Publications by authors named "Sonia Saad"

66 Publications

Maternal Particulate Matter Exposure Impairs Lung Health and Is Associated with Mitochondrial Damage.

Antioxidants (Basel) 2021 Jun 25;10(7). Epub 2021 Jun 25.

Faculty of Science, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia.

Relatively little is known about the transgenerational effects of chronic maternal exposure to low-level traffic-related air pollution (TRAP) on the offspring lung health, nor are the effects of removing such exposure before pregnancy. Female BALB/c mice were exposed to PM (PM 5 µg/day) for 6 weeks before mating and during gestation and lactation; in a subgroup, PM was removed when mating started to model mothers moving to cleaner areas during pregnancy to protect their unborn child (Pre-exposure). Lung pathology was characterised in both dams and offspring. A subcohort of female offspring was also exposed to ovalbumin to model allergic airways disease. PM and Pre-exposure dams exhibited airways hyper-responsiveness (AHR) with mucus hypersecretion, increased mitochondrial reactive oxygen species (ROS) and mitochondrial dysfunction in the lungs. Female offspring from PM and Pre-exposure dams displayed AHR with increased lung inflammation and mitochondrial ROS production, while males only displayed increased lung inflammation. After the ovalbumin challenge, AHR was increased in female offspring from PM dams compared with those from control dams. Using an in vitro model, the mitochondria-targeted antioxidant MitoQ reversed mitochondrial dysfunction by PM stimulation, suggesting that the lung pathology in offspring is driven by dysfunctional mitochondria. In conclusion, chronic exposure to low doses of PM exerted transgenerational impairment on lung health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antiox10071029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300816PMC
June 2021

Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse.

Sci Rep 2021 Jun 14;11(1):12437. Epub 2021 Jun 14.

Renal Medicine, Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.

Calcineurin inhibitors, such as Cyclosporin (CsA), are the mainstay of anti-rejection therapy in solid organ transplants but can paradoxically induce progressive nephropathy characterised by renal dysfunction and interstitial fibrosis. Lysyl oxidases (LOXs), a group of enzymes that catalyse extracellular matrix (ECM) crosslinking, were shown to implicate in tissue scarring. It is hypothesized that inhibition of these enzymes may render therapeutic effects against CsA-induced nephropathy. In this study, 6-to-8 weeks old C57BL/6 J mice were administered saline or CsA (30 mg/kg/day s.c) for 16 weeks. At 8 weeks, CsA-treated animals were divided into 5 groups respectively treated with: (1) vehicle, (2) PXS-5505 (Pan-LOX inhibitor), (3) PXS-5382 (LOX-like 2 inhibitor), (4) PXS-5505 for 4 weeks then PXS-5382 for 4 weeks (sequential therapy), and (5) Telmisartan (standard therapy). Our results indicate that CsA administration significantly increased the levels of blood urea nitrogen, glomerular and tubular injury, tubulointerstitial fibrosis, inflammation and oxidative stress in mouse kidney. These changes were associated with upregulated mRNA expression of LOX and LOXL2. Administration of Pan-LOX or LOXL2 inhibitors or the sequential therapy suppressed the expression of ECM proteins (α-SMA, FN and COL1A), matrix metalloproteases (MMP)2 and 9, inflammatory markers (TNFα and MCP-1) and TGF-β1-Smad3 signalling. Among all regimens including telmisartan, only Pan-LOX inhibitor PXS-5505 was able to attenuate uraemia. Collectively, our study suggests that Pan-LOX and LOXL2 inhibition can attenuate progressive nephropathy due to CsA administration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-91772-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203624PMC
June 2021

Particulate Matter, an Intrauterine Toxin Affecting Foetal Development and Beyond.

Antioxidants (Basel) 2021 May 6;10(5). Epub 2021 May 6.

Renal Research Laboratory, Kolling Institute of Medical Research, Sydney, NSW 2065, Australia.

Air pollution is the 9th cause of the overall disease burden globally. The solid component in the polluted air, particulate matters (PMs) with a diameter of 2.5 μm or smaller (PM) possess a significant health risk to several organ systems. PM has also been shown to cross the blood-placental barrier and circulate in foetal blood. Therefore, it is considered an intrauterine environmental toxin. Exposure to PM during the perinatal period, when the foetus is particularly susceptible to developmental defects, has been shown to reduce birth weight and cause preterm birth, with an increase in adult disease susceptibility in the offspring. However, few studies have thoroughly studied the health outcome of foetuses due to intrauterine exposure and the underlying mechanisms. This perspective summarises currently available evidence, which suggests that intrauterine exposure to PM promotes oxidative stress and inflammation in a similar manner as occurs in response to direct PM exposure. Oxidative stress and inflammation are likely to be the common mechanisms underlying the dysfunction of multiple systems, offering potential targets for preventative strategies in pregnant mothers for an optimal foetal outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antiox10050732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148178PMC
May 2021

Non-invasive assessment of exfoliated kidney cells extracted from urine using multispectral autofluorescence features.

Sci Rep 2021 May 20;11(1):10655. Epub 2021 May 20.

Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, 2052, Australia.

Optimally preserved urinary exfoliated renal proximal tubule cells were assessed by multispectral imaging of cell autofluorescence. We demonstrated different multispectral autofluorescence signals in such cells extracted from the urine of patients with healthy or diseased kidneys. Using up to 10 features, we were able to differentiate cells from individuals with heathy kidneys and impaired renal function (indicated by estimated glomerular filtration rate (eGFR) values) with the receiver operating characteristic area under the curve (AUC) of 0.99. Using the same method, we were also able to discriminate such urine cells from patients with and without renal fibrosis on biopsy, where significant differences in multispectral autofluorescence signals (AUC = 0.90) were demonstrated between healthy and diseased patients (p < 0.05). These findings show that multispectral assessment of the cell autofluorescence in urine exfoliated proximal tubule kidney cells has the potential to be developed as a sensitive, non-invasive diagnostic method for CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-89758-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138006PMC
May 2021

Low-dose hydralazine during gestation reduces renal fibrosis in rodent offspring exposed to maternal high fat diet.

PLoS One 2021 18;16(3):e0248854. Epub 2021 Mar 18.

Renal Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.

Background: Maternal high fat diet (HFD) promotes chronic kidney disease (CKD) in offspring. This is in accordance with the theory of fetal programming, which suggests adverse conditions occurring in utero predispose offspring to chronic conditions later in life. DNA methylation has been proposed as a key mechanism by which fetal programming occurs and is implicated in CKD progression. DNA demethylating drugs may interrupt the fetal programming of CKD by maternal obesity. Hydralazine, an antihypertensive agent, demethylates DNA at low doses which do not reduce blood pressure. We used a mouse model of maternal obesity to determine whether gestational administration of low-dose hydralazine to mothers can prevent CKD in offspring.

Methods: C57BL/6 dams received HFD or chow from 6 weeks prior to mating and were administered subcutaneous hydralazine (5mg/kg) or saline thrice weekly during gestation. Male offspring were weaned to chow and were sacrificed at either postnatal week 9 or week 32. Biometric and metabolic parameters, renal global DNA methylation, renal structural and functional changes and markers of fibrosis, oxidative stress and inflammation were measured in offspring at weeks 9 and 32.

Results: In week 9 offspring, maternal HFD consumption did not significantly alter anthropometric or metabolic parameters, or renal global DNA methylation. Week 32 offspring had increased renal global DNA methylation, together with albuminuria, glomerulosclerosis, renal fibrosis and oxidative stress. Administration of low-dose hydralazine to obese mothers during gestation reduced renal global DNA methylation and renal fibrotic markers in week 32 offspring.

Conclusion: Gestational hydralazine reduced renal global DNA methylation in offspring of obese mothers and attenuated maternal obesity-induced renal fibrosis. These data support the use of low-dose hydralazine as a demethylating agent to prevent CKD arising in offspring due to maternal HFD consumption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248854PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971884PMC
March 2021

Brain health is independently impaired by E-vaping and high-fat diet.

Brain Behav Immun 2021 02 20;92:57-66. Epub 2020 Nov 20.

School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW 2007, Australia; Respiratory Cellular and Molecular Biology, Woolcock Institute of Medical Research, NSW 2037, Australia. Electronic address:

Tobacco smoking and high-fat diet (HFD) independently impair short-term memory. E-cigarettes produce e-vapour containing flavourings and nicotine. Here, we investigated whether e-vapour inhalation interacts with HFD to affect short-term memory and neural integrity. Balb/c mice (7 weeks, male) were fed a HFD (43% fat, 20 kJ/g) for 16 weeks. In the last 6 weeks, half of the mice were exposed to tobacco-flavoured e-vapour from nicotine-containing (18 mg/L) or nicotine-free (0 mg/L) e-fluids twice daily. Short-term memory function was measured in week 15. HFD alone did not impair memory function, but increased brain phosphorylated (p)-Tau and astrogliosis marker, while neuron and microglia levels were decreased. E-vapour exposure significantly impaired short-term memory function independent of diet and nicotine. Nicotine free e-vapour induced greater changes compared to the nicotine e-vapour and included, increased systemic cytokines, increased brain p-Tau and decreased postsynaptic density protein (PSD)-95 levels in chow-fed mice, and decreased astrogliosis marker, increased microglia and increased glycogen synthase kinase levels in HFD-fed mice. Increased hippocampal apoptosis was also differentially observed in chow and HFD mice. In conclusion, E-vapour exposure impaired short-term memory independent of diet and nicotine, and was correlated to increased systemic inflammation, reduced PSD-95 level and increased astrogliosis in chow-fed mice, but decreased gliosis and increased microglia in HFD-fed mice, indicating the inflammatory nature of e-vapour leading to short term memory impairment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2020.11.028DOI Listing
February 2021

Parental SIRT1 Overexpression Attenuate Metabolic Disorders Due to Maternal High-Fat Feeding.

Int J Mol Sci 2020 Oct 5;21(19). Epub 2020 Oct 5.

Renal medicine, Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, NSW 2065, Australia.

Maternal obesity can contribute to the development of obesity and related metabolic disorders in progeny. Sirtuin (SIRT)1, an essential regulator of metabolism and stress responses, has recently emerged as an important modifying factor of developmental programming. In this study, to elucidate the effects of parental SIRT1 overexpression on offspring mechanism, four experimental groups were included: (1) Chow-fed wild-type (WT)-dam × Chow-fed WT-sire; (2) High-fat diet (HFD)-fed WT-dam × Chow-fed WT-sire; (3) HFD-fed hemizygous SIRT1-transgenic (Tg)-dam × Chow-fed WT-sire; and (4) HFD-fed WT dam × Chow-fed Tg-sire. Our results indicate that Tg breeders had lower body weight and fat mass compared to WT counterparts and gave birth to WT offspring with reductions in body weight, adiposity and hyperlipidaemia compared to those born of WT parents. Maternal SIRT1 overexpression also reversed glucose intolerance, and normalised abnormal fat morphology and the expression of dysregulated lipid metabolism markers, including SIRT1. Despite having persistent hepatic steatosis, offspring born to Tg parents showed an improved balance of hepatic glucose/lipid metabolic markers, as well as reduced levels of inflammatory markers and TGF-β/Smad3 fibrotic signalling. Collectively, the data suggest that parental SIRT1 overexpression can ameliorate adverse metabolic programming effects by maternal obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21197342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582993PMC
October 2020

Offspring sex affects the susceptibility to maternal smoking-induced lung inflammation and the effect of maternal antioxidant supplementation in mice.

J Inflamm (Lond) 2020 5;17:24. Epub 2020 Aug 5.

Faculty of Science, School of Life Sciences, University of Technology Sydney, Sydney, NSW 2007 Australia.

Background: Cigarette smoke exposure (SE) during pregnancy is the largest modifiable risk factor for the development of lung disorders in offspring. We have previously shown that maternal L-Carnitine treatment can reduce the adverse impacts of maternal SE on renal and brain disorders in offspring. Here, we investigated the effect of maternal L-Carnitine supplementation on lung inflammatory pathways, autophagy, and mitophagy markers in the offspring in response to maternal SE.

Methods: Female BALB/c mice (8 weeks) were exposed to cigarette smoke for 6 weeks prior to mating, during gestation and lactation. Some of the SE dams were given L-Carnitine supplementation (1.5 mM in drinking water, SE + LC) during gestation and lactation. Lungs from the offspring were studied at birth and adulthood (13 weeks).

Results: At birth, in male offspring, there were increased levels of inflammatory markers (phosphorylated(p)-ERK1,2, p-P38 MAPK, p- NF-κB), and inflammasome marker (NLRP3), as well as mitophagy fission marker Drp-1 and autophagosome marker (LC3A/B-II) in the lung. Maternal L-Carnitine supplementation significantly reduced NLRP3 level. In contrast, maternal SE only increased IL1-β in female offspring, which was reversed by maternal L-Carnitine supplementation. At 13 weeks, there was an increase in LC3A/B-II and p- NF-κB in the male SE offspring with reduced p-JNK1,2, which were partially normalised by maternal L-Carnitine treatment. Female offspring were not affected by maternal SE at this age.

Conclusion: Maternal SE had adverse impacts on the male offspring's lung, which were partially alleviated by maternal L-Carnitine supplementation. Females seem to be less affected by the adverse effects of maternal SE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12950-020-00253-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409429PMC
August 2020

Replacing smoking with vaping during pregnancy: Impacts on metabolic health in mice.

Reprod Toxicol 2020 Aug 1;96:293-299. Epub 2020 Aug 1.

School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia.

Smoking is a significant risk factor for the development of metabolic diseases. Due to social pressures to quit smoking, many pregnant women are vaping as an alternative nicotine source. However, the metabolic consequences of replacing tobacco cigarettes with e-cigarettes during pregnancy are unknown. Therefore, in the mothers and their offspring, we investigated the metabolic and hepatic impacts of replacing cigarette smoke with e-vapour during pregnancy. Female BALB/c mice were either air-exposed or cigarette smoke-exposed (SE) from six weeks before pregnancy until lactation. At mating, a subset of the SE mice were instead exposed to e-vapour. Markers of glucose and lipid metabolism were measured in the livers and plasma, from the mothers and their male offspring (13 weeks). In the SE mothers, plasma insulin levels were reduced, leading to downstream increases in hepatic gluconeogenesis and plasma non-esterified fatty acids (NEFA). In the e-vapour replacement mothers, these changes were not as significant. In the SE offspring, there was impaired glucose tolerance, and increased plasma NEFA and liver triglyceride concentrations. E-vapour replacement restored lipid homeostasis but did not improve glucose tolerance. Therefore, in a murine model, low dose e-cigarette replacement during pregnancy is less toxic than cigarette smoke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.reprotox.2020.07.012DOI Listing
August 2020

E-cigarettes damage the liver and alter nutrient metabolism in pregnant mice and their offspring.

Ann N Y Acad Sci 2020 09 17;1475(1):64-77. Epub 2020 Jun 17.

School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, New South Wales, Australia.

Approximately 15% of pregnant women vape electronic cigarettes (e-cigarettes), exposing the fetus to a range of toxic compounds, including nicotine and by-products of e-cigarette liquid (e-liquid) pyrolysis. Owing to the recent emergence of these products, research mainly focuses on immediate users, and not on in utero exposure. Therefore, this study aimed to understand the impact of intrauterine e-cigarette vapor (e-vapor) exposure, with and without nicotine, on liver metabolic markers in the male offspring. E-vapor was generated using an e-cigarette filled with tobacco-flavored e-liquid (18 or 0 mg/mL nicotine). Female Balb/c mice were exposed to e-vapor for 6 weeks before mating, through gestation and lactation, without direct exposure to the offspring. Livers and plasma from dams and male offspring (13 weeks old) were examined. Exposure to nicotine-free e-vapor promoted metabolic changes and liver damage in both the dams and their offspring. Furthermore, exposure to nicotine-containing e-vapor did not cause liver damage but induced hepatic steatosis in the adult offspring. Therefore, maternal vaping is detrimental to both the dams and their offspring, with nicotine providing a potential protective effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/nyas.14411DOI Listing
September 2020

Semicarbazide-sensitive amine oxidase inhibition ameliorates albuminuria and glomerulosclerosis but does not improve tubulointerstitial fibrosis in diabetic nephropathy.

PLoS One 2020 18;15(6):e0234617. Epub 2020 Jun 18.

Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, New South Wales, Australia.

Semicarbazide-sensitive amine oxidase (SSAO) is an enzyme with a unique dual function in controlling inflammation as well as reactive oxygen species (ROS) generation. We have demonstrated benefit of SSAO inhibition in acute kidney fibrosis. However the function of SSAO in chronic kidney disease (CKD) and diabetic kidney disease (DKD) is yet to be determined. We aimed to assess the effectiveness of a SSAO inhibitor (SSAOi; PXS-4728A) as an antifibrotic agent using a diabetic model of CKD. Diabetic mice were treated with SSAOi for 24 weeks and outcomes compared with untreated diabetic mice and telmisartan treated animals as a standard of care comparator. Extracellular matrix markers, fibronectin and oxidative stress, were downregulated in diabetic mice treated with SSAOi compared with untreated diabetic mice. Expression of the pan-leukocyte marker CD45 was also supressed by SSAOi. SSAO inhibition in diabetic mice resulted in a significant reduction in glomerulosclerosis and associated albuminuria compared to untreated diabetic mice. However, the effect of SSAO inhibition was less obvious in the tubulointerstitial compartment than in the glomeruli. Therefore, SSAO may be a potential target for diabetic glomerulosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234617PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302447PMC
August 2020

Non-invasive real-time imaging of reactive oxygen species (ROS) using auto-fluorescence multispectral imaging technique: A novel tool for redox biology.

Redox Biol 2020 07 12;34:101561. Epub 2020 May 12.

ARC Centre of Excellence Centre for Nanoscale Biophotonics, University of New South Wales, Kensington, 2052, NSW, Australia.

Detecting reactive oxygen species (ROS) that play a critical role as redox modulators and signalling molecules in biological systems currently requires invasive methods such as ROS -specific indicators for imaging and quantification. We developed a non-invasive, real-time, label-free imaging technique for assessing the level of ROS in live cells and thawed cryopreserved tissues that is compatible with in-vivo imaging. The technique is based on autofluorescence multispectral imaging (AFMI) carried out in an adapted fluorescence microscope with an expanded number of spectral channels spanning specific excitation (365 nm-495 nm) and emission (420 nm-700 nm) wavelength ranges. We established a strong quantitative correlation between the spectral information obtained from AFMI and the level of ROS obtained from CellROX staining. The results were obtained in several cell types (HeLa, PANC1 and mesenchymal stem cells) and in live kidney tissue. Additioanly,two spectral regimes were considered: with and without UV excitation (wavelengths > 400 nm); the latter being suitable for UV-sensitive systems such as the eye. Data were analyzed by linear regression combined with an optimization method of swarm intelligence. This allowed the calibration of AFMI signals to the level of ROS with excellent correlation (R = 0.84, p = 0.00) in the entire spectral range and very good correlation (R = 0.78, p = 0.00) in the limited, UV-free spectral range. We also developed a strong classifier which allowed us to distinguish moderate and high levels of ROS in these two regimes (AUC = 0.91 in the entire spectral range and AUC = 0.78 for UV-free imaging). These results indicate that ROS in cells and tissues can be imaged non-invasively, which opens the way to future clinical applications in conditions where reactive oxygen species are known to contribute to progressive disease such as in ophthalmology, diabetes, kidney disease, cancer and neurodegenerative diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.redox.2020.101561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287272PMC
July 2020

Nitroxides affect neurological deficits and lesion size induced by a rat model of traumatic brain injury.

Nitric Oxide 2020 04 13;97:57-65. Epub 2020 Feb 13.

School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia. Electronic address:

Research has attributed tissue damage post-traumatic brain injury (TBI) to two-pronged effects, increased reactive oxygen species (ROS) and impairment of endogenous antioxidant defence systems, underpinned by manganese superoxide dismutase (MnSOD). Novel antioxidant nitroxides have been shown to mimic MnSOD to ameliorate oxidative stress related disorders. This study aimed to investigate the effects of two nitroxides, CTMIO and DCTEIO, on the neurological outcomes following moderate TBI in rats induced by a weight drop device. The rats were immediately treated with CTMIO and DCTEIO (40 mM in drinking water) post-injury for up to 2 weeks. The brains were histologically examined at 24 h and 6 weeks post injury. DCTEIO reduced the lesion size at both 24h and 6 weeks, with normalised performance in sensory, motor and cognitive tests at 24h post-injury. Astrogliosis was heightened by DCTEIO at 24h and still elevated at 6 weeks in this group. In TBI brains, cellular damage was evident as reflected by changes in markers of mitophagy and autophagy (increased fission marker dynamin-related protein (Drp)-1, and autophagy marker light chain 3 (LC3)A/B and reduced fusion marker optic atrophy (Opa)-1). These were normalised by DCTEIO treatment. CTMIO, on the other hand, seems to be toxic to the injured brains, by increasing injury size at 6 weeks. In conclusion, DCTEIO significantly improved tissue repair and preserved neurological function in rats with TBI possibly via a mitophagy mechanism. This study provides evidence for DCTEIO as a promising new option to alleviate lesion severity after moderate TBI, which is not actively treated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.niox.2020.02.001DOI Listing
April 2020

Pulmonary inflammation induced by low-dose particulate matter exposure in mice.

Am J Physiol Lung Cell Mol Physiol 2019 09 31;317(3):L424-L430. Epub 2019 Jul 31.

School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.

Air pollution is a ubiquitous problem and comprises gaseous and particulate matter (PM). Epidemiological studies have clearly shown that exposure to PM is associated with impaired lung function and the development of lung diseases, such as chronic obstructive pulmonary disease and asthma. To understand the mechanisms involved, animal models are often used. However, the majority of such models represent high levels of exposure and are not representative of the exposure levels in less polluted countries, such as Australia. Therefore, in this study, we aimed to determine whether low dose PM exposure has any detrimental effect on the lungs. Mice were intranasally exposed to saline or traffic-related PM (1μg or 5μg/day) for 3 wk. Bronchoalveolar lavage (BAL) and lung tissue were analyzed. PM at 1 μg did not significantly affect inflammatory and mitochondrial markers. At 5 μg, PM exposure increased lymphocytes and macrophages in BAL fluid. Increased NACHT, LRR and PYD domains-containing protein 3 (NLRP3) and IL-1β production occurred following PM exposure. PM (5 μg) exposure reduced mitochondrial antioxidant manganese superoxide (antioxidant defense system) and mitochondrial fusion marker (OPA-1), while it increased fission marker (Drp-1). Autophagy marker light-chain 3 microtubule-associated protein (LC3)-II and phosphorylated-AMPK were reduced, and apoptosis marker (caspase 3) was increased. No significant change of remodeling markers was observed. In conclusion, a subchronic low-level exposure to PM can have an adverse effect on lung health, which should be taken into consideration for the planning of roads and residential buildings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajplung.00232.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766715PMC
September 2019

A Mitochondrial Specific Antioxidant Reverses Metabolic Dysfunction and Fatty Liver Induced by Maternal Cigarette Smoke in Mice.

Nutrients 2019 Jul 21;11(7). Epub 2019 Jul 21.

School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia.

Maternal smoking leads to glucose and lipid metabolic disorders and hepatic damage in the offspring, potentially due to mitochondrial oxidative stress. Mitoquinone mesylate (MitoQ) is a mitochondrial targeted antioxidant with high bioavailability. This study aimed to examine the impact of maternal cigarette smoke exposure (SE) on offspring's metabolic profile and hepatic damage, and whether maternal MitoQ supplementation during gestation can affect these changes. Female Balb/c mice (eight weeks) were either exposed to air or SE for six weeks prior to mating and throughout gestation and lactation. A subset of the SE dams were supplied with MitoQ in the drinking water (500 µmol/L) during gestation and lactation. Intraperitoneal glucose tolerance test was performed in the male offspring at 12 weeks and the livers and plasma were collected at 13 weeks. Maternal SE induced glucose intolerance, hepatic steatosis, mitochondrial oxidative stress and related damage in the adult offspring. Maternal MitoQ supplementation reduced hepatic mitochondrial oxidative stress and improved markers of mitophagy and mitochondrial biogenesis. This may restore hepatic mitochondrial health and was associated with an amelioration of glucose intolerance, hepatic steatosis and pathological changes induced by maternal SE. MitoQ supplementation may potentially prevent metabolic dysfunction and hepatic pathology induced by intrauterine SE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu11071669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682890PMC
July 2019

Impact of maternal e-cigarette vapor exposure on renal health in the offspring.

Ann N Y Acad Sci 2019 09 17;1452(1):65-77. Epub 2019 Jul 17.

Faculty of Science, School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.

Maternal smoking during pregnancy is a significant risk factor of renal pathology in the offspring. E-cigarettes are perceived to be a safe option and are increasingly used by pregnant women either continuously during pregnancy or as a replacement for tobacco cigarettes. This study aimed to determine the effects of replacing tobacco cigarettes with e-cigarettes during pregnancy, and continuous e-cigarette use during pregnancy on the offspring's kidneys. Female Balb/c mice were exposed to either air (sham) or tobacco cigarette smoke (SE) for 6 weeks prior to mating, during gestation and lactation. A subset of the "SE group" received e-cigarette vapor (containing nicotine) after mating until pups weaned. Additional female mice were continuously exposed to e-vapor (either with or without nicotine) for 6 weeks prior to mating until pups weaned. Kidneys and urine from the male offspring were assessed at postnatal day 1, day 20 (weaning), and 13 weeks of age (adulthood). E-cigarette replacement was less detrimental to renal development and albuminuria than continuous SE during pregnancy. However, continuous e-vapor exposure during pregnancy increased markers of oxidative stress, inflammation, and fibrosis in the adult offspring, independent of nicotine. E-cigarette use during pregnancy confers future risk to the offspring's kidneys.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/nyas.14174DOI Listing
September 2019

SIRT1 Attenuates Kidney Disorders in Male Offspring Due to Maternal High-Fat Diet.

Nutrients 2019 Jan 11;11(1). Epub 2019 Jan 11.

Renal medicine, Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, New South Wales 2065, Australia.

Maternal obesity has been associated with kidney disorders in male offspring. Our previous studies have demonstrated that Sirtuin (SIRT)1, an essential regulator of metabolic stress responses, is suppressed in the offspring as the result of maternal high-fat diet (HFD) consumption, which is likely to underpin the adverse metabolic and renal outcomes. To examine if SIRT1 overexpression or activation early in life can protect the offspring kidney, wild-type (WT) and transgenic (Tg) offspring were born to the same diet-induced obese female C57BL/6 mice through breeding with hemizygous SIRT1-transgenic (Tg) male mice and examined for renal pathological changes. In separate experiments, SIRT1 activator SRT1720 (25 mg/kg/2 days i.p) was administrated in WT offspring over 6 weeks of postnatal high-fat diet exposure. The results show that offspring born to obese dams have increased kidney weight, higher levels of renal triglycerides, and increased expression of oxidative stress, inflammatory, and fibrotic markers, as well as increased albuminuria compared to offspring of control dams. Both SIRT1 overexpression and SRT1720 treatment attenuated renal lipid contents and expression of lipogenesis, oxidative stress, and inflammatory markers; however, fibrosis was modestly reduced and albuminuria was not affected. The findings suggest that SIRT1 therapy can ameliorate some pathological mechanisms of kidney programming due to maternal obesity but may not be sufficient to prevent the resulting chronic kidney injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu11010146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356703PMC
January 2019

SIRT1 overexpression attenuates offspring metabolic and liver disorders as a result of maternal high-fat feeding.

J Physiol 2019 01 31;597(2):467-480. Epub 2018 Oct 31.

Renal medicine, Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.

Key Points: Maternal high-fat diet (MHF) consumption led to metabolic and liver disorders in male offspring, which are associated with reduced sirtuin (SIRT)1 expression and activity in the offspring liver SIRT1 overexpression in MHF offspring reduced their body weight and adiposity and normalized lipid metabolic markers in epididymal and retroperitoneal adipose tissues SIRT1 overexpression in MHF offspring improved glucose tolerance, as well as systemic and hepatic insulin sensitivity SIRT1 overexpression ameliorated MHF-induced lipogenesis, oxidative stress and fibrogenesis in the liver of offspring.

Abstract: Maternal obesity can increase the risk of metabolic disorders in the offspring. However, the underlying mechanism responsible for this is not clearly understood. Previous evidence implied that sirtuin (SIRT)1, a potent regulator of energy metabolism and stress responses, may play an important role. In the present study, we have shown, in C57BL/6 mice, that maternal high-fat diet (HFD) consumption can induce a pre-diabetic and non-alcoholic fatty liver disease phenotype in the offspring, associated with reduced SIRT1 expression in the hypothalamus, white adipose tissues (WAT) and liver. Importantly, the overexpression of SIRT1 in these offspring significantly attenuated the excessive accumulation of epididymal (Epi) white adipose tissue (WAT) and retroperitoneal (Rp)WAT (P < 0.001), glucose intolerance and insulin resistance (both P < 0.05) at weaning age. These changes were associated with the suppression of peroxisome proliferator-activated receptor gamma (PPAR)γ (P < 0.01), PPARγ-coactivator 1-alpha (P < 0.05) and sterol regulatory element-binding protein-1c in EpiWAT (P < 0.01), whereas there was increased expression of PPARγ in RpWAT (P < 0.05). In the liver, PPARγ mRNA expression, as well as Akt protein expression and activity, were increased (P < 0.05), whereas fatty acid synthase and carbohydrate response element binding protein were downregulated (P < 0.05), supporting increased insulin sensitivity and reduced lipogenesis in the liver. In addition, hepatic expression of endogenous anti-oxidants, including glutathione peroxidase 1 and catalase, was increased (P < 0.01 and P < 0.05 respectively), whereas collagen and fibronectin deposition was suppressed (P < 0.01). Collectively, the present study provides direct evidence of the mechanistic significance of SIRT1 in maternal HFD-induced metabolic dysfunction in offspring and suggests that SIRT1 is a promising target for fetal reprogramming.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/JP276957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332732PMC
January 2019

Maternal L-carnitine supplementation ameliorates renal underdevelopment and epigenetic changes in male mice offspring due to maternal smoking.

Clin Exp Pharmacol Physiol 2019 02 22;46(2):183-193. Epub 2018 Nov 22.

Renal Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, New South Wales, Australia.

Objectives: Epidemiological and animal studies showed that L-carnitine (LC) supplementation can ameliorate oxidative stress-induced tissues damage. We have previously shown that maternal cigarette smoke exposure (SE) can increase renal oxidative stress in newborn offspring with postnatal kidney underdevelopment and renal dysfunction in adulthood, which were normalised by LC administration in the SE dams during pregnancy. Exposure to an adverse intrauterine environment may lead to alteration in the epigenome, a mechanism by which adverse prenatal conditions increase the susceptibility to chronic disease later in life. The current study aimed to determine whether maternal SE induces epigenetic changes in the offspring's kidney are associated with renal underdevelopment, and the protective effect of maternal LC supplementation.

Method: Female Balb/c mice (7 weeks) were exposed to cigarette smoke (SE) or air (Sham) for 6 weeks prior to mating, during gestation and lactation. A subgroup of the SE dams received LC via drinking water (SE + LC, 1.5 mmol/L) throughout gestation and lactation. Male offspring were studied at postnatal day (P)1, P20, and 13 weeks.

Results: Maternal SE altered the expression of renal development markers glial cell line-derived neurotrophic factor and fibroblast growth factor 2, which were associated with increased renal global DNA methylation and DNA methyltransferase 1 mRNA expression at birth. These disorders were reversed by maternal LC administration.

Conclusion: The effect of maternal SE on renal underdevelopment involves global epigenetic alterations from birth, which can be prevented by maternal LC supplementation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1440-1681.13038DOI Listing
February 2019

Heat or Burn? Impacts of Intrauterine Tobacco Smoke and E-Cigarette Vapor Exposure on the Offspring's Health Outcome.

Toxics 2018 Aug 1;6(3). Epub 2018 Aug 1.

School of Life Sciences, University of Technology Sydney, Sydney, NSW 2007, Australia.

Maternal smoking during pregnancy leads to gestational complications and organ disorders in the offspring. As nicotine replacement therapy is often ineffective for smoking cessation, pregnant women turn to alternatives such as heat-not-burn tobacco and e-cigarettes. Recently, the popularly of e-cigarettes has been increasing especially among the youth and pregnant women, mainly due to the advertisements claiming their safety. This has even led to some clinicians recommending their use during pregnancy. E-cigarettes heat e-liquid to produce an aerosol (e-vapor), delivering flavorings and nicotine to the user. However, e-vapor also contains toxins such as formaldehyde along with heavy metals and carcinogenic nitrosamines. In addition, specific flavoring compounds such as diacetyl can be toxic themselves or decompose into toxic compounds such as benzaldehydes. These compounds can induce toxicity, inflammation and oxidative stress in the mothers and can accumulate in the developing fetus, affecting intrauterine development. Recent animal studies suggest that maternal e-vapor exposure during pregnancy could cause respiratory and neurological disorders in the offspring. This review will examine the available literature to shed light on the current understanding of this problem-to-be from lessons learned in animal models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/toxics6030043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160993PMC
August 2018

L-Carnitine and extendin-4 improve outcomes following moderate brain contusion injury.

Sci Rep 2018 07 25;8(1):11201. Epub 2018 Jul 25.

School of Life Sciences, Faculty of Science, University of Technology Sydney, Broadway, NSW, 2007, Australia.

There is a need for pharmaceutical agents that can reduce neuronal loss and improve functional deficits following traumatic brain injury (TBI). Previous research suggests that oxidative stress and mitochondrial dysfunction play a major role in neuronal damage after TBI. Therefore, this study aimed to investigate two drugs known to have antioxidant effects, L-carnitine and exendin-4, in rats with moderate contusive TBI. L-carnitine (1.5 mM in drinking water) or exendin-4 (15 µg/kg/day, ip) were given immediately after the injury for 2 weeks. Neurological function and brain histology were examined (24 h and 6 weeks post injury). The rats with TBI showed slight sensory, motor and memory functional deficits at 24 h, but recovered by 6 weeks. Both treatments improved sensory and motor functions at 24 h, while only exendin-4 improved memory. Both treatments reduced cortical contusion at 24 h and 6 weeks, however neither affected gliosis and inflammatory cell activation. Oxidative stress was alleviated and mitochondrial reactive oxygen species was reduced by both treatments, however only mitochondrial functional marker protein transporter translocase of outer membrane 20 was increased at 24 h post injury. In conclusion, L-carnitine and exendin-4 treatments immediately after TBI can improve neurological functional outcome and tissue integrity by reducing oxidative stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-29430-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060156PMC
July 2018

Modulation of neural regulators of energy homeostasis, and of inflammation, in the pups of mice exposed to e-cigarettes.

Neurosci Lett 2018 09 4;684:61-66. Epub 2018 Jul 4.

School of Life Sciences & Centre for Health Technologies, Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007, Australia; Respiratory Cellular and Molecular Biology, Woolcock Institute of Medical Research, The University of Sydney, NSW, 2037, Australia. Electronic address:

Background: Maternal smoking can lead to perturbations in central metabolic regulators such as neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) signalling components in offspring. With the growing interest in e-cigarettes as a tobacco replacement, this short report assessed central metabolic regulation in offspring of mouse dams exposed to e-cigarettes. We examined the impact of continuous use of e-cigarettes, and e-cigarette replacement of tobacco cigarettes during pregnancy. Supplementation of an antioxidant l-carnitine was also co-used with tobacco cigarette in the mother to determine whether the impact of maternal tobacco smoking was oxidative stress driven.

Methods: Balb/c mice were exposed to either nicotine-containing (E-cig18) or nicotine-free (E-cig0) e-cigarette aerosols or tobacco smoke (SE) prior to mating and until their pups were weaned. After mating, two SE sub-groups were changed to E-cig18 exposure (Replacement), or supplementation l-carnitine while SE was continued. Male offspring were studied at weaning age.

Results: The offspring of E-cig0 dams were the heaviest with the most body fat. Replacing SE with E-cig18 during pregnancy resulted in offspring with significantly less body fat. E-cig0 offspring had significantly increased mRNA expression of brain NPY and iNOS. Maternal SE upregulated mRNA expression of NPY, NPY Y1 receptor, POMC downstream components, and iNOS expression, which were normalised in Replacement offspring, but only partially normalised with maternal L-carnitine supplementation during gestation and lactation.

Conclusions: Maternal exposure to either tobacco and nicotine-free e-cigarettes lead to disturbances in the level of central homeostatic control markers in offspring, suggesting that maternal exposure to e-cigarettes is not without risks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neulet.2018.07.001DOI Listing
September 2018

Lysyl oxidase-like 2 inhibition ameliorates glomerulosclerosis and albuminuria in diabetic nephropathy.

Sci Rep 2018 06 21;8(1):9423. Epub 2018 Jun 21.

Renal Research, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Sydney, Australia.

Diabetic nephropathy is characterised by the excessive amount of extracellular matrix in glomeruli and tubulointerstitial space. Lysyl oxidase-like 2 (LOXL2) is elevated in renal fibrosis and known to play key roles in ECM stabilisation by facilitating collagen cross-links, epithelial to mesenchymal transition and myofibroblast activation. Thus, targeting LOXL2 may prove to be a useful strategy to prevent diabetic nephropathy. We explored the renoprotective effect of a selective small molecule LOXL2 inhibitor (PXS-S2B) in a streptozotocin-induced diabetes model. Diabetic mice were treated with PXS-S2B for 24 weeks and outcomes compared with untreated diabetic mice and with telmisartan treated animals as comparator of current standard of care. Diabetic mice had albuminuria, higher glomerulosclerosis scores, upregulation of fibrosis markers and increased renal cortical LOXL2 expression. Treatment with PXS-S2B reduced albuminuria and ameliorated glomerulosclerosis. This was associated with reduced expression of glomerular fibronectin and tubulointerstitial collagen I. The renoprotective effects of both PXS-S2B and telmisartan were more marked in the glomerular compartment than in the tubulointerstitial space. The study reveals that LOXL2 inhibition was beneficial in preserving glomerular structure and function. Thus, LOXL2 may be a potential therapeutic target in diabetic nephropathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-27462-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013429PMC
June 2018

MitoQ supplementation prevent long-term impact of maternal smoking on renal development, oxidative stress and mitochondrial density in male mice offspring.

Sci Rep 2018 04 26;8(1):6631. Epub 2018 Apr 26.

School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007, Australia.

To investigate the effect of maternal MitoQ treatment on renal disorders caused by maternal cigarette smoke exposure (SE). We have demonstrated that maternal SE during pregnancy increases the risk of developing chronic kidney disease (CKD) in adult offspring. Mitochondrial oxidative damage contributes to the adverse effects of maternal smoking on renal disorders. MitoQ is a mitochondria-targeted antioxidant that has been shown to protect against oxidative damage-related pathologies in many diseases. Female Balb/c mice (8 weeks) were divided into Sham (exposed to air), SE (exposed to cigarette smoke) and SEMQ (exposed to cigarette smoke with MitoQ supplemented from mating) groups. Kidneys from the mothers were collected when the pups weaned and those from the offspring were collected at 13 weeks. Maternal MitoQ supplementation during gestation and lactation significantly reversed the adverse impact of maternal SE on offspring's body weight, kidney mass and renal pathology. MitoQ administration also significantly reversed the impact of SE on the renal cellular mitochondrial density and renal total reactive oxygen species in both the mothers and their offspring in adulthood. Our results suggested that MitoQ supplementation can mitigate the adverse impact of maternal SE on offspring's renal pathology, renal oxidative stress and mitochondrial density in mice offspring.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-24949-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919980PMC
April 2018

DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease.

FASEB J 2018 10 24;32(10):5215-5226. Epub 2018 Apr 24.

Renal Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.

Chronic kidney disease (CKD) is a global epidemic, and its major risk factors include obesity and type 2 diabetes. Obesity not only promotes metabolic dysregulation and the development of diabetic kidney disease but also may independently lead to CKD by a variety of mechanisms, including endocrine and metabolic dysfunction, inflammation, oxidative stress, altered renal hemodynamics, and lipotoxicity. Deleterious renal effects of obesity can also be transmitted from one generation to the next, and it is increasingly recognized that offspring of obese mothers are predisposed to CKD. Epigenetic modifications are changes that regulate gene expression without altering the DNA sequence. Of these, DNA methylation is the most studied. Epigenetic imprints, particularly DNA methylation, are laid down during critical periods of fetal development, and they may provide a mechanism by which maternal-fetal transmission of chronic disease occurs. Our current review explores the evidence for the role of DNA methylation in the development of CKD, diabetic kidney disease, diabetes, and obesity. DNA methylation has been implicated in renal fibrosis-the final pathophysiologic pathway in the development of end-stage kidney disease-which supports the notion that demethylating agents may play a potential therapeutic role in preventing development and progression of CKD.-Larkin, B. P., Glastras, S. J., Chen, H., Pollock, C. A., Saad, S. DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201800205RDOI Listing
October 2018

SRT1720 attenuates obesity and insulin resistance but not liver damage in the offspring due to maternal and postnatal high-fat diet consumption.

Am J Physiol Endocrinol Metab 2018 08 13;315(2):E196-E203. Epub 2018 Mar 13.

Renal Medicine, Kolling Institute, Royal North Shore Hospital, University of Sydney , Sydney, New South Wales , Australia.

Recent studies indicate that sirtuin-1 (SIRT1), an important metabolic sensor and regulator of life span, plays a mechanistic role in maternal obesity-induced programming of metabolic disorders in the offspring. In this study we investigate whether SIRT1 activation in early childhood can mitigate metabolic disorders due to maternal and postnatal high-fat feeding in mice. Male offspring born to chow-fed (MC) or high fat diet-fed dams (MHF) were weaned onto postnatal chow or high-fat diet and treated with SRT1720 (25 mg/kg ip every 2 days) or vehicle control for 6 wk and examined for metabolic disorders. MHF exacerbated offspring body weight and insulin resistance in the offspring exposed to postnatal HFD (OHF). These metabolic changes were associated with reduced hepatic lipid droplet accumulation but increased plasma levels of alanine aminotransferase (ALT), a marker of liver damage. SRT1720 significantly decreased offspring body weight, adiposity, glucose intolerance, and hyperleptinemia due to OHF and reversed hyperinsulinemia and adipocyte hypertrophy due to the additive effects of MHF. Although SRT1720 suppresses liver lipogenesis, inflammation, and oxidative stress markers, it also reduces antioxidants and increased liver collagen deposition in OHF offspring independent of MHF. Hepatic steatosis was attenuated only in MC/OHF offspring in association with elevated plasma ALT levels. The study suggests that postnatal SRT1720 administration can mitigate obesity and insulin resistance in the offspring due to maternal and postnatal HFD exposure. However, the possibility of liver toxicity needs to be further examined.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpendo.00472.2017DOI Listing
August 2018

Maternal obesity increases the risk of metabolic disease and impacts renal health in offspring.

Biosci Rep 2018 04 29;38(2). Epub 2018 Mar 29.

Department of Medicine, Kolling Institute, University of Sydney, Sydney, Australia.

Obesity, together with insulin resistance, promotes multiple metabolic abnormalities and is strongly associated with an increased risk of chronic disease including type 2 diabetes (T2D), hypertension, cardiovascular disease, non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). The incidence of obesity continues to rise in astronomical proportions throughout the world and affects all the different stages of the lifespan. Importantly, the proportion of women of reproductive age who are overweight or obese is increasing at an alarming rate and has potential ramifications for offspring health and disease risk. Evidence suggests a strong link between the intrauterine environment and disease programming. The current review will describe the importance of the intrauterine environment in the development of metabolic disease, including kidney disease. It will detail the known mechanisms of fetal programming, including the role of epigenetic modulation. The evidence for the role of maternal obesity in the developmental programming of CKD is derived mostly from our rodent models which will be described. The clinical implication of such findings will also be discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/BSR20180050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874265PMC
April 2018

Maternal Cigarette Smoke Exposure Worsens Neurological Outcomes in Adolescent Offspring with Hypoxic-Ischemic Injury.

Front Mol Neurosci 2017 26;10:306. Epub 2017 Sep 26.

School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia.

Hypoxic-ischemic (HI) encephalopathy occurs in approximately 6 per 1000 term newborns leading to devastating neurological consequences, such as cerebral palsy and seizures. Maternal smoking is one of the prominent risk factors contributing to HI injury. Mitochondrial integrity plays a critical role in neural injury and repair during HI. We previously showed that maternal cigarette smoke exposure (SE) can reduce brain mitochondrial fission and autophagosome markers in male offspring. This was accompanied by increased brain cell apoptosis (active caspase-3) and DNA fragmentation (TUNEL staining). Here, we aimed to investigate whether maternal SE leads to more severe neurological damage after HI brain injury in male offspring. Female BALB/c mice (8 weeks) were exposed to cigarette smoke prior to mating, during gestation, and lactation. At postnatal day 10, half of the pups from each litter underwent left carotid artery occlusion, followed by exposure to 8% oxygen (92% nitrogen). At postnatal day 40-44, maternal SE reduced grip strength in grip traction and foot fault tests, which were also reduced by HI injury to similar levels regardless of the maternal group. Limb coordination was impaired by maternal SE which was not worsened by HI injury. Maternal SE increased anxiety level in the offspring, which was normalized by HI injury. Apoptosis markers were increased in different brain regions by maternal SE, with the cortex having further increased TUNEL by HI injury, along with increased markers of inflammation and mitophagy. We conclude that maternal SE can worsen HI-induced cellular damage in male offspring well into adolescence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnmol.2017.00306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623008PMC
September 2017

SIRT1 reduction is associated with sex-specific dysregulation of renal lipid metabolism and stress responses in offspring by maternal high-fat diet.

Sci Rep 2017 08 21;7(1):8982. Epub 2017 Aug 21.

Renal medicine, Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, New South Wales, Australia.

Rodent models of maternal obesity have been associated with kidney damage and dysfunction in offspring. However, the underlying mechanisms are yet to be elucidated. In this study, female rats were fed a high-fat diet (HFD) for 6 weeks prior to mating, throughout gestation and lactation; both male and female offspring were examined at weaning. Our results demonstrate that renal lipid deposition was increased in male offspring only, which is associated with reduced protein expression of Sirtuin (SIRT) 1, an essential regulator of lipid metabolism and stress response. Other components in its signalling network including phosphorylated 5'-AMP-activated protein kinase (pAMPKα), Forkhead box FOXO3a and Peroxisome proliferator-activated receptor (PPAR)γ coactivator 1-alpha (PGC-1α) were also downregulated. By contrast, in female offspring, renal fat/lipid distribution was unchanged in coupling with normal SIRT1 regulation. Specific autophagy and antioxidant markers were suppressed in both sexes. On the other hand, fibronectin and Collagen type IV protein expression was significantly higher in the offspring born HFD-fed dams, particularly in the males. Collectively, these findings suggest that maternal HFD consumption can induce sex-specific changes in offspring kidney lipid metabolism and stress responses at early ages, which may underpin the risk of kidney diseases later in life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-08694-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567163PMC
August 2017

Effect of long-term maternal smoking on the offspring's lung health.

Am J Physiol Lung Cell Mol Physiol 2017 08 18;313(2):L416-L423. Epub 2017 May 18.

Centre for Health Technologies & Molecular Biosciences, School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia;

Maternal smoking during pregnancy contributes to long-term health problems in offspring, especially respiratory disorders that can manifest in either childhood or adulthood. Receptors for advanced glycation end products (RAGE) are multiligand receptors abundantly localized in the lung, capable of responding to by-products of reactive oxygen species and proinflammatory responses. RAGE signaling is a key regulator of inflammation in cigarette smoking-related pulmonary diseases. However, the impact of maternal cigarette smoke exposure on lung RAGE signaling in the offspring is unclear. This study aims to investigate the effect of maternal cigarette smoke exposure (SE), as well as mitochondria-targeted antioxidant [mitoquinone mesylate (MitoQ)] treatment, during pregnancy on the RAGE-mediated signaling pathway in the lung of male offspring. Female Balb/c mice (8 wk) were divided into a sham group (exposed to air), an SE group (exposed to cigarette smoke), and an SE + MQ group (exposed to cigarette smoke with MitoQ supplement from mating). The lungs from male offspring were collected at 13 wk. RAGE and its downstream signaling, including nuclear factor-κB and mitogen-activated protein kinase family consisting of extracellular signal-regulated kinase 1, ERK2, c-JUN NH-terminal kinase (JNK), and phosphorylated JNK, in the lung were significantly increased in the SE offspring. Mitochondrial antioxidant manganese superoxide dismutase was reduced, whereas IL-1β and oxidative stress response nuclear factor (erythroid-derived 2)-like 2 were significantly increased in the SE offspring. Maternal MitoQ treatment normalized RAGE, IL-1β, and Nrf-2 levels in the SE + MQ offspring. Maternal SE increased RAGE and its signaling elements associated with increased oxidative stress and inflammatory cytokines in offspring lungs, whereas maternal MitoQ treatment can partially normalize these changes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajplung.00134.2017DOI Listing
August 2017
-->