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Molecular and Metabolic Analysis of Arsenic-Exposed Humanized AS3MT Mice.

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Title: Molecular and Metabolic Analysis of Arsenic-Exposed Humanized AS3MT Mice.
Authors: Todero, Jenna1, Douillet, Christelle2, Shumway, Alexandria J.1, Koller, Beverly H.3, Kanke, Matt1, Phuong, Daryl J.1, Stýblo, Miroslav2, Sethupathy, Praveen1 pr46@cornell.edu
Source: Environmental Health Perspectives. Dec2023, Vol. 131 Issue 12, p127021-1-127021-16. 16p.
Subject Terms: *Animal experimentation, Arsenic metabolism, Biological models, Mann Whitney U Test, MicroRNA, Sex distribution, Rats, Pearson correlation (Statistics), Gene expression, Descriptive statistics, Research funding, Data analysis software, Adipose tissues, Phenotypes
Abstract: BACKGROUND: Chronic exposure to inorganic arsenic (iAs) has been associated with type 2 diabetes (T2D). However, potential sex divergence and the underlying mechanisms remain understudied. iAs is not metabolized uniformly across species, which is a limitation of typical exposure studies in rodent models. The development of a new “humanized” mouse model overcomes this limitation. In this study, we leveraged this model to study sex differences in the context of iAs exposure. OBJECTIVES: The aim of this study was to determine if males and females exhibit different liver and adipose molecular profiles and metabolic phenotypes in the context of iAs exposure. METHODS: Our study was performed on wild-type (WT) 129S6/SvEvTac and humanized arsenic +3 methyl transferase (human AS3MT) 129S6/SvEvTac mice treated with 400 ppb of iAs via drinking water ad libitum. After 1 month, mice were sacrificed and the liver and gonadal adipose depots were harvested for iAs quantification and sequencing-based microRNA and gene expression analysis. Serum blood was collected for fasting blood glucose, fasting plasma insulin, and homeostatic model assessment for insulin resistance (HOMA-IR). RESULTS: We detected sex divergence in liver and adipose markers of diabetes (e.g., miR-34a, insulin signaling pathways, fasting blood glucose, fasting plasma insulin, and HOMA-IR) only in humanized (not WT) mice. In humanized female mice, numerous genes that promote insulin sensitivity and glucose tolerance in both the liver and adipose are elevated compared to humanized male mice. We also identified Klf11 as a putative master regulator of the sex divergence in gene expression in humanized mice. DISCUSSION: Our study underscored the importance of future studies leveraging the humanized mouse model to study iAs-associated metabolic disease. The findings suggested that humanized males are at increased risk for metabolic dysfunction relative to humanized females in the context of iAs exposure. Future investigations should focus on the detailed mechanisms that underlie the sex divergence. [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: Molecular and Metabolic Analysis of Arsenic-Exposed Humanized AS3MT Mice.
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  Data: <searchLink fieldCode="AR" term="%22Todero%2C+Jenna%22">Todero, Jenna</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Douillet%2C+Christelle%22">Douillet, Christelle</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Shumway%2C+Alexandria+J%2E%22">Shumway, Alexandria J.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Koller%2C+Beverly+H%2E%22">Koller, Beverly H.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Kanke%2C+Matt%22">Kanke, Matt</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Phuong%2C+Daryl+J%2E%22">Phuong, Daryl J.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Stýblo%2C+Miroslav%22">Stýblo, Miroslav</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Sethupathy%2C+Praveen%22">Sethupathy, Praveen</searchLink><relatesTo>1</relatesTo><i> pr46@cornell.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Environmental+Health+Perspectives%22">Environmental Health Perspectives</searchLink>. Dec2023, Vol. 131 Issue 12, p127021-1-127021-16. 16p.
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  Data: *<searchLink fieldCode="DE" term="%22Animal+experimentation%22">Animal experimentation</searchLink><br /><searchLink fieldCode="DE" term="%22Arsenic+metabolism%22">Arsenic metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22Biological+models%22">Biological models</searchLink><br /><searchLink fieldCode="DE" term="%22Mann+Whitney+U+Test%22">Mann Whitney U Test</searchLink><br /><searchLink fieldCode="DE" term="%22MicroRNA%22">MicroRNA</searchLink><br /><searchLink fieldCode="DE" term="%22Sex+distribution%22">Sex distribution</searchLink><br /><searchLink fieldCode="DE" term="%22Rats%22">Rats</searchLink><br /><searchLink fieldCode="DE" term="%22Pearson+correlation+%28Statistics%29%22">Pearson correlation (Statistics)</searchLink><br /><searchLink fieldCode="DE" term="%22Gene+expression%22">Gene expression</searchLink><br /><searchLink fieldCode="DE" term="%22Descriptive+statistics%22">Descriptive statistics</searchLink><br /><searchLink fieldCode="DE" term="%22Research+funding%22">Research funding</searchLink><br /><searchLink fieldCode="DE" term="%22Data+analysis+software%22">Data analysis software</searchLink><br /><searchLink fieldCode="DE" term="%22Adipose+tissues%22">Adipose tissues</searchLink><br /><searchLink fieldCode="DE" term="%22Phenotypes%22">Phenotypes</searchLink>
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  Label: Abstract
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  Data: BACKGROUND: Chronic exposure to inorganic arsenic (iAs) has been associated with type 2 diabetes (T2D). However, potential sex divergence and the underlying mechanisms remain understudied. iAs is not metabolized uniformly across species, which is a limitation of typical exposure studies in rodent models. The development of a new “humanized” mouse model overcomes this limitation. In this study, we leveraged this model to study sex differences in the context of iAs exposure. OBJECTIVES: The aim of this study was to determine if males and females exhibit different liver and adipose molecular profiles and metabolic phenotypes in the context of iAs exposure. METHODS: Our study was performed on wild-type (WT) 129S6/SvEvTac and humanized arsenic +3 methyl transferase (human AS3MT) 129S6/SvEvTac mice treated with 400 ppb of iAs via drinking water ad libitum. After 1 month, mice were sacrificed and the liver and gonadal adipose depots were harvested for iAs quantification and sequencing-based microRNA and gene expression analysis. Serum blood was collected for fasting blood glucose, fasting plasma insulin, and homeostatic model assessment for insulin resistance (HOMA-IR). RESULTS: We detected sex divergence in liver and adipose markers of diabetes (e.g., miR-34a, insulin signaling pathways, fasting blood glucose, fasting plasma insulin, and HOMA-IR) only in humanized (not WT) mice. In humanized female mice, numerous genes that promote insulin sensitivity and glucose tolerance in both the liver and adipose are elevated compared to humanized male mice. We also identified Klf11 as a putative master regulator of the sex divergence in gene expression in humanized mice. DISCUSSION: Our study underscored the importance of future studies leveraging the humanized mouse model to study iAs-associated metabolic disease. The findings suggested that humanized males are at increased risk for metabolic dysfunction relative to humanized females in the context of iAs exposure. Future investigations should focus on the detailed mechanisms that underlie the sex divergence. [ABSTRACT FROM AUTHOR]
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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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      – Type: doi
        Value: 10.1289/EHP12785
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      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 16
        StartPage: 127021-1
    Subjects:
      – SubjectFull: Animal experimentation
        Type: general
      – SubjectFull: Arsenic metabolism
        Type: general
      – SubjectFull: Biological models
        Type: general
      – SubjectFull: Mann Whitney U Test
        Type: general
      – SubjectFull: MicroRNA
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      – SubjectFull: Sex distribution
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      – SubjectFull: Rats
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      – SubjectFull: Data analysis software
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      – SubjectFull: Adipose tissues
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      – SubjectFull: Phenotypes
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      – TitleFull: Molecular and Metabolic Analysis of Arsenic-Exposed Humanized AS3MT Mice.
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              M: 12
              Text: Dec2023
              Type: published
              Y: 2023
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