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Prenatal arsenic exposure alters transcriptional, post-transcriptional and post-translational programming of the glucocorticoid system in a sexually dimorphic manner

Award Number: R01ES019583
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 Developmental exposure to inorganic arsenic has been associated with several adverse health effects, including reduction in cognitive performance and increased rates of psychiatric disorders. Altered programming of the glucocorticoid receptor (GR) could account for many of the long-lasting consequences of arsenic. While the impact of arsenic exposure on the epigenome has been studied in the context of cancer research, the influence of this toxicant in the developing brain, particularly as it relates to epigenetics, is not well understood. In our previous work, we found that male offspring exposed to 50 ppb arsenic prenatally (PAE) had decreased expression of both GR protein and mRNA in brain. Female PAE mice were resistant to arsenic induced changes in GR protein despite elevations in GR (Nr3c1) mRNA. In assessing epigenetic mechanisms, we found PAE affected levels of histone3 lysine4 trimethylation (H3K4me3) as well as several noncoding RNAs (miRs and lncRNA) in a sex-dependent manner. The goal of this competing renewal is to demonstrate that changes in transcriptional, posttranscriptional and posttranslational regulation result in PAE sex-dependent effects at a molecular, physiological and behavioral level. Specific Aim 1 will test the hypothesis that PAE alters histone modifications that control the transcription of stress-related genes during fetal development in a sex-specific manner. We will assess histone posttranslational modifications (HPTMs), H3K4 me3/ H3K27 me3, histone writers and erasers, and associated genes by western and sequential ChIP-qPCR techniques. We will confirm a functional link by pharmacologically altering specific histone marks at embryonic day 12.5 (E12.5). Specific Aim 2 will test the hypothesis that PAE alters the posttranscriptional regulation of stress-related mRNA levels through micro-RNAs (miRs) during fetal development in a sex- specific manner. These experiments will assess miR expression using qPCR and miR-RIP to target the GR signaling system. We will confirm a functional link using LNA microRNA mimics and LNA-antimiR at E12.5. Specific Aim 3 will test the hypothesis that PAE alters the posttranslational regulation of stress- related proteins through long noncoding RNA (lncRNA) during fetal development in a sex- specific manner. These experiments will assess growth arrest-specific 5 (Gas-5) expression at E12-18. We will confirm a functional link to the GR system using LNA-GAPmer and LNA–antimir approaches. Specific Aim 4 will test the mechanistic link between PAE-induced transcriptional, posttranscriptional and/or posttranslational changes and the functional outcomes in the adult animal. These experiments will assess the impact of interventions identified in Aims 1-3 on arsenic-induced deficits: corticosterone response, learning and depression.


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: 2023 ( Subtotal = -$531,894 )
2023	2021	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	001	10	11/24/2022	NON-COMPETING CONTINUATION	-$335,025
2023	2020	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	9	11/24/2022	NON-COMPETING CONTINUATION	-$196,869
														Subtotal = -$531,894

Issue Date FY: 2021 ( Subtotal = $335,025 )
2021	2021	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	10	3/19/2021	NON-COMPETING CONTINUATION	$335,025
														Subtotal = $335,025

Issue Date FY: 2020 ( Subtotal = $335,363 )
2020	2020	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	9	4/7/2020	NON-COMPETING CONTINUATION	$335,363
														Subtotal = $335,363

Issue Date FY: 2019 ( Subtotal = $335,604 )
2019	2019	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	8	3/21/2019	NON-COMPETING CONTINUATION	$335,604
														Subtotal = $335,604

Issue Date FY: 2018 ( Subtotal = $335,871 )
2018	2018	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	7	3/9/2018	NON-COMPETING CONTINUATION	$335,871
														Subtotal = $335,871

Issue Date FY: 2017 ( Subtotal = $334,791 )
2017	2017	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	001	6	4/26/2017	COMPETING CONTINUATION	$334,792
2017	2015	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	5	3/23/2017	NON-COMPETING CONTINUATION	-$1
														Subtotal = $334,791

Issue Date FY: 2015 ( Subtotal = $335,492 )
2015	2015	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	001	5	1/28/2015	NON-COMPETING CONTINUATION	$33,550
2015	2015	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	5	11/18/2014	NON-COMPETING CONTINUATION	$301,942
														Subtotal = $335,492

Issue Date FY: 2014 ( Subtotal = $332,352 )
2014	2014	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	001	4	4/10/2014	NON-COMPETING CONTINUATION	$30,214
2014	2014	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	4	11/27/2013	NON-COMPETING CONTINUATION	$302,138
														Subtotal = $332,352

Issue Date FY: 2013 ( Subtotal = $329,196 )
2013	2013	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	001	3	7/16/2013	NON-COMPETING CONTINUATION	$26,873
2013	2013	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	3	11/30/2012	NON-COMPETING CONTINUATION	$302,323
														Subtotal = $329,196

Issue Date FY: 2012 ( Subtotal = $335,421 )
2012	2012	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	001	2	3/29/2012	NON-COMPETING CONTINUATION	$33,542
2012	2012	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	2	12/7/2011	NON-COMPETING CONTINUATION	$301,879
														Subtotal = $335,421

Issue Date FY: 2011 ( Subtotal = $335,658 )
2011	2011	UNIVERSITY OF NEW MEXICO (THE)	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	1	11/19/2010	NEW	$335,658
														Subtotal = $335,658

Grand Total All Awards = $2,812,879

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Prenatal arsenic exposure alters transcriptional, post-transcriptional and post-translational programming of the glucocorticoid system in a sexually dimorphic manner

Award Number: R01ES019583

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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