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Mutational Signatures of a Combined Environmental Exposure: Arsenic and Ultraviolet Radiation

Award Number: R01ES030993
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Over 200 million people worldwide are chronically exposed to arsenic in drinking water at concentrations above the EPA or World Health Organization safety standard. There is strong experimental and epidemiological evidence that low levels of arsenic in combination with other environmental insults such as ultraviolet radiation (UVR) increases carcinogenesis, suggesting arsenic is a co-carcinogen in humans. However, little is known about the molecular mechanisms of arsenic co-carcinogenesis or effective strategies for prevention of arsenic- augmented cancers. Recent advances in analysis of next generation sequencing have given rise to powerful tools to define distinct mutational signatures in tumors that identify specific defects in DNA repair processes or carcinogenic exposures as part of cancer etiology. In current proposed study we will apply this new technology to advance our understanding of arsenic as a co-carcinogen when combined with the DNA damaging UVR. We have published an extensive body of work demonstrating that arsenic interferes with the zinc finger motifs of select DNA repair proteins leading to decreased repair capacity and increased DNA damage and mutations that are alleviated by zinc. A preliminary mutation pattern analysis of normal human keratinocytes exposed to 0.1 µM arsenite, UVR, or both revealed that this low concentration of arsenite was sufficient to enhance UVR- induced C>T mutations and zinc supplement reduced C>T mutations suggesting a potential intervention. Furthermore, the mutational signatures generated by UVR and arsenite differ from those of UVR alone, indicating that arsenite modifies the mutation spectrum rather than simply amplify the UVR signature. Based on our published and preliminary findings, we hypothesize that arsenic enhances UVR-induced skin carcinogenesis by disrupting the zinc finger function of the key DNA repair protein XPA, which in turn, results in deficient nucleotide excision repair leading to greater accumulation of somatic mutations. In Aim 1, we will determine whether exposure to arsenic, UVR or both generates unique mutational signatures and the impact of zinc on identified signatures using whole genome sequencing and advanced computational approaches developed by co-investigator Dr. Alexandrov. Aim 2 will investigate the molecular mechanism of C>T mutation enhancement by arsenic through transcription-coupled nucleotide excision repair inhibition using both biochemical approaches and computational analysis of whole genome sequencing data. In Aim 3, we will use a proven animal model of UVR-induced skin carcinogenesis to define in vivo mutational signatures from UVR- induced tumors with or without arsenic and the impact of zinc on the mutation signature. The outcomes from our rigorously designed studies are expected to provide the first experimental definition of a metal-induced mutation signature and the first analysis of mutational signatures generated by combination exposures to two important and relevant environmental insults, as well as the insights into mechanisms by which arsenic enhances UVR-induced carcinogenesis and how zinc confers protection.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $495,601 )
2024	2024	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	5	2/21/2024	NON-COMPETING CONTINUATION	$495,601
														Subtotal = $495,601

Issue Date FY: 2023 ( Subtotal = $503,327 )
2023	2023	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	001	4	6/28/2023	NON-COMPETING CONTINUATION	$0
2023	2023	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	4	6/16/2023	NON-COMPETING CONTINUATION	$503,327
														Subtotal = $503,327

Issue Date FY: 2022 ( Subtotal = $508,478 )
2022	2022	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	3	1/31/2022	NON-COMPETING CONTINUATION	$508,478
														Subtotal = $508,478

Issue Date FY: 2021 ( Subtotal = $510,966 )
2021	2021	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	2	1/19/2021	NON-COMPETING CONTINUATION	$510,966
														Subtotal = $510,966

Issue Date FY: 2020 ( Subtotal = $523,581 )
2020	2020	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	1	4/3/2020	NEW	$523,581
														Subtotal = $523,581

Grand Total All Awards = $2,541,953

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Mutational Signatures of a Combined Environmental Exposure: Arsenic and Ultraviolet Radiation

Award Number: R01ES030993

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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