLink><br /><searchLink fieldCode="DE" term="%22Polymerase+chain+reaction%22">Polymerase chain reaction</searchLink><br /><searchLink fieldCode="DE" term="%22Mann+Whitney+U+Test%22">Mann Whitney U Test</searchLink><br /><searchLink fieldCode="DE" term="%22Descriptive+statistics%22">Descriptive statistics</searchLink><br /><searchLink fieldCode="DE" term="%22Mice%22">Mice</searchLink><br /><searchLink fieldCode="DE" term="%22Experimental+design%22">Experimental design</searchLink><br /><searchLink fieldCode="DE" term="%22Immunohistochemistry%22">Immunohistochemistry</searchLink><br /><searchLink fieldCode="DE" term="%22One-way+analysis+of+variance%22">One-way analysis of variance</searchLink><br /><searchLink fieldCode="DE" term="%22Statistics%22">Statistics</searchLink><br /><searchLink fieldCode="DE" term="%22Sperm+motility%22">Sperm motility</searchLink><br /><searchLink fieldCode="DE" term="%22Comparative+studies%22">Comparative studies</searchLink><br /><searchLink fieldCode="DE" term="%22Stains+%26+staining+%28Microscopy%29%22">Stains & staining (Microscopy)</searchLink><br /><searchLink fieldCode="DE" term="%22Data+analysis+software%22">Data analysis software</searchLink><br /><searchLink fieldCode="DE" term="%22Sperm+count%22">Sperm count</searchLink><br /><searchLink fieldCode="DE" term="%22Sequence+analysis%22">Sequence analysis</searchLink><br /><searchLink fieldCode="DE" term="%22Fetus%22">Fetus</searchLink><br /><searchLink fieldCode="DE" term="%22Pregnancy%22">Pregnancy</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: BACKGROUND: Exposure to endocrine-disrupting chemicals (EDCs), such as bisphenol (BP) A, disrupts reproduction across generations. Germ cell epigenetic alterations are proposed to mediate these transgenerational defects. Previously, we have shown that prenatal exposure to environmentally relevant doses of BPA or its substitute, BPS, caused transgenerationally maintained reproductive impairments associated with neonatal spermatogonial epigenetic changes in male mice. However, the mechanisms sustaining these changes across generations remain unclear. OBJECTIVES: This study aimed to systematically elucidate the mechanism of transgenerational inherence by prenatal BPA and BPS exposure in the murine germline from F1 to F3 generations at both transcriptomic and epigenetic levels. METHODS: Pregnant CD-1 females (F0) were orally administered BPA or BPS at doses of 0 (vehicle control), 0.5, 50, or 1000 μg/kg/b.w./day from gestational day 7 to birth. Sperm counts and motility were examined in F1, F2, and F3 adult males. THY1+ germ cells on postnatal day 6 from F1, F2, and F3 males at a dose of 50 μg/kg/b.w./day were used for analysis by single-nucleus (sn) multiomics (paired snRNA-seq and snATAC-seq on the same nucleus). RESULTS: Prenatal exposure to BPA and BPS with 0.5, 50, and 1000 μg/kg/b.w./day reduced sperm counts in mice across F1 to F3 generations. In the F1 generation, BPA or BPS exposure with 50 μg/kg/b.w./day disrupted the balance between maintaining the undifferentiated and differentiating spermatogonial populations. Differentially accessible peaks (DAPs) by snATACseq were primarily located in the promoter regions, with elevated activity of key transcription factors, including SP1, SP4, and DMRT1. Notably, similar gene expression and chromatin changes were observed in directly exposed F1 and F2 generations but differed in the indirectly exposed F3 generation. Approximately 80% of DAPs in F1 and F2 spermatogonia overlapped with histone post-translational modifications linked to transcription activation (e.g., H3K4me1/2/3 and H3K27ac). Across F1 to F3 generations, although BPA exerted more potent effects on gene expression in F1 spermatogonia, BPS induced longer-lasting effects. Interestingly, DMRT1 motif activity was persistently elevated in all three generations following ancestral BPA or BPS exposure. DISCUSSION: Our work provides the first systematic analyses of transgenerational gene and chromatin dynamics following prenatal exposure to BPA or BPS. These results suggest that prenatal exposure to environmentally relevant doses of BPA or BPS alters chromatin accessibility and transcription factor motif activities, consequently contributing to disrupted transcriptional levels in neonatal spermatogonia, and some are sustained to F3 generations, ultimately leading to the reduction of sperm counts in adults. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
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  Data: <i>Copyright of Environmental Health Perspectives is the property of National Institute of Environmental Health Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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    Identifiers:
      – Type: doi
        Value: 10.1021/EHP.6c00322
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      – Code: eng
        Text: English
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        PageCount: 17
        StartPage: 210
    Subjects:
      – SubjectFull: Phenols
        Type: general
      – SubjectFull: Animal experimentation
        Type: general
      – SubjectFull: Maternal exposure
        Type: general
      – SubjectFull: Germ cells
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      – SubjectFull: Prenatal exposure delayed effects
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      – SubjectFull: Data analysis
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      – SubjectFull: Research funding
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      – SubjectFull: Multiomics
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      – SubjectFull: Epigenomics
        Type: general
      – SubjectFull: Polymerase chain reaction
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      – SubjectFull: Mann Whitney U Test
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      – SubjectFull: Descriptive statistics
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      – SubjectFull: Mice
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      – TitleFull: Environmentally Relevant Doses of Bisphenol A and S Exposure In Utero Disrupt Germ Cell Programming across Generations Resolved by Single Nucleus Multiomics.
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              Text: Jun2026
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