Mitochondrial dysfunction as a potential pathway linking DL-PCB exposure to intrauterine growth retardation.

The role of the kidney in the pathogenesis of hypertension has long been established, although recent studies challenge renal hegemony and suggest an important role for vascular cells as well (1,2). In recent years, the formulation has expanded and now includes the concept that chronic hypertension and kidney disease are also related to events that occur during the prenatal period and usually result in low birth weight (LBW). A recent overview considered the role of fetal programming in the development of adult kidney disease and hypertension (3). The aim of this review is to present further evidence to support an association between LBW and the increased prevalence of hypertension as well as progression toward chronic kidney disease (CKD) in adult life. Various potential mechanisms for this association are discussed, specifically the low nephron number (LNN) hypothesis and related cellular and molecular mechanisms that have been proposed. LBW infants are defined as infants who weigh ≤2500 g at birth. Infants who are delivered before 37 wk from the first day of the last menstrual period are termed preterm. The LBW infant population can be divided into preterm, appropriate for gestational age (AGA), or small for gestational age (SGA). The predominant cause of LBW infants in the United States is preterm birth, whereas in developing countries, the cause is often intrauterine growth restriction (IUGR). During the year 2004, 8.1% of births in the United States were LBW, and more than half of these were preterm. During the past two decades, there has been an increase in the prevalence of LBW as higher risk pregnancies progress to term and postnatal survival improves (4) (Figure 1). Figure 1. Percentage of infants who were born preterm and percentage who were born with low birth weight (LBW; defined in text): United States, 1990, 1995, 2000, …

The present study investigated the potential of polydatin to protect against liver injury and the mitochondrial dysfunction of weanling piglets suffering from intra-uterine growth retardation (IUGR). Thirty-six normal birth weight weanling piglets and an equal number of IUGR littermates were given a basal diet with or without polydatin (250 mg/kg) from 21 to 35 d of age. Plasma and liver samples were collected to measure biochemistry parameters at 35 d of age. IUGR caused hepatic apoptosis, mitochondrial dysfunction, and oxidative damage, along with a lower efficiency of energy metabolism and inferior antioxidant ability. Polydatin decreased apoptotic rate, improved the features of mitochondrial damage, inhibited mitochondrial swelling and superoxide anion formation, and preserved mitochondrial membrane potential in the liver. Concurrently, polydatin promoted mitochondrial biogenesis, increased sirtuin 1 activity, and upregulated the expression levels of several genes related to mitochondrial function and fitness. Polydatin also facilitated mitochondrial oxidative metabolism with a beneficial outcome of increased energy production. Furthermore, polydatin mitigated the IUGR-induced reduction in manganese superoxide dismutase activity and prevented the excessive accumulation of oxidative damaging products in the liver. These findings indicate that polydatin confers protection against hepatic injury and mitochondrial dysfunction in the IUGR piglets by improving energy metabolism and redox balance.

Introduction: Fetuses that do not grow to normal weight in utero, also known as intrauterine growth restriction (IUGR), have an increased risk of developing hypertension (HTN) in adulthood, especially males. The sex difference in blood pressure may be due to cerebral mitochondrial dysfunction and oxidative stress. Epigenetic changes, such as miRNA, can alter mitochondrial development, structure, and function to increase oxidative stress. The purpose of this study is to observe the changes in differentially expressed miRNAs and blood pressure of male (M) and female (F) IUGR rats. We hypothesize that adult IUGR rats, particularly males, will display high blood pressure (HBP) and increased expression of miRNAs that influence cerebrum mitochondrial function, electron transport chain (ETC) proteins, and oxidative stress. Methods: To perform these experiments, IUGR and control (CON) M and F Sprague Dawley rats were evaluated at 16-18 weeks (adulthood). CON pups were produced from normal pregnant dams, and IUGR pups were generated from placental ischemic dams. Results: Results show that IUGR M have HBP (136±2 vs 120±7 mmHg, p=0.0488) compared to CON M, while IUGR F exhibit no difference in blood pressure vs CON F. Using Ingenuity Pathway Analysis (IPA), we identified 11 differentially expressed miRNAs in IUGR vs CON rats. Nine miRNAs that were differentially expressed in IUGR M vs CON M, six miRNAs in IUGR F vs CON F, and four shared downregulated miRNAs in IUGR rats from both sexes. miRNA let-7d-3p was uniquely upregulated in IUGR M vs CON M and had a 1.2-fold increase in expression between IUGR M vs CON M (1.2±0.2 vs 1.0±0.1-fold-change, ns ) with qPCR. GFM-1, the gene for mitochondrial elongation factor G1 that is predicted to be regulated by let-7d-3p, increased in IUGR F vs CON F (114±2 vs 100±4 IU/Protein/CON%, p=0.013) and did not change in M. ETC proteins were unchanged in M, but complexes 3 (110±4 vs 100±2 IU/Protein/CON%, p=0.068) and 4 (121.1±4.3 vs 100±5.5 IU/Protein/CON%, p=0.013) were elevated in IUGR F vs CON F. There were no alterations in oxidative stress for F, but a ~50% increase in H2O2 concentration in IUGR M vs CON M (3.3±0.9 vs 1.8±0.4 nmol H2O2/mg Protein, p=0.1254). Conclusion: In summary, IUGR M have HBP and an increase in let-7d-3p expression in the cerebrum. We predict that the increase in let-7d-3p inhibited the compensatory increase in GFM-1 and ETC proteins that are needed to prevent cerebrum oxidative stress and HBP in IUGR M. However, unchanged let-7d-3p in IUGR F vs CON F, allowed for the increase in GFM-1 and ETC proteins to inhibit cerebrum mitochondrial dysfunction, oxidative stress, and HBP. Findings from this study will provide insights into the pathway linking epigenetic changes to mitochondrial dysfunction, oxidative stress, and HTN in adults born IUGR. Neurobiology of Aging and Alzheimer’s Disease Training Program (NIH T32AG020494), start-up (Cunningham), and AHA Career Development (AHA 18CDA34110264, Cunningham) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Intrauterine growth retardation is recognized as one of the leading causes of incidence and mortality in infancy and early childhood in all the countries of the world. The causes and mechanisms of development of this process are decisive when choosing the tactics of nursing such children. Of particular importance is the understanding of the functioning of the mother-placenta-fetus system, in particular the mechanisms of suppression of the detoxification function of the placenta in connection with the polymorphisms of the genes of the I and II phases of the xenobiotic biotransformation system. The aim of the study was to determine the relationship between the polymorphism of the genes of the I and II phases of the xenobiotic biotransformation system with the intrauterine fetal growth retardation in women living in the South of the Kemerovo region and working under harmful labor conditions. A survey of 39 women of reproductive age living in the territory of Novokuznetsk was carried out, 20 of them worked at various enterprises of the city. The study group included 14 women who gave birth to children with intrauterine growth retardation of varying severity. The comparison group (control) consisted of 25 women. They did not have spontaneous miscarriages and they carried a child without the intrauterine growth retardation. The work investigated the frequency of occurrence of polymorphisms of genes of the xenobiotic biotransformation system - CYP1A2*1F, GSTM1 (they determine the activity of detoxification enzymes), as well as their combinations - in a group of working women and housewives who gave birth to children with intrauterine growth retardation. The forms of genes associated with the intrauterine fetal growth retardation, as well as genes associated with the resistance to this pathology, were identified. Combinations of gene forms of different phases of the xenobiotic biotransformation and their relationship with intrauterine fetal growth retardation were shown. There were no statistically reliable differences between various cohorts of women. A positive association of a high risk of the intrauterine fetal growth retardation in women with A/A CYP1A2*1F genotype and deletion polymorphism of the GSTM1 "-" gene has been shown. The heterozygous form of the C/A CYP1A2*1F gene polymorphism is statistically reliably associated with the resistance to this pathology, as well as the normally functioning GSTM1 "+" gene. Genotype A/A CYP1A2*1F in the combination with the deletion polymorphism of GSTM1 "-" gene is statistically reliably associated with intrauterine fetal growth retardation, and C/A CYP1A2*1F genotype in the combination with normally functioning GSTM1 "+" gene is associated with a low risk of the intrauterine fetal growth retardation. Comparative analysis of the relationship of the studied forms of genes of the xenobiotic biotransformation system with the intrauterine fetal growth retardation in the groups of female workers and housewives did not show statistically reliable differences.

Placental ischemia (PI), a prenatal stressor, affects ∼1 in 10 human pregnancies worldwide and is associated with several pregnancy complications such as preeclampsia, placental abruption, and intrauterine growth restriction (IUGR). Both human and animal IUGR fetuses have an increased risk of developing hypertension (HTN) in adulthood, with males having a higher risk. Furthermore, multiple studies suggest that changes in brain function and molecular markers may contribute to HTN development. However, the alterations in brain mitochondrial dysfunction (MtDys), oxidative stress (OS), and epigenetic changes (miRNAs) in forebrain and midbrain collectively have not been investigated. Thus, we hypothesize that the sex difference in high blood pressure (HBP) is due to changes in miRNAs, brain MtDys, and increased OS in IUGR males (M) but not IUGR females (F). To test this hypothesis, IUGR and control (CON) M and F Sprague Dawley rats were evaluated at 16-18 wk (adulthood). IUGR adults were generated from PI dams, and CON adults from normal pregnant dams. Results identified 11 differentially expressed miRNAs in IUGR versus CON, with let-7d-3p miRNA being upregulated in IUGR M. IUGR M also displayed HBP, MtDys [decreased adenosine triphosphate (ATP)], and OS (∼50% increase in hydrogen peroxide). Conversely, mitochondrial G protein elongation factor (GFM-1), a protein regulated by let-7d-3p, and electron transport chain (ETC) proteins were increased with no changes in ATP production in IUGR F. In summary, our data suggest that increases in let-7d-3p will inhibit the compensatory increase in GFM-1 and ETC proteins needed to prevent HBP and cerebral OS in IUGR M. However, unchanged let-7d-3p may increase GFM-1 and ETC proteins in IUGR F to inhibit brain MtDys, OS, and HBP. Findings from this study provide insights into the mechanisms linking epigenetic changes to brain MtDys and OS along with HTN in adults born IUGR.NEW & NOTEWORTHY Adult IUGR male rodent offspring exposed to placental ischemia in utero have elevated mean arterial blood pressure with increased brain miRNA let-7d-3p expression, mitochondrial dysfunction, and oxidative stress, while adult IUGR females do not. Moreover, our results suggest that brain epigenetic changes may contribute to mitochondrial dysfunction and oxidative stress, eventually leading to hypertension. In conclusion, lifetime health begins in utero, and patients and healthcare providers should be aware of the consequences that prenatal stressors have on long-term health.

Fetal growth restriction (FGR) and pre-eclampsia with fetal growth restriction (PE/FGR) are high-risk perinatal diseases that may involve high levels of human chorionic gonadotropin (hCG) and mitochondrial dysfunction. However, little is known about how these factors affect placental function. We investigated how mitochondrial dysfunction and high hCG expression affected placental function in unexplained FGR and PE/FGR. We observed elevated expression of hCGβ and growth differentiation factor 15 mRNA and protein levels in the placenta with both diseases. Likewise, antiangiogenic factors, such as Ang2, IP10, sFlt1, IL8, IL1B, and TNFα, were also upregulated at the mRNA level. In addition, the expression of COXI and COXII which encoded by mitochondrial DNA were significantly decreased in both diseases, suggesting that mitochondrial translation was impaired. Treatment with hCG increased Ang2, IP10, IL8, and TNFα mRNA levels in a dose-dependent manner via the p38 and JNK pathways. Mitochondrial translation inhibitors increased hCGβ expression through stabilization of HIF1α, and increased IL8 and TNFα mRNA expression. These results revealed that high expression of hCG due to mitochondrial translational dysfunction plays an important role in the pathogenesis of FGR and PE/FGR.

A key adaptation enabling the fetus to survive in a limited energy environment may be the reprogramming of mitochondrial function, which can have deleterious effects. Critical questions are whether mitochondrial dysfunction progressively declines after birth, and if so, what mechanism might underlie this process. To address this, we developed a model of intrauterine growth retardation (IUGR) in the rat that leads to diabetes in adulthood. Reactive oxygen species (ROS) production and oxidative stress gradually increased in IUGR islets. ATP production was impaired and continued to deteriorate with age. The activities of complex I and III of the electron transport chain progressively declined in IUGR islets. Mitochondrial DNA point mutations accumulated with age and were associated with decreased mitochondrial DNA content and reduced expression of mitochondria-encoded genes in IUGR islets. Mitochondrial dysfunction resulted in impaired insulin secretion. These results demonstrate that IUGR induces mitochondrial dysfunction in the fetal beta-cell, leading to increased production of ROS, which in turn damage mitochondrial DNA. A self-reinforcing cycle of progressive deterioration in mitochondrial function leads to a corresponding decline in beta-cell function. Finally, a threshold in mitochondrial dysfunction and ROS production is reached, and diabetes ensues.

TCDD-Induced Mitochondrial Dysfunction in Trophoblast

Mutations in the gene encoding the enzyme tafazzin, TAZ, cause Barth syndrome (BTHS). Individuals with this X-linked multisystem disorder present cardiomyopathy (CM) (often dilated), skeletal muscle weakness, neutropenia, growth retardation, and 3-methylglutaconic aciduria. Biopsies of the heart, liver and skeletal muscle of patients have revealed mitochondrial malformations and dysfunctions. It is the purpose of this review to summarize recent results of studies on various animal or cell models of Barth syndrome, which have characterized biochemically the strong cellular defects associated with TAZ mutations. Tafazzin is a mitochondrial phospholipidlysophospholipid transacylase that shuttles acyl groups between phospholipids and regulates the remodeling of cardiolipin (CL), a unique inner mitochondrial membrane phospholipid dimer consisting of two phosphatidyl residues linked by a glycerol bridge. After their biosynthesis, the acyl chains of CLs may be modified in remodeling processes involving up to three different enzymes. Their characteristic acyl chain composition depends on the function of tafazzin, although the enzyme itself surprisingly lacks acyl specificity. CLs are crucial for correct mitochondrial structure and function. In addition to their function in the basic mitochondrial function of ATP production, CLs play essential roles in cardiac function, apoptosis, autophagy, cell cycle regulation and Fe-S cluster biosynthesis. Recent developments in tafazzin research have provided strong insights into the link between mitochondrial dysfunction and the production of reactive oxygen species (ROS). An important tool has been the generation of BTHS-specific induced pluripotent stem cells (iPSCs) from BTHS patients. In a complementary approach, disease-specific mutations have been introduced into wild-type iPSC lines enabling direct comparison with isogenic controls. iPSC-derived cardiomyocytes were then characterized using biochemical and classical bioenergetic approaches. The cells are tested in a “heart-on-chip” assay to model the pathophysiology in vitro, to characterize the underlying mechanism of BTHS deriving from TAZ mutations, mitochondrial deficiencies and ROS production and leading to tissue defects, and to evaluate potential therapies with the use of mitochondrially targeted antioxidants.

Both short telomere length and mitochondrial dysfunction have been associated with pregnancy complications, such as preeclampsia and intrauterine growth restriction. However, the relationship between these two biomarkers of oxidative stress, during pregnancy, is unknown. This study investigated the association of leukocyte telomere length with mitochondrial DNA (mtDNA) copy number, an indicator of mitochondrial density and possible mitochondrial dysfunction, using maternal blood samples collected from women with pregnancies uncomplicated by gestational diabetes or hypertensive disorders. Leukocyte telomere length and mtDNA copy number were determined in 75 pregnant women using quantitative real-time quantitative PCR. Bivariate and multivariable linear regression procedures were used to evaluate associations of these two biomarkers. Leukocyte mtDNA copy number (natural-logarithm) was positively associated with telomere length (Pearson correlation coefficient = 0.30, p-value = 0.009). After adjusting for maternal age and plasma vitamin B12, natural-log mtDNA copy number increased by 0.80 (f = 0.80; 95% CI 0.25 - 1.34, p-value = 0.005) for every 1 unit increase of telomere length. Approximately 11% of the variation in natural-long mtDNA copy number was explained by the model (adjusted R2 = 0.11). This cross sectional data suggests an association of mtDNA copy number with telomere length, two emergent biological markers of potential importance in perinatal health research. The consequences of oxidative stress, cellular senescence (as reflected by relatively shorter telomere length) and mitochondrial dysfunction, on the course and outcomes of pregnancy remain to be elucidated in larger prospective studies that include these biological markers.

Intrauterine growth retardation (IUGR) is a risk factor of type 2 diabetes (T2DM) with complicated mechanisms.Existence of predisposing genes of T2DM,abnormal regulation of epigenetic alterations such as acetylation of histone,methylation of DNA and gene scilence,insulin resistance and impaired β cell functions,activation of oxidative stress,mitochondrial dysfunctions and improperly elevated levels of glucocorticoids and insulin-like growth factor-1 are important factors.Clarificating the relationships of IUGR and T2DM will supply the new direction of prevention and treatment for T2DM. Key words: Intrauterine growth retardation; Type 2 diabetes mellitus; β Cell function; Epigenetic; Oxidative stress

Dimethylglycine sodium salt activates Nrf2/SIRT1/PGC1α leading to the recovery of muscle stem cell dysfunction in newborns with intrauterine growth restriction

The rates of gestational cannabis use have increased despite limited evidence for its safety in fetal life. Recent animal studies demonstrate that prenatal exposure to Δ9-tetrahydrocannabinol (Δ9-THC, the psychoactive component of cannabis) promotes intrauterine growth restriction (IUGR), culminating in postnatal metabolic deficits. Given IUGR is associated with impaired hepatic function, we hypothesized that Δ9-THC offspring would exhibit hepatic dyslipidemia. Pregnant Wistar rat dams received daily injections of vehicular control or 3 mg/kg Δ9-THC i.p. from embryonic day (E) 6.5 through E22. Exposure to Δ9-THC decreased the liver to body weight ratio at birth, followed by catch-up growth by three weeks of age. At six months, Δ9-THC-exposed male offspring exhibited increased visceral adiposity and higher hepatic triglycerides. This was instigated by augmented expression of enzymes involved in triglyceride synthesis (ACCα, SCD, FABP1, and DGAT2) at three weeks. Furthermore, the expression of hepatic DGAT1/DGAT2 was sustained at six months, concomitant with mitochondrial dysfunction (i.e., elevated p66shc) and oxidative stress. Interestingly, decreases in miR-203a-3p and miR-29a/b/c, both implicated in dyslipidemia, were also observed in these Δ9-THC-exposed offspring. Collectively, these findings indicate that prenatal Δ9-THC exposure results in long-term dyslipidemia associated with enhanced hepatic lipogenesis. This is attributed by mitochondrial dysfunction and epigenetic mechanisms.

BackgroundThe skeletal muscle of pigs is vulnerable to oxidative damage, resulting in growth retardation. Selenoproteins are important components of antioxidant systems for animals, which are generally regulated by dietary selenium (Se) level. Here, we developed the dietary oxidative stress (DOS)-inducing pig model to investigate the protective effects of selenoproteins on DOS-induced skeletal muscle growth retardation.ResultsDietary oxidative stress caused porcine skeletal muscle oxidative damage and growth retardation, which is accompanied by mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and protein and lipid metabolism disorders. Supplementation with Se (0.3, 0.6 or 0.9 mg Se/kg) in form of hydroxy selenomethionine (OH-SeMet) linearly increased muscular Se deposition and exhibited protective effects via regulating the expression of selenotranscriptome and key selenoproteins, which was mainly reflected in lower ROS levels and higher antioxidant capacity in skeletal muscle, and the mitigation of mitochondrial dysfunction and ER stress. What's more, selenoproteins inhibited DOS induced protein and lipid degradation and improved protein and lipid biosynthesis via regulating AKT/mTOR/S6K1 and AMPK/SREBP-1 signalling pathways in skeletal muscle. However, several parameters such as the activity of GSH-Px and T-SOD, the protein abundance of JNK2, CLPP, SELENOS and SELENOF did not show dose-dependent changes. Notably, several key selenoproteins such as MSRB1, SELENOW, SELENOM, SELENON and SELENOS play the unique roles during this protection.ConclusionsIncreased expression of selenoproteins by dietary OH-SeMet could synergistically alleviate mitochondrial dysfunction and ER stress, recover protein and lipid biosynthesis, thus alleviate skeletal muscle growth retardation. Our study provides preventive measure for OS-dependent skeletal muscle retardation in livestock husbandry.

It has been recognized that there is a relationship between prenatal growth restriction and the development of metabolic-related diseases in later life, a process involved in mitochondrial dysfunction. In addition, intrauterine growth retardation (IUGR) increases the susceptibility of offspring to high-fat (HF) diet-induced metabolic syndrome. Recent findings suggested that HF feeding decreased mitochondrial oxidative capacity and impaired mitochondrial function in skeletal muscle. Therefore, we hypothesized that the long-term consequences of IUGR on mitochondrial biogenesis and function make the offspring more susceptible to HF diet-induced mitochondrial dysfunction. Normal birth weight (NBW), and IUGR pigs were allotted to control or HF diet in a completely randomized design, individually. After 4 weeks of feeding, growth performance and molecular pathways related to mitochondrial function were determined. The results showed that IUGR decreased growth performance and plasma insulin concentrations. In offspring fed a HF diet, IUGR was associated with enhanced plasma leptin levels, increased concentrations of triglyceride and malondialdehyde (MDA), and reduced glycogen and ATP contents in skeletal muscle. High fat diet-fed IUGR offspring exhibited decreased activities of lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G6PD). These alterations in metabolic traits of IUGR pigs were accompanied by impaired mitochondrial respiration function, reduced mitochondrial DNA (mtDNA) contents, and down-regulated mRNA expression levels of genes responsible for mitochondrial biogenesis and function. In conclusion, our results suggest that IUGR make the offspring more susceptible to HF diet-induced mitochondrial dysfunction.