<i>In utero</i>
            exposure to diesel exhaust particulates is associated with an altered cardiac transcriptional response to transverse aortic constriction and altered DNA methylation

Goodson, Jamie M.; Weldy, Chad S.; MacDonald, James W.; Liu, Yonggang; Bammler, Theo K.; Chien, Wei-Ming; Chin, Michael T.

doi:10.1096/fj.201700032r

Cited by 21 publications

(13 citation statements)

References 62 publications

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“…Although AT 1 a is expressed in all tissues, AT 1 b is expressed only in the adrenal glands. A previous study by Goodson et al [72] adds support to the finding that in utero exposure to PM promotes susceptibility to cardiovascular disease, inasmuch as they observed differential methylation of a gene identified as likely playing an important role in mediating adult sensitivity to heart failure (Mir133a-2) after in utero exposure to DEP.…”

Section: Discussionmentioning

confidence: 71%

In utero exposure to ultrafine particles promotes placental stress-induced programming of renin-angiotensin system-related elements in the offspring results in altered blood pressure in adult mice

et al. 2019

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BackgroundExposure to particulate matter (PM) is associated with an adverse intrauterine environment, which can promote adult cardiovascular disease (CVD) risk. Ultrafine particles (UFP) (small size and large surface area/mass ratio) are systemically distributed, induce inflammation and oxidative stress, and have been associated with vascular endothelial dysfunction and arterial vasoconstriction, increasing hypertension risk. Placental stress and alterations in methylation of promoter regions of renin-angiotensin system (RAS)-related elements could be involved in UFP exposure-related programming of hypertension. We investigated whether in utero UFP exposure promotes placental stress by inflammation and oxidative stress, alterations in hydroxysteroid dehydrogenase 11b-type 2 (HSD11B2) and programming of RAS-related elements, and result in altered blood pressure in adult offspring. UFP were collected from ambient air using an aerosol concentrator and physicochemically characterized. Pregnant C57BL/6J pun/pun female mice were exposed to collected UFP (400 μg/kg accumulated dose) by intratracheal instillation and compared to control (nonexposed) and sterile H2O (vehicle) exposed mice. Embryo reabsorption and placental stress by measurement of the uterus, placental and fetal weights, dam serum and fetal cortisol, placental HSD11B2 DNA methylation and protein levels, were evaluated. Polycyclic aromatic hydrocarbon (PAH) biotransformation (CYP1A1 and NQO1 (NAD(P)H dehydrogenase (quinone)1)) enzymes, inflammation and oxidative stress in placentas and fetuses were measured. Postnatal day (PND) 50 in male offspring blood pressure was measured. Methylation and protein expression of (RAS)-related elements, angiotensin II receptor type 1 (AT1R) and angiotensin I-converting enzyme (ACE) in fetuses and lungs of PND 50 male offspring were also assessed.ResultsIn utero UFP exposure induced placental stress as indicated by an increase in embryo reabsorption, decreases in the uterus, placental, and fetal weights, and HSD11B2 hypermethylation and protein downregulation. In utero UFP exposure induced increases in the PAH-biotransforming enzymes, intrauterine oxidative damage and inflammation and stimulated programming and activation of AT1R and ACE, which resulted in increased blood pressure in the PND 50 male offspring.ConclusionsIn utero UFP exposure promotes placental stress through inflammation and oxidative stress, and programs RAS-related elements that result in altered blood pressure in the offspring. Exposure to UFP during fetal development could influence susceptibility to CVD in adulthood.Electronic supplementary materialThe online version of this article (10.1186/s12989-019-0289-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 71%

In utero exposure to ultrafine particles promotes placental stress-induced programming of renin-angiotensin system-related elements in the offspring results in altered blood pressure in adult mice

et al. 2019

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“…This is consistent with our previous findings for DEHP exposed heart, as well as lead-exposed liver [ 8 , 24 ]. Genome-wide and site-specific changes in cardiac DNA methylation have been reported for other environmental exposures, but studies thus far have largely focused on males [ 7 , 86 ]. Notably, although the epigenetic mechanisms underlying sex differences in CVD are unclear, sexually dimorphic patterns of DNA methylation are associated with various CVDs [ 87 ].…”

Section: Discussionmentioning

confidence: 99%

“…DNA methylation, or the addition of a methyl group to cytosine bases on DNA (5-methylcytosine), plays a critical role in normal development, and disruptions in DNA methylation have been linked to environment-induced disease. The development of the heart is characterized by dynamic changes in DNA methylation [ 5 ], and alterations in this epigenetic mark have been identified in a variety of cardiovascular disease states [ 1 , 5 , 6 ], as well as with toxicant exposures [ 6 , 7 , 8 ]. Notably, sex differences in epigenetic modifications and transcriptional profiles are present in the embryonic stem cell stage and persist throughout cardiac differentiation and into adulthood [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Sex-Specific Alterations in Cardiac DNA Methylation in Adult Mice by Perinatal Lead Exposure

Svoboda

Wang

Jones

et al. 2021

IJERPH

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Environmental factors play an important role in the etiology of cardiovascular diseases. Cardiovascular diseases exhibit marked sexual dimorphism; however, the sex-specific effects of environmental exposures on cardiac health are incompletely understood. Perinatal and adult exposures to the metal lead (Pb) are linked to several adverse cardiovascular outcomes, but the sex-specific effects of this toxicant on the heart have received little attention. Perinatal environmental exposures can lead to disease through disruption of the normal epigenetic programming that occurs during early development. Using a mouse model of human-relevant perinatal environmental exposure, we investigated the effects of exposure to Pb during gestation and lactation on DNA methylation in the hearts of adult offspring mice (n = 6 per sex). Two weeks prior to mating, dams were assigned to control or Pb acetate (32 ppm) water, and exposure continued until offspring were weaned at three weeks of age. Enhanced reduced-representation bisulfite sequencing was used to measure DNA methylation in the hearts of offspring at five months of age. Although Pb exposure stopped at three weeks of age, we discovered hundreds of differentially methylated cytosines (DMCs) and regions (DMRs) in males and females at five months of age. DMCs/DMRs and their associated genes were sex-specific, with a small, but statistically significant subset overlapping between sexes. Pathway analysis revealed altered methylation of genes important for cardiac and other tissue development in males, and histone demethylation in females. Together, these data demonstrate that perinatal exposure to Pb induces sex-specific changes in cardiac DNA methylation that are present long after cessation of exposure, and highlight the importance of considering sex in environmental epigenetics and mechanistic toxicology studies.

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“…27 Indeed, it is increasingly clear that disruption of normal DNAm patterning during early cardiovascular development may have long-term, adverse health consequences. 28,29 Recent studies demonstrate that DNAm in the heart is altered in disease states, 28,29 after obesogenic diet exposure, 28 and with toxicant exposures, 30,31 suggesting that this modification may play a key role in CVD pathogenesis. Despite this, the effects of early-life phthalate exposure on cardiac DNAm have not been investigated.…”

Section: Introductionmentioning

confidence: 99%

Sex-Specific Programming of Cardiac DNA Methylation by Developmental Phthalate Exposure

et al. 2020

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Phthalate plasticizers are ubiquitous chemicals linked to several cardiovascular diseases in animal models and humans. Despite this, the mechanisms by which phthalate exposures cause adverse cardiac health outcomes are unclear. In particular, whether phthalate exposures during pregnancy interfere with normal developmental programming of the cardiovascular system, and the resulting implications this may have for long-term disease risk, are unknown. Recent studies suggest that the effects of phthalates on metabolic and neurobehavioral outcomes are sex-specific. However, the influence of sex on cardiac susceptibility to phthalate exposures has not been investigated. One mechanism by which developmental exposures may influence long-term health is through altered programming of DNA methylation. In this work, we utilized an established mouse model of human-relevant perinatal exposure and enhanced reduced representation bisulfite sequencing to investigate the long-term effects of diethylhexyl phthalate (DEHP) exposure on DNA methylation in the hearts of adult male and female offspring at 5 months of age (n = 5-7 mice per sex and exposure). Perinatal DEHP exposure led to hundreds of sex-specific, differentially methylated cytosines (DMCs) and differentially methylated regions (DMRs) in the heart. Pathway analysis of DMCs revealed enrichment for several pathways in females, including insulin signaling, regulation of histone methylation, and tyrosine phosphatase activity. In males, DMCs were enriched for glucose transport, energy generation, and developmental programs. Notably, many sex-specific genes differentially methylated with DEHP exposure in our mouse model were also differentially methylated in published data of heart tissues collected from human heart failure patients. Together, these data highlight the potential role for DNA methylation in DEHP-induced cardiac effects and emphasize the importance of sex as a biological variable in environmental health studies.

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In utero exposure to diesel exhaust particulates is associated with an altered cardiac transcriptional response to transverse aortic constriction and altered DNA methylation

Cited by 21 publications

References 62 publications

In utero exposure to ultrafine particles promotes placental stress-induced programming of renin-angiotensin system-related elements in the offspring results in altered blood pressure in adult mice

In utero exposure to ultrafine particles promotes placental stress-induced programming of renin-angiotensin system-related elements in the offspring results in altered blood pressure in adult mice

Sex-Specific Alterations in Cardiac DNA Methylation in Adult Mice by Perinatal Lead Exposure

Sex-Specific Programming of Cardiac DNA Methylation by Developmental Phthalate Exposure

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