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At least 253 records · Page 14
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

Latitudinal exposure to DDTs, HCB, PCBs, PBDEs and DP in giant petrels (Macronectes spp.) across the Southern Ocean

Studies on Persistent Organic Pollutants (POPs) in Antarctic wildlife are scarce, and usually limited to a single locality. As a result, wildlife exposure to POPs across the Southern Ocean is poorly understood. In this study, we report the differential exposure of the major southern ocean scavengers, the giant petrels, to POPs across a wide latitudinal gradient. Selected POPs (PCBs, HCB, DDTs, PBDEs) and related compounds, such as Dechlorane Plus (DP), were analyzed in plasma of southern giant petrels (Macronectes giganteus) breeding on Livingston (62°S 61°W, Antarctica), Marion (46°S 37°E, sub-Antarctic), and Gough (40°S 10°W, cool temperate) islands. Northern giant petrels (Macronectes halli) from Marion Island were also studied. Stable isotope ratios of C and N (δ{sup 13}C and δ{sup 15}N) were used as dietary tracers of the marine habitat and trophic level, respectively. Breeding locality was a major factor explaining petrel exposure to POPs compared with species and sex. Significant relationships between δ{sup 13}C values and POP burdens, at both inter- and intra-population levels, support latitudinal variations in feeding grounds as a key factor in explaining petrel pollutant burdens. Overall, pollutant levels in giant petrels decreased significantly with latitude, but the relative abundance (%) of the more volatile POPs increased towards Antarctica. DP was found at negligible levels compared with legacy POPs in Antarctic seabirds. Spatial POP patterns found in giant petrels match those predicted by global distribution models, and reinforce the hypothesis of atmospheric long-range transport as the main source of POPs in Antarctica. Our results confirm that wildlife movements out of the polar region markedly increase their exposure to POPs. Therefore, strategies for Antarctic wildlife conservation should consider spatial heterogeneity in exposure to marine pollution. Of particular relevance is the need to clarify the exposure of Antarctic predators to emerging contaminants that are not yet globally regulated. - Highlights: • Latitude of petrels' foraging areas explains their exposure to legacy and emerging POPs. • Spatial patterns of POPs in giant petrels across the Southern Ocean are congener-dependent. • Overall POP burdens in giant petrels decrease southwards across the Southern Ocean. • Latitudinal patterns of POP in giant petrels agree with global distribution models. • POP patterns in giant petrels suggest long-range transport as their main source.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2016

Environmental exposure to arsenic and chromium in children is associated with kidney injury molecule-1

Environmental hazards from natural or anthropological sources are widespread, especially in the north-central region of Mexico. Children represent a susceptible population due to their unique routes of exposure and special vulnerabilities. In this study we evaluated the association of exposure to environmental kidney toxicants with kidney injury biomarkers in children living in San Luis Potosi (SLP), Mexico. A cross-sectional study was conducted with 83 children (5–12 years of age) residents of Villa de Reyes, SLP. Exposure to arsenic, cadmium, chromium, fluoride and lead was assessed in urine, blood and drinking water samples. Almost all tap and well water samples had levels of arsenic (81.5%) and fluoride (100%) above the permissible levels recommended by the World Health Organization. Mean urine arsenic (45.6 ppb) and chromium (61.7 ppb) were higher than the biological exposure index, a reference value in occupational settings. Using multivariate adjusted models, we found a dose-dependent association between kidney injury molecule-1 (KIM-1) across chromium exposure tertiles [(T1: reference, T2: 467 pg/mL; T3: 615 pg/mL) (p-trend=0.001)]. Chromium upper tertile was also associated with higher urinary miR-200c (500 copies/μl) and miR-423 (189 copies/μL). Arsenic upper tertile was also associated with higher urinary KIM-1 (372 pg/mL). Other kidney injury/functional biomarkers such as serum creatinine, glomerular filtration rate, albuminuria, neutrophil gelatinase-associated lipocalin and miR-21 did not show any association with arsenic, chromium or any of the other toxicants evaluated. We conclude that KIM-1 might serve as a sensitive biomarker to screen children for kidney damage induced by environmental toxic agents. - Highlights: • Children living in Mexico had exceedingly high arsenic and chromium exposure. • Arsenic and chromium exposure was significantly associated with urinary KIM-1. • KIM-1 might serve as a sensitive biomarker to evaluate kidney injury in children.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2016

Prospective study of ultraviolet radiation exposure and risk of breast cancer in the United States

Although there are few environmental risk factors for breast cancer, some epidemiologic studies found that exposure to solar UV radiation (UVR) may lower risk. Prior epidemiologic studies are limited by narrow ambient UVR ranges and lack lifetime exposure assessment. To address these issues, we studied a cohort with residences representing a wide range of ambient UVR. Using the nationwide U.S. Radiologic Technologists study (USRT), we examined the association between breast cancer risk and UVR based on ambient UVR, time outdoors, a combined variable of ambient UVR and time outdoors (combined UVR), and sun susceptibility factors. Participants reported location of residence and hours spent outdoors during five age periods. Ambient UVR was derived by linking satellite-based annual UVR estimates to self-reported residences. Lifetime values were calculated by averaging these measures accounting for years spent in that location. We examined the risk of breast cancer among 36,725 participants (n=716 cases) from baseline questionnaire completion (2003–2005) through 2012–2013 using Cox proportional hazards models. Breast cancer risk was unrelated to ambient UVR (HR for lifetime 5th vs 1st quintile=1.22, 95% CI: 0.95–1.56, p-trend=0.36), time outdoors (HR for lifetime 5th vs 1st quintile=0.87, 95% confidence interval (CI): 0.68–1.10, p-trend=0.46), or combined UVR (HR lifetime 5th vs 1st quintile =0.85, 95% CI: 0.67–1.08, p-trend=0.46). Breast cancer risk was not associated with skin complexion, eye or hair color, or sunburn history. This study does not support the hypothesis that UVR exposure lowers breast cancer risk. - Highlights: • Prior studies of UVR and breast cancer are inconsistent and limited. • We assessed UVR exposure across the lifetime and in three ways. • Conducted a prospective analysis of UVR exposure and breast cancer risk. • No association of any UVR exposure metric at any age with breast cancer risk. • Our findings suggest UVR exposure does not reduce risk of breast cancer.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Genetic polymorphisms of GRIN2A and GRIN2B modify the neurobehavioral effects of low-level lead exposure in children

Highlights: • Genetic polymorphisms may increase adverse effects of Pb on neurobehavioral processes. • We studied 330 participants of the Casa Pia Dental Amalgams Trial in Children. • Adverse interactions were found with variants of GRIN2A and GRIN2B in boys. • Our results implicate genetic factors in defining susceptibility to Pb neurotoxicity. Lead (Pb) is neurotoxic and children are highly susceptible to this effect, particularly within the context of continuous low-level Pb exposure. A current major challenge is identification of children who may be uniquely susceptible to Pb toxicity because of genetic predisposition. Learning and memory are among the neurobehavioral processes that are most notably affected by Pb exposure, and modification of N-methyl-D-aspartate receptors (NMDAR) that regulate these processes during development are postulated to underlie these adverse effects of Pb. We examined the hypothesis that polymorphic variants of genes encoding glutamate receptor, ionotropic, NMDAR subunits 2A and 2B, GRIN2A and GRIN2B, exacerbate the adverse effects of Pb exposure on these processes in children. Participants were subjects who participated as children in the Casa Pia Dental Amalgam Clinical Trial and for whom baseline blood Pb concentrations and annual neurobehavioral test results over the 7 year course of the clinical trial were available. Genotyping assays were performed for variants of GRIN2A (rs727605 and rs1070503) and GRIN2B (rs7301328 and rs1806201) on biological samples acquired from 330 of the original 507 trial participants. Regression modeling strategies were employed to evaluate the association between genotype status, Pb exposure, and neurobehavioral test outcomes. Numerous significant adverse interaction effects between variants of both GRIN2A and GRIN2B, individually and in combination, and Pb exposure were observed particularly among boys, preferentially within the domains of Learning & Memory and Executive Function. In contrast, very few interaction effects were observed among similarly genotyped girls with comparable Pb exposure. These findings support observations of an essential role of GRIN2A and GRIN2B on developmental processes underlying learning and memory as well as other neurological functions in children and demonstrate, further, modification of Pb effects on these processes by specific variants of both GRIN2A and GRIN2B genes. These observations highlight the importance of genetic factors in defining susceptibility to Pb neurotoxicity and may have important public health implications for future strategies aimed at protecting children and adolescents from potential health risks associated with low-level Pb exposure.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Can explicit suggestions about the harmfulness of EMF exposure exacerbate a nocebo response in healthy controls?

Highlights: • Results do not support a relationship between radiofrequency exposure and symptoms. • Healthy participants exhibited a nocebo response during believed radiofrequency exposure. • Awareness and belief are crucial in the presentation of symptoms. • The nocebo response may be exacerbated by alarmist media reports. While there has been consistent evidence that symptoms reported by individuals who suffer from Idiopathic Environmental Intolerance attributed to Electromagnetic Fields (IEI-EMF) are not caused by EMF and are more closely associated with a nocebo effect, whether this response is specific to IEI-EMF sufferers and what triggers it, remains unclear. The present experiment tested whether perceived EMF exposure could elicit symptoms in healthy participants, and whether viewing an ‘alarmist’ video could exacerbate a nocebo response. Participants were randomly assigned to watch either an alarmist (N = 22) or control video (N = 22) before completing a series of sham and active radiofrequency (RF) EMF exposure provocation trials (2 open-label, followed by 12 randomized, double-blind, counterbalanced trials). Pre- and post-video state anxiety and risk perception, as well as belief of exposure and symptom ratings during the open-label and double-blind provocation trials, were assessed. Symptoms were higher in the open-label RF-ON than RF-OFF trial (p < .001). No difference in either symptoms (p = .183) or belief of exposure (p = .144) was observed in the double-blind trials. Participants who viewed the alarmist video had a significant increase in symptoms (p = .041), state anxiety (p < .01) and risk perception (p < .001) relative to the control group. These results reveal the crucial role of awareness and belief in the presentation of symptoms during perceived exposure to EMF, showing that healthy participants exhibit a nocebo response, and that alarmist media reports emphasizing adverse effects of EMF also contribute to a nocebo response.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2021

Translating nanoparticle dosimetry from conventional in vitro systems to occupational inhalation exposures

As encouraged by Toxicity Testing in the 21st Century, researchers increasingly apply high-throughput in vitro approaches to identify and characterize nanoparticle hazards, including conventional aqueous cell culture systems to assess respiratory hazards. Translating nanoparticle dose from conventional toxicity testing systems to relevant human exposures remains a major challenge for assessing occupational risk of nanoparticle exposures. Here, we explored existing computational tools and data available to translate nanoparticle dose metrics from cellular test systems to inhalation exposures of silver nanoparticles in humans. We used the Multiple-Path Particle Dosimetry (MPPD) Model to predict deposition of humans exposed to 20 and 110 nm silver nanoparticles at 0.9 µg/m3 over an 8 hr period, the proposed a National Institute of Occupational Safety and Health (NIOSH) recommended exposure limit (REL). MPPD predicts 1.88 and 0.98 µg of silver deposited in an 8 hr period for 20 and 110 nm nanoparticles, respectively, with 20 nm particles displaying nearly 11-fold higher total surface area deposited. Peak nanoparticle concentrations occurred more proximal in the pulmonary tract compared to mass deposition patterns (generation 5 vs. generations 20-21, respectively) due to regional differences in lung lining fluid volumes. Assuming 0.4% nanoparticle dissolution by mass as previously measured, we predict peak concentrations of silver ions in cells of 0.24 and 0.17 µg/mL for 20 and 110 nm particles, respectively. Both predicted concentrations are below the measured toxic threshold of 1.7 µg/mL of silver ions in cells from in vitro assessments. Assuming 4% dissolution by mass, we predict 10-fold higher silver concentrations in tissues, peaking at 2.4 and 1.7 µg/mL, for 20 and 110 nm nanoparticles respectively, exceeding the observed in vitro toxic threshold and highlighting the importance and sensitivity of dissolution rates. Overall, this approach offers a framework for extrapolating nanotoxicity results from in vitro cell culture systems to human exposures. Aligning appropriate dose metrics from in vitro and in vivo hazard characterizations and human pulmonary doses from occupational exposures are critical components for successful nanoparticle risk assessment and worker protection and provide guidance for designing future in vitro studies aimed at relevant human exposures.

Smith, Jordan N.↗
DOE OSTI2011

Exposure to diesel exhaust up-regulates iNOS expression in ApoE knockout mice

Traffic related particulate matter air pollution is a risk factor for cardiovascular events; however, the biological mechanisms are unclear. We hypothesize that diesel exhaust (DE) inhalation induces up-regulation of inducible nitric oxide synthase (iNOS), which is known to contribute to vascular dysfunction, progression of atherosclerosis and ultimately cardiovascular morbidity and mortality. Methods: ApoE knockout mice (30-week) were exposed to DE (at 200 {mu}g/m{sup 3} of particulate matter) or filtered-air (control) for 7 weeks (6 h/day, 5 days/week). iNOS expression in the blood vessels and heart was evaluated by immunohistochemistry and western blotting analysis. To examine iNOS activity, thoracic aortae were mounted in a wire myograph, and vasoconstriction stimulated by phenylephrine (PE) was measured with and without the presence of the specific inhibitor for iNOS (1400 W). NF-{kappa}B (p65) activity was examined by ELISA. The mRNA expression of iNOS and NF-{kappa}B (p65) was determined by real-time PCR. Results: DE exposure significantly enhanced iNOS expression in the thoracic aorta (4-fold) and heart (1.5 fold). DE exposure significantly attenuated PE-stimulated vasoconstriction by {approx} 20%, which was partly reversed by 1400 W. The mRNA expression of iNOS and NF-{kappa}B was significantly augmented after DE exposure. NF-{kappa}B activity was enhanced 2-fold after DE inhalation, and the augmented NF-{kappa}B activity was positively correlated with iNOS expression (R{sup 2} = 0.5998). Conclusions: We show that exposure to DE increases iNOS expression and activity possibly via NF-{kappa}B-mediated pathway. We suspect that DE exposure-caused up-regulation of iNOS contributes to vascular dysfunction and atherogenesis, which could ultimately lead to urban air pollution-associated cardiovascular morbidity and mortality. - Highlights: > Exposed ApoE knockout mice (30-week) to diesel exhaust (DE) for 7 weeks. > Examine iNOS expression and activity in the blood vessels and heart. > DE exposure enhanced iNOS protein and mRNA expression in the aorta and heart. > iNOS activity was also increased after DE exposure. > This up-regulation of iNOS may contribute to vascular dysfunction and atherogenesis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2011

Exposure to tri-o-cresyl phosphate detected in jet airplane passengers

The aircraft cabin and flight deck ventilation are supplied from partially compressed unfiltered bleed air directly from the engine. Worn or defective engine seals can result in the release of engine oil into the cabin air supply. Aircrew and passengers have complained of illness following such 'fume events'. Adverse health effects are hypothesized to result from exposure to tricresyl phosphate mixed esters, a chemical added to jet engine oil and hydraulic fluid for its anti-wear properties. Our goal was to develop a laboratory test for exposure to tricresyl phosphate. The assay was based on the fact that the active-site serine of butyrylcholinesterase reacts with the active metabolite of tri-o-cresyl phosphate, cresyl saligenin phosphate, to make a stable phosphorylated adduct with an added mass of 80 Da. No other organophosphorus agent makes this adduct in vivo on butyrylcholinesterase. Blood samples from jet airplane passengers were obtained 24-48 h after completing a flight. Butyrylcholinesterase was partially purified from 25 ml serum or plasma, digested with pepsin, enriched for phosphorylated peptides by binding to titanium oxide, and analyzed by mass spectrometry. Of 12 jet airplane passengers tested, 6 were positive for exposure to tri-o-cresyl phosphate that is, they had detectable amounts of the phosphorylated peptide FGEpSAGAAS. The level of exposure was very low. No more than 0.05 to 3% of plasma butyrylcholinesterase was modified. None of the subjects had toxic symptoms. Four of the positive subjects were retested 3 to 7 months following their last airplane trip and were found to be negative for phosphorylated butyrylcholinesterase. In conclusion, this is the first report of an assay that detects exposure to tri-o-cresyl phosphate in jet airplane travelers. -- Highlights: Black-Right-Pointing-Pointer Travel on jet airplanes is associated with an illness, aerotoxic syndrome. Black-Right-Pointing-Pointer A possible cause is exposure to tricresyl phosphate in engine lubricating oil. Black-Right-Pointing-Pointer A blood test for exposure to tri-o-cresyl phosphate is reported.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Reactive oxygen species produced by NADPH oxidase and mitochondrial dysfunction in lung after an acute exposure to Residual Oil Fly Ashes

Reactive O{sub 2} species production triggered by particulate matter (PM) exposure is able to initiate oxidative damage mechanisms, which are postulated as responsible for increased morbidity along with the aggravation of respiratory diseases. The aim of this work was to quantitatively analyse the major sources of reactive O{sub 2} species involved in lung O{sub 2} metabolism after an acute exposure to Residual Oil Fly Ashes (ROFAs). Mice were intranasally instilled with a ROFA suspension (1.0 mg/kg body weight), and lung samples were analysed 1 h after instillation. Tissue O{sub 2} consumption and NADPH oxidase (Nox) activity were evaluated in tissue homogenates. Mitochondrial respiration, respiratory chain complexes activity, H{sub 2}O{sub 2} and ATP production rates, mitochondrial membrane potential and oxidative damage markers were assessed in isolated mitochondria. ROFA exposure was found to be associated with 61% increased tissue O{sub 2} consumption, a 30% increase in Nox activity, a 33% increased state 3 mitochondrial O{sub 2} consumption and a mitochondrial complex II activity increased by 25%. During mitochondrial active respiration, mitochondrial depolarization and a 53% decreased ATP production rate were observed. Neither changes in H{sub 2}O{sub 2} production rate, nor oxidative damage in isolated mitochondria were observed after the instillation. After an acute ROFA exposure, increased tissue O{sub 2} consumption may account for an augmented Nox activity, causing an increased O{sub 2}{sup ·−} production. The mitochondrial function modifications found may prevent oxidative damage within the organelle. These findings provide new insights to the understanding of the mechanisms involving reactive O{sub 2} species production in the lung triggered by ROFA exposure. - Highlights: • Exposure to ROFA alters the oxidative metabolism in mice lung. • The augmented Nox activity contributes to the high tissue O{sub 2} consumption. • Exposure to ROFA produces alterations in mitochondrial function. • ΔΨ{sub m} decrease in state 3 may be responsible for the decreased ATP production. • Mild uncoupling prevents mitochondrial oxidative damage.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

In utero and early life arsenic exposure in relation to long-term health and disease

Background: There is a growing body of evidence that prenatal and early childhood exposure to arsenic from drinking water can have serious long-term health implications. Objectives: Our goal was to understand the potential long-term health and disease risks associated with in utero and early life exposure to arsenic, as well as to examine parallels between findings from epidemiological studies with those from experimental animal models. Methods: We examined the current literature and identified relevant studies through PubMed by using combinations of the search terms “arsenic”, “in utero”, “transplacental”, “prenatal” and “fetal”. Discussion: Ecological studies have indicated associations between in utero and/or early life exposure to arsenic at high levels and increases in mortality from cancer, cardiovascular disease and respiratory disease. Additional data from epidemiologic studies suggest intermediate effects in early life that are related to risk of these and other outcomes in adulthood. Experimental animal studies largely support studies in humans, with strong evidence of transplacental carcinogenesis, atherosclerosis and respiratory disease, as well as insight into potential underlying mechanisms of arsenic's health effects. Conclusions: As millions worldwide are exposed to arsenic and evidence continues to support a role for in utero arsenic exposure in the development of a range of later life diseases, there is a need for more prospective studies examining arsenic's relation to early indicators of disease and at lower exposure levels. - Highlights: • We review in utero and early-life As exposure impacts on lifelong disease risks. • Evidence indicates that early-life As increases risks of lung disease, cancer and CVD. • Animal work largely parallels human studies and may lead to new research directions. • Prospective studies and individual exposure assessments with biomarkers are needed. • Assessing intermediary endpoints may aid early intervention and establish causality.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice

In utero bisphenol A (BPA) exposure affects reproductive function in the first generation (F1) of mice; however, not many studies have examined the reproductive effects of BPA exposure on subsequent generations. In this study, pregnant mice (F0) were orally dosed with vehicle, BPA (0.5, 20, and 50 μg/kg/day) or diethylstilbestrol (DES; 0.05 μg/kg/day) daily from gestation day 11 until birth. F1 females were used to generate the F2 generation, and F2 females were used to generate the F3 generation. Breeding studies at the ages of 3, 6, and 9 months were conducted to evaluate reproductive capacity over time. Further, studies were conducted to evaluate pubertal onset, litter size, and percentage of dead pups; and to calculate pregnancy rate, and mating, fertility, and gestational indices. The results indicate that BPA exposure (0.5 and 50 μg/kg/day) significantly delayed the age at vaginal opening in the F3 generation compared to vehicle control. Both DES (0.05 μg/kg/day) and BPA (50 μg/kg/day) significantly delayed the age at first estrus in the F3 generation compared to vehicle control. BPA exposure reduced gestational index in the F1 and F2 generations compared to control. Further, BPA exposure (0.5 μg/kg/day) compromised the fertility index in the F3 generation compared to control. Finally, in utero BPA exposure reduced the ability of female mice to maintain pregnancies as they aged. Collectively, these data suggest that BPA exposure affects reproductive function in female mice and that some effects may be transgenerational in nature. - Highlights: • In utero BPA delayed vaginal opening in the F3 generation compared to control. • In utero BPA delayed estrus in the F3 generation compared to control. • In utero BPA reduced the ability of F1 and F2 female mice to maintain pregnancies. • In utero BPA compromised the ability of F3 female mice to become pregnant. • Some effects of in utero BPA may be transgenerational in nature.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Immunotoxicological and neurotoxicological profile of health effects following subacute exposure to geogenic dust from sand dunes at the Nellis Dunes Recreation Area, Las Vegas, NV

Exposure to geogenic particulate matter (PM) comprised of mineral particles has been linked to human health effects. However, very little data exist on health effects associated with geogenic dust exposure in natural settings. Therefore, we characterized particulate matter size, metal chemistry, and health effects of dust collected from the Nellis Dunes Recreation Area (NDRA), a popular off-road vehicle area located near Las Vegas, NV. Adult female B6C3F1 mice were exposed to several concentrations of mineral dust collected from active and vegetated sand dunes in NDRA. Dust samples (median diameter: 4.4 μm) were suspended in phosphate-buffered saline and delivered at concentrations ranging from 0.01 to 100 mg dust/kg body weight by oropharyngeal aspiration. ICP-MS analyses of total dissolution of the dust resulted in aluminum (55,090 μg/g), vanadium (70 μg/g), chromium (33 μg/g), manganese (511 μg/g), iron (21,600 μg/g), cobalt (9.4 μg/g), copper (69 μg/g), zinc (79 μg/g), arsenic (62 μg/g), strontium (620 μg/g), cesium (13 μg/g), lead 25 μg/g) and uranium (4.7 μg/g). Arsenic was present only as As(V). Mice received four exposures, once/week over 28-days to mimic a month of weekend exposures. Descriptive and functional assays to assess immunotoxicity and neurotoxicity were performed 24 h after the final exposure. The primary observation was that 0.1 to 100 mg/kg of this sand dune derived dust dose-responsively reduced antigen-specific IgM antibody responses, suggesting that dust from this area of NDRA may present a potential health risk. - Graphical abstract: During periods of heavy wind erosion, dense dust clouds of locally emitted geogenic dust enrobe the central Nellis Dune Recreation Area dunes. - Highlights: • Toxicological effects were characterized specific to geogenic dust exposure from a recreational sand dune site in Nevada. • The geogenic dust is a mixture of many metals and crystalline silica. • Exposure to geogenic dust dose-responsively decreased IgM antibody responses in a mouse model.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Valproic acid exposure decreases Cbp/p300 protein expression and histone acetyltransferase activity in P19 cells

The teratogenicity of the antiepileptic drug valproic acid (VPA) is well established and its inhibition of histone deacetylases (HDAC) is proposed as an initiating factor. Recently, VPA-mediated HDAC inhibition was demonstrated to involve transcriptional downregulation of histone acetyltransferases (HATs), which was proposed to compensate for the increased acetylation resulting from HDAC inhibition. Cbp and p300 are HATs required for embryonic development and deficiencies in either are associated with congenital malformations and embryolethality. The objective of the present study was to characterize Cbp/p300 following VPA exposure in P19 cells. Consistent with previous studies, exposure to 5 mM VPA over 24 h induced a moderate decrease in Cbp/p300 mRNA, which preceded a strong decrease in total cellular protein mediated by ubiquitin-proteasome degradation. Nuclear Cbp/p300 protein was also decreased following VPA exposure, although to a lesser extent. Total cellular and nuclear p300 HAT activity was reduced proportionately to p300 protein levels, however while total cellular HAT activity also decreased, nuclear HAT activity was unaffected. Using the Cbp/p300 HAT inhibitor C646, we demonstrated that HAT inhibition similarly affected many of the same endpoints as VPA, including increased reactive oxygen species and caspase-3 cleavage, the latter of which could be attenuated by pre-treatment with the antioxidant catalase. C646 exposure also decreased NF-κB/p65 protein, which was not due to reduced mRNA and was not attenuated with catalase pre-treatment. This study provides support for an adaptive HAT response following VPA exposure and suggests that reduced Cbp/p300 HAT activity could contribute to VPA-mediated alterations. - Highlights: • VPA exposure in vitro downregulates Cbp/p300 mRNA and induces protein degradation. • Cbp/p300 histone acetyltransferase activity is similarly reduced with VPA exposure. • Inhibition of Cbp/p300 acetyltransferase activity induces apoptosis, involving ROS. • This inhibition of activity also reduces NFκB expression independently of ROS. • Reduced Cbp/p300 acetyltransferase activity may contribute to VPA teratogenesis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Relationships among DNA hypomethylation, Cd, and Pb exposure and risk of cigarette smoking-related urothelial carcinoma

Cigarette smoking and environmental exposure to heavy metals are important global health issues, especially for urothelial carcinoma (UC). However, the effects of cadmium and lead exposure, as well as the levels of DNA hypomethylation, on UC risk are limited. We evaluated the possible exposure sources of Cd and Pb and the relationship among DNA hypomethylation, urinary Cd and Pb levels, and UC risk. We recruited 209 patients with UC and 417 control patients for a hospital-based case–control study between June 2011 and August 2014. We collected environmental exposure-related information with questionnaires. Blood and urine samples were analyzed to measure the Cd and Pb exposure and 5-methyl-2′-deoxycytidine levels as a proxy for DNA methylation. Multivariate logistic regression and 95% confidence intervals were applied to estimate the risk for UC. Study participants with high Cd and Pb exposure in blood or urine had significantly increased risk of UC, especially among the smokers. After adjusting for age and gender, the possible connections of individual cumulative cigarette smoking or herb medicine exposure with the increased levels of Cd and Pb were observed in the controls. Participants with 8.66%–12.39% of DNA hypomethylation had significantly increased risk of UC compared with those with ≥ 12.39% of DNA hypomethylation. Environmental factors including cigarette smoking and herb medicine may contribute to the internal dose of heavy metals levels. Repeat measurements of heavy metals with different study design, detailed dietary information, and types of herb medicine should be recommended for exploring UC carcinogenesis in future studies. - Highlights: • Smoking and herb medicine ingestion is associated with increased urinary Cd and Pb levels. • Urinary levels of Cd and Pb are associated with increased risk of UC. • UC carcinogenesis might have partially resulted from DNA hypomethylation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) promotes the transgenerational inheritance of adult-onset reproductive dysfunctions through the female germline in mice

Endocrine disruptors (EDs) are compounds known to promote transgenerational inheritance of adult-onset disease in subsequent generations after maternal exposure during fetal gonadal development. This study was designed to establish whether gestational and lactational exposure to the plasticizer di(2-ethylhexyl)phthalate (DEHP) at environmental doses promotes transgenerational effects on reproductive health in female offspring, as adults, over three generations in the mouse. Gestating F0 mouse dams were exposed to 0, 0.05, 5 mg/kg/day DEHP in the diet from gestational day 0.5 until the end of lactation. The incidence of adult-onset disease in reproductive function was recorded in F1, F2 and F3 female offspring. In adult F1 females, DEHP exposure induced reproductive adverse effects with: i) altered ovarian follicular dynamics with reduced primordial follicular reserve and a larger growing pre-antral follicle population, suggesting accelerated follicular recruitment; ii) reduced oocyte quality and embryonic developmental competence; iii) dysregulation of the expression profile of a panel of selected ovarian and pre-implantation embryonic genes. F2 and F3 female offspring displayed the same altered reproductive morphological phenotype and gene expression profiles as F1, thus showing transgenerational transmission of reproductive adverse effects along the female lineage. These findings indicate that in mice exposure to DEHP at doses relevant to human exposure during gonadal sex determination significantly perturbs the reproductive indices of female adult offspring and subsequent generations. Evidence of transgenerational transmission has important implications for the reproductive health and fertility of animals and humans, significantly increasing the potential biohazards of this toxicant. - Highlights: • Maternal exposure to DEHP transgenerationally affects female reproductive health. • DEHP reduced ovarian follicular reserve up to the third generation. • DEHP reduced oocyte and blastocyst developmental competence up to F3. • DEHP altered expression levels for key genes in ovary and blastocysts up to F4. • DEHP's adverse effects were observed at doses relevant for human exposure.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Maternal exposure to a mixture of persistent organic pollutants (POPs) affects testis histology, epididymal sperm count and induces sperm DNA fragmentation in mice

Persistent organic pollutants (POPs) are widespread throughout the environment and some are suspected to induce reproductive toxicity. As animals and humans are exposed to complex mixtures of POPs, it is reasonable to assess how such mixtures could interact with the reproductive system. Our aim is to investigate how maternal exposure to a mixture of 29 different persistent organic pollutants, formulated to mimic the relative POP levels in the food basket of the Scandinavian population, could alter reproductive endpoints. Female mice were exposed via feed from weaning, during pregnancy and lactation in 3 exposure groups (control (C), low (L) and high (H)). Testicular morphometric endpoints, epididymal sperm concentration and sperm DNA integrity were assessed in adult male offspring. We found that the number of tubules, proportion of tubule compartments and epididymal sperm concentration significantly decreased in both POP exposed groups. Epididymal sperm from both POP exposed groups showed increased DNA fragmentation. It is concluded that maternal exposure to a defined POP mixture relevant to human exposure can affect testicular development, sperm production and sperm chromatin integrity. - Highlights: • Male mice were maternally exposed to a mixture of persistent organic pollutants. • Exposure significantly affected the testis histology. • Exposure significantly decreased sperm count and induced sperm DNA fragmentation. • Maternal exposure to POP mixture induced reproductive toxicity in male offspring.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Effect of low-dose zearalenone exposure on reproductive capacity of male mice

Zearalenone (ZEA), a kind of nonsteroidal mycotoxin with estrogenic effects, can influence animal reproductive capacity through interfering with estrogen signaling pathway. Previous studies have shown exposure to ZEA at high doses (higher than No-Observed Effect Level, NOEL) had a significant impact on mouse sperm quality and pregnant rate, but little is known about the effect of exposure to ZEA at low doses (lower than NOEL) on mouse reproductive capacity. This study evaluated the effects of exposure to low-dose ZEA on mouse spermatogenesis and semen quality. Male mice (CD-1) of 21 days were exposed to ZEA at 20, or 40 μg/kg body weight for 14, 28 or 42 days. After exposure to ZEA for 14 days, the spermatogenic cells in seminiferous tubules were declined dose-independently; however in groups treated by ZEA for 28 days, the spermatogenic cells were declined dose-dependently. Moreover, after treatment for 28 days or 42 days, the DNA double stand break (DSB) in spermatogenic cells were increased in a dose-dependent manner in treated groups. Compared with the control group, the sperm concentration, viability, motility, and hyperactive rate in treated groups were decreased dose-dependently and time-dependently. Meanwhile, deformity and mortality rate of sperm in treated groups were increased remarkably dose-dependently too. In conclusion, low dose ZEA impaired male reproductive capacity especially in spermatogenesis and semen quality of mouse. - Highlights: • Exposure of low dose Zearalenone decrease sperm concentration, viability, motility, and hyperactive rate of male mice. • Exposure of low dose Zearalenone impairs spermatogenesis. • Exposure of low dose Zearalenone leads to DSBs incidence increase in mouse germ cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Inequity in consumption of goods and services adds to racial–ethnic disparities in air pollution exposure

Fine particulate matter (PM 2.5 ) air pollution exposure is the largest environmental health risk factor in the United States. Here, we link PM 2.5 exposure to the human activities responsible for PM 2.5 pollution. We use these results to explore “pollution inequity”: the difference between the environmental health damage caused by a racial–ethnic group and the damage that group experiences. We show that, in the United States, PM 2.5 exposure is disproportionately caused by consumption of goods and services mainly by the non-Hispanic white majority, but disproportionately inhaled by black and Hispanic minorities. On average, non-Hispanic whites experience a “pollution advantage”: They experience ∼17% less air pollution exposure than is caused by their consumption. Blacks and Hispanics on average bear a “pollution burden” of 56% and 63% excess exposure, respectively, relative to the exposure caused by their consumption. The total disparity is caused as much by how much people consume as by how much pollution they breathe. Differences in the types of goods and services consumed by each group are less important. PM 2.5 exposures declined ∼50% during 2002–2015 for all three racial–ethnic groups, but pollution inequity has remained high.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗