Maternal titanium dioxide nanomaterial inhalation exposure compromises placental hemodynamics

Abukabda, Alaeddin B.; Bowdridge, Elizabeth C.; McBride, Carroll R.; Batchelor, Thomas P.; Goldsmith, William T.; Garner, Krista L; Friend, Sherri; Nurkiewicz, Timothy R.

doi:10.1016/j.taap.2019.01.024

Cited by 29 publications

(29 citation statements)

References 38 publications

(34 reference statements)

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“…2e). Following an ENM exposure paradigm similar to the paradigm used for the current study, an increase in placental vascular resistance was reported, substantiating the antagonistic effects of nano-TiO 2 exposure during gestation [19]. Valentino et al further validate placental circulatory remodeling through a significant decline in placental flow in rabbits, which was observed following gestational exposure to diesel exhaust [54].…”

Section: Discussionsupporting

confidence: 69%

“…2e). This effect may be occurring as a result of increased vascular resistance in the in utero circulation, which has been shown to reduce placental perfusion [19] and could increase the rate of perinatal mortality [49].…”

Section: Resultsmentioning

confidence: 99%

“…During maternal ENM exposure, toxic metals can interact with the uterine environment and cross the placental barrier causing direct fetal exposure or indirectly eliciting a maternal immune response [1, 18]. Additionally, a direct effect on the fetus may be occurring as a result of changes in maternal-fetal hemodynamics following maternal ENM inhalation exposure [19]. ENM exposure during gestation may affect fetal cardiac methylation transiently or permanently, resulting in epigenetic reprogramming.…”

Section: Introductionmentioning

confidence: 99%

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ROS promote epigenetic remodeling and cardiac dysfunction in offspring following maternal engineered nanomaterial (ENM) exposure

et al. 2019

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Nano‐titanium dioxide (nano‐TiO2) is one of the most prevalently utilized ENMs. However, little is known regarding the ramifications that maternal inhalation exposure during gestation can have on growing progeny. Mitochondrial bioenergetics are critical for the maintenance of sufficient ATP for cardiac contractile function and data suggest that ENM exposure can cause deficits in this important mitochondrial role. Further, ENM inhalation exposure has been associated with an increase in mitochondrially‐derived reactive oxygen species (ROS). Nevertheless, it is unclear if such a dynamic occurs in the growing fetus or whether ROS is involved in fetal epigenome remodeling. The purpose of this study was to determine how maternal ENM exposure influences fetal ROS and epigenomic remodeling in a mouse model. Wild‐type pregnant dams were exposed to nano‐TiO2 with an aerodynamic diameter of 156 ± 2 nm and a mass concentration of 12 mg/m3 starting at gestational day 5 (GD 5), for 6 hours over 6 non‐consecutive days. Echocardiographic imaging was used to asses cardiac dysfunction in maternal, fetal (GD 16–19), and young adult (10–12 weeks) contexts. Electron transport chain complex (ETC) activities, mitochondrial size, complexity, and respiration were assessed. 5‐methylcytosine, and Dnmt1 protein and Hif1‐α activity, central contributors to epigenomic remodeling, were assessed. Cardiac function assessment revealed a 43% increase in left ventricular mass, 25% decrease in cardiac output in fetal pups, and 18.2% decrease in fractional shortening in young adult pups. In fetal pups, ROS levels were significantly increased (~10 fold) with a subsequent decrease in mitochondria phospholipid hydroperoxide glutathione peroxidase (mPHGPx) expression. ETC complex activity IV was decreased 68% and 46% in fetal and adult hearts, respectively. DNA Methylation was significantly increased in fetal pups following exposure, along with increased Hif1‐α activity and Dnmt1 protein expression. Significant increases in mitochondrial size and internal complexity persisted into adulthood following exposure. Maternal exposure to nano‐ TiO2 during gestation results in adverse effects on cardiac function by causing an increase in ROS levels and associated dysregulation via a Hif1‐α/Dnmt1 regulatory axis in the fetal offspring. The elevated ROS levels results in mitochondrial dysfunction at the fetal stage, which precipitates alterations in mitochondrial structure and persistent cardiac dysfunction. Our findings suggest a distinct interplay between ROS signaling and epigenetic remodeling that lead to sustained cardiac contractile dysfunction in growing and adult offspring mice following maternal ENM exposure. Support or Funding Information Supported by: RO1 HL‐128485 (JMH), RO1‐ES015022 (TRN), AHA‐17PRE33660333 (QAH). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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Section: Discussionsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ROS promote epigenetic remodeling and cardiac dysfunction in offspring following maternal engineered nanomaterial (ENM) exposure

et al. 2019

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“…Maternal or intrauterine inflammatory pathways were also proposed to mediate developmental toxicity from exposure to air pollution [ 49 , 104 ] carbon black (CB) [ 17 , 101 ] and MWCNTs [ 100 ]. Besides inflammatory pathways, interference with the placenta (structure, growth or function/reactivity) has been suggested to constitute another indirect pathway for developmental toxicity of air pollution particles [ 104 ], cadmium telluride (CdTe) QDs [ 97 ], TiO 2 NP [ 96 ] in vivo or graphene oxide (GO) in vitro [ 103 ]. For prenatal exposure to CB, TiO 2 and CeO NPs (intratracheal instillation: 50 μg/mouse on GD 14), Fedulov et al observed increased allergic susceptibility in the offspring that was proposed to occur due to NM-induced production of Th2 cytokines in maternal lungs [ 102 ].…”

Section: Introductionmentioning

confidence: 99%

“…NO release plays a crucial role in maintaining the low basal tone of the materno-fetal circulation [ 169 ] and was therefore hypothesized to be implicated in the signaling causing the decrease in outflow pressure. Increased sensitivity to angiotensin II, a potent vasoconstrictor implicated in preeclampsia [ 170 ], was observed in both the placental and umbilical artery [ 96 ], also identifying the renin-angiotensin system as a perhaps crucial modulator of tissue tone.…”

Section: Introductionmentioning

confidence: 99%

Recent insights on indirect mechanisms in developmental toxicity of nanomaterials

et al. 2020

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Background: Epidemiological and animal studies provide compelling indications that environmental and engineered nanomaterials (NMs) pose a risk for pregnancy, fetal development and offspring health later in life. Understanding the origin and mechanisms underlying NM-induced developmental toxicity will be a cornerstone in the protection of sensitive populations and the design of safe and sustainable nanotechnology applications. Main body: Direct toxicity originating from NMs crossing the placental barrier is frequently assumed to be the key pathway in developmental toxicity. However, placental transfer of particles is often highly limited, and evidence is growing that NMs can also indirectly interfere with fetal development. Here, we outline current knowledge on potential indirect mechanisms in developmental toxicity of NMs. Short conclusion: Until now, research on developmental toxicity has mainly focused on the biodistribution and placental translocation of NMs to the fetus to delineate underlying processes. Systematic research addressing NM impact on maternal and placental tissues as potential contributors to mechanistic pathways in developmental toxicity is only slowly gathering momentum. So far, maternal and placental oxidative stress and inflammation, activation of placental toll-like receptors (TLRs), impairment of placental growth and secretion of placental hormones, and vascular factors have been suggested to mediate indirect developmental toxicity of NMs. Therefore, NM effects on maternal and placental tissue function ought to be comprehensively evaluated in addition to placental transfer in the design of future studies of developmental toxicity and risk assessment of NM exposure during pregnancy.

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Nephroblastoma in a Sprague Dawley rat unrelated to titanium dioxide nanoparticle exposure in utero

Glaspell

Knapek

Washington

et al. 2020

Veterinary Medicine & Sci

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Maternal titanium dioxide nanomaterial inhalation exposure compromises placental hemodynamics

Cited by 29 publications

References 38 publications

ROS promote epigenetic remodeling and cardiac dysfunction in offspring following maternal engineered nanomaterial (ENM) exposure

ROS promote epigenetic remodeling and cardiac dysfunction in offspring following maternal engineered nanomaterial (ENM) exposure

Recent insights on indirect mechanisms in developmental toxicity of nanomaterials

Nephroblastoma in a Sprague Dawley rat unrelated to titanium dioxide nanoparticle exposure in utero

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