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Background
Phototherapy has remained the standard therapeutic approach for neonatal hyperbilirubinemia. Oxidative effects of phototherapy on cell membranes and cell components may have a wide range of potential adverse effects, including enhanced lipid peroxidation and DNA damage. Apoptosis is an indispensable mechanism for maintaining many cellula...
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Background Phototherapy is used to treat neonatal hyperbilirubinemia, but is currently thought to cause photodynamic stress and can induce lipid peroxidation. There is increasing evidence that many severe diseases of the neonates are caused by oxidative injury and lipid peroxidation. In the present communique, we review the oxidative succeptibility...
Citations
... The conventional treatments used for neonatal hyperbilirubinemia are mainly phototherapy and blood exchange transfusion [8]. Although phototherapy is widely used by number of countries, may damage DNA [9], interfere with maternal-infant bonding [10], and trigger intestinal hypermotility [11]. Blood exchange transfusion is generally performed after failure a phototherapy failure, and is reported to cause blood-related or cardiorespiratory complications [10,12]. ...
This is an Open Access Journal / article distributed under the terms of the Creative Commons Attribution License (CC BY-NC-ND 3.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. All rights reserved. Jaundice is characterised by a yellowish colouring of the skin, sclera, and mucous membranes. The conventional treatments used for neonatal hyperbilirubinemia are mainly phototherapy and blood exchange transfusion which may damage DNA, interfere with maternal-infant bonding, and trigger intestinal hypermotility. Blood exchange transfusion is generally performed after failure a phototherapy failure, and is reported to cause blood-related or cardiorespiratory complications. These limitations show that new therapies by natural plants for neonatal hyperbilirubinemia are required because plant materials are a source of numerous effective and dominant drugs as they synthesize hundreds of phytoconstituents for therapeutic purposes like defense against insects, fungi, diseases, etc. The obtainable data were collected via search engines like Firefox, Google Chrome, different journals and data bases available. Approximately, 60 journals, several books and online sources were reviewed. The primary source of data collection was research and review articles published by reputed publishers such as Elsevier, Informa, Springer, Taylor and Francis, and several others; online databases such as PubMed, Google scholar, Science hub, Research gate, Scopus and Science Direct. About 22 species were found to utilized potentially for the treatment of jaundice in different regions of Assam. These includes 54004 metabolic pathway that is useful to researchers for further scientifical analysis as well as formulation development.
... However, a different theory suggested that the carcinogenic effect noticed in neonates receiving phototherapy may be due to hyperbilirubinemia. This was supported by studies that found that high levels of serum bilirubin had genotoxic effects [44,45]. However, two other studies failed to demonstrate any correlation between bilirubin and oxidative stress or DNA damage scores [46,47]. ...
Phototherapy is the main treatment of neonatal hyperbilirubinemia to prevent encephalopathy. It is generally believed to be safe; however, some studies have shown it might be associated with cancer development. In this systematic review and meta-analysis, we aimed to assess the effect of neonatal phototherapy on future cancer risk. A systematic search in 13 databases was conducted in December 2018 and updated in August 2022 to identify studies that report cancer development after exposure to phototherapy. Throughout the study period, regular manual searches were also conducted to include new studies. A meta-analysis using R programming language was done in which the odds ratios (ORs) with 95% confidence intervals (CIs) were estimated and pooled using the reported adjusted and unadjusted data. Fifteen studies were included. A statistically significant association was detected between neonatal phototherapy and any type of cancer (OR 1.24; 95% CI 1.1, 1.4), any hematopoietic cancer (OR 1.49; 95% CI 1.17, 1.91), any leukemia (OR 1.35; 95% CI 1.08, 1.67), and myeloid leukemia (OR 2.86; 95% CI 1.4, 5.84). The other investigated cancers (lymphoid leukemia, Hodgkin’s lymphoma, kidney cancer, nervous system cancer, and skin cancer) were not associated with phototherapy. Conclusions: Phototherapy may carry a possible risk of future cancers. Future research is needed to quantify the magnitude of the cancer risk. These future studies should consider predictors of preterm birth or exclude premature babies from their analysis.
What is Known
• There were various reports about the possible association between phototherapy in neonates and the increased risk of cancer in the future.
What is New
• A statistically significant association between phototherapy and various hematopoietic cancers (especially myeloid leukemia) was recorded.
• The effect of the duration of phototherapy on the increased risk of hematopoietic cancers is yet unclear.
... In this study, we found significant DNA damage after phototherapy in group I and our findings are consistent with that of other investigators [18][19][20][21]. Furthermore, Tatli et al. [22] have observed that DNA damage increased significantly with the duration of phototherapy as revealed by measurements at 24, 48, and 72 h. ...
Background
Phototherapy induces DNA damage by direct and indirect (oxidative) effects, which are prevented by ultraviolet (UV) filters and antioxidants.
Aim
Our goal was to assess DNA damage and oxidative stress associated with phototherapy and to prove the efficacy of UV filters and antioxidants for the prevention of DNA damage.
Patients and methods
The study included 160 jaundiced neonates who had been exposed to phototherapy for at least 48 h. The neonates were divided into four groups, 40 neonates in each group. The first (control) group received phototherapy only; the second group received antioxidants before and during phototherapy; the third group received phototherapy under an umbrella of UV filters; and the fourth group received phototherapy under both UV filters and antioxidants. DNA damage was assayed by the comet assay. Plasma total antioxidant capacity and total oxidant status levels were also measured and then oxidative stress index was calculated for all the four groups before and 48 h after phototherapy.
Results
The first group showed significant DNA damage accompanied with severe deterioration in all oxidative stress parameters by about 19%; the second group showed a decreasing trend as regards DNA damage and oxidative stress parameter deterioration to about 9%; the third group showed a more decreasing trend than group II to about 5%; but on the other hand, the fourth group showed complete DNA protection from damage with no changes in oxidative stress parameters.
Conclusion
Phototherapy causes DNA damage that can be completely prevented by combined concurrent use of UV filters and antioxidants.
... A variety of studies have shown a correlation between hyperbilirubinemia and Deoxyribonucleic acid (DNA) damage in hyperbilirubinemic newborns [15,16]. The negative impacts of phototherapy have previously been investigated on the antioxidant defense system of jaundiced neonates [17]. ...
Background
Neonatal phototherapy (NNPT) has long been used as an effective and relatively safe method of treating neonatal hyperbilirubinemia. Considering the subsequent evidence of long-term impacts of NNPT such as malignancies, this study was conducted to evaluate the relationship between NNPT and childhood cancers.
Methods
This case-control study assessed 116 children up to 4 years old with every kind of cancer referred to the Oncology department of Afzalipour hospital, Kerman, Iran, from 2011 to 18. Moreover, 116 pediatric patients without cancer hospitalized at the same Center were included after sex and age matching as the control group. The history of phototherapy and its duration were evaluated in these two groups.
Results
We found no association between the NNPT and malignancies in children. However, high intensive phototherapy was higher historically among affected cancerous patients than in non-cancerous cases without any statistically significant difference (25% vs 19%; P = 0.26). Maternal educational level and history of maternal infection during pregnancy, which initially appeared to be two factors associated with malignancy in single variable regression analyses, were not significant based on the adjusted models.
Conclusions
The results did not show a positive correlation between NNPT and childhood cancers, which may partly be due to the relatively small sample size of the study. However, some other evidence is worrisome enough that NNPT should not be considered risk-free. Additional multi-centric studies should be undertaken to specify that phototherapy is really safe.
... Zein El-Abdin şi colab. au observat o creștere semnificativă a fragmentării ADN-ului în limfocitele circulante comparativ cu grupul martor (29). După fototerapie, a fost observată o creștere semnificativă statistic a fragmentării ADN comparativ cu nivelul său înainte de fototerapie printre cazurile expuse la fototerapie. ...
Neonatal jaundice is the most common condition in the neonatal period, affecting up to 85% of newborns. The treatment of neonatal jaundice is represented in most cases by phototherapy. Even though phototherapy has proven its usefulness and effectiveness in treating neonatal jaundice, the possible short-term and long-term side effects are still being studied. Studies have found that there are effects that could be easily intuited, such as skin lesions, but also effects that until recently had not been discussed, such as alteration of cellular DNA. In order to maximize the effects of phototherapy, in parallel with minimizing the side effects, it is necessary to use phototherapy as sparingly as possible, carefully following the nomograms specific to exposure to phototherapy according to bilirubin values. The specialized literature on this topic is vast, as a result it was necessary to collect the most important data in order to use phototherapy as correctly as possible, avoiding the effects of medically unjustified exposure.
... Hence, changes at the molecular level may not be apparent when using non-specific methods, such as the Comet assay (used in our study), where the negative result could be explained by its decreased sensitivity during the analysis of small pro-apoptotic changes [41]. On the other hand, the data are in contrast with observations on DNA damage in peripheral blood lymphocytes [42][43][44][45] and increased serum apoptotic markers [46] in phototherapy-treated newborn infants suggesting cell-specific responsiveness to BR and LR. ...
The 'gold standard' treatment of severe neonatal jaundice is phototherapy with blue-green light, which produces more polar photo-oxidation products that are easily excreted via the bile or urine. The aim of this study was to compare the effects of bilirubin (BR) and its major photo-oxidation product lumirubin (LR) on the proliferation, differentiation, morphology, and specific gene and protein expressions of self-renewing human pluripotent stem cell-derived neural stem cells (NSC). Neither BR nor LR in biologically relevant concentrations (12.5 and 25 µmol/L) affected cell proliferation or the cell cycle phases of NSC. Although none of these pigments affected terminal differentiation to neurons and astrocytes, when compared to LR, BR exerted a dose-dependent cy-totoxicity on self-renewing NSC. In contrast, LR had a substantial effect on the morphology of the NSC, inducing them to form highly polar rosette-like structures associated with the redistribution of specific cellular proteins (β-catenin/N-cadherin) responsible for membrane polarity. This observation was accompanied by lower expressions of NSC-specific proteins (such as SOX1, NR2F2, or PAX6) together with the upregulation of phospho-ERK. Collectively, the data indicated that both BR and LR affect early human neurodevelopment in vitro, which may have clinical relevance in phototherapy-treated hyperbilirubinemic neonates.
... However, during the treatment of neonatal hyperbilirubinemia, the level of free bilirubin in the serum is decreased, which may weaken the protective effect of bilirubin on the cell membrane, thus making the cell membrane susceptible to injury and causing cell apoptosis. This injury may be associated with the oxidative stress induced by phototherapy, or with the upregulation of the BAX gene, which promotes apoptosis induced by phototherapy (10). ...
... After exploring the genotoxicity and apoptosis induced by phototherapy in peripheral blood lymphocytes of full-term infants, Yahia et al (106) reported that the DNA damage markers (tail DNA% and tail moment) and the p53 levels of newborns with hyperbilirubinemia subjected to phototherapy were significantly higher compared with those prior to phototherapy (all P<0.0001). Furthermore, it has been proposed that the DNA damage and cell apoptosis caused by bilirubin and phototherapy in newborns with hyperbilirubinemia may be associated with the downregulation of the BCL-2 gene (which can inhibit apoptosis) and the upregulation of the BAX gene (which can promote apoptosis) (10). ...
Phototherapy is universally recognized as the first option for treating neonatal jaundice due to its unparalleled efficiency and safety in reducing the high serum free bilirubin levels and limiting its neurotoxic effects. However, several studies have suggested that phototherapy may elicit a series of short- and long-term adverse reactions associated with pediatric diseases, including hemolysis, allergic diseases, DNA damage or even cancer. The aim of the present review was to summarize the etiology, mechanism, associated risks and therapeutic strategies for reducing high neonatal serum bilirubin levels. In order to shed light on the negative effects of phototherapy and to encourage implementation of a reasonable and standardized phototherapy scheme in the clinic, the present review sought to highlight the current understanding of the adverse reactions of phototherapy, as it is necessary to further study the mechanism underlying the development of the adverse effects of phototherapy in infants in order to explore novel therapeutic alternatives.
... Moreover, phototherapy increase apoptosis in neonatal small intestine cells and the mouse lymphoma cell line [7]. Recently, neonatal jaundice and phototherapy were found to enhance apoptosis of peripheral blood lymphocytes from infants with hyperbilirubinemia, mostly through downregulation of BCL2 expression and upregulation of BAX gene expression [8]. Human cells use many strategies for the protection of genomic DNA from accumulating such lesions. ...
... Also, there was no significant correlation between total bilirubin, BCL2, and bax protein before phototherapy, so hyperbilirubinemia did not influence apoptosis in the peripheral blood of hyperbilirubinemic full-term neonates. The serum level of BCL2 protein was lower between the cases before phototherapy compared to controls explaining that bilirubin and phototherapy had genotoxic effects [8]. A high level of bilirubin may conduct to oxidative damage in newborns as photochemical reactions may produce toxic photoproducts, probably peroxides [16,17], agreeing the results of Yahia et al [18] that found no significant difference in P53 level (marker of apoptosis) in the tested groups before exposure to phototherapy. ...
... After phototherapy, lower serum compared to their levels before and serum levels of bax proteins were significantly higher compared to their levels before; in hyperbilirubinemic full-term neonates, all can be attributed to an increase in DNA damage and a concomitant increase of rate of apoptosis, clarified by BCL2 downregulation and increased BAX gene expression. Also, P53 levels significantly increase after exposure to phototherapy [8,18]. PUVA phototherapy influences evident downregulation of BCL2 level and produces early significant depletion of epidermal and dermal T cells in psoriatic tissues by the induction of apoptosis [20]. ...
Background
Phototherapy is the main therapeutic interference for neonatal hyperbilirubinemia used to escape an exchange transfusion and to decrease the risk of bilirubin-induced encephalopathy (kernikterus). Phototherapy has an oxidative effect on cell components and cell membranes by enhancing peroxidation of lipid and damage to DNA. Many genes function as apoptosis regulatory genes. Examples of these genes involve the BCL2 gene as an anti-apoptotic oncogene, and the BAX gene which is a promoter of apoptosis.
We aimed to evaluate the effect of phototherapy on expression of BAX and Bcl2 genes in hyperbilirubinemic full-term neonates.
Eighteen full-term neonates with indirect hyperbilirubinemia who received phototherapy for 24 h were enrolled as a study group and nine apparently healthy full-term neonates with a normal serum bilirubin level were included as a control group. Assessment of the anti-apoptotic effect(s) of BCL2 and the pro-apoptotic effect(s) of (Bax) genes was achieved by quantitative assay of their products (BCL2 and BAX proteins) by ELISA assay after phototherapy.
Results
Significant decrease in the bcl2 ( p < 0.001) and increase in Bax protein ( p < 0.001) serum levels after phototherapy in hyperbilirubinemic full-term neonates.
Conclusion
Hyperbilirubinemia has no apoptotic influence, while phototherapy induces apoptosis in the peripheral blood of hyperbilirubinemic full-term infants.
... Karakukcu et al. (2009) suggested that high bilirubin concentrations (19.3 ± 3.22 mg/ dL) can also be toxic, as is clear from the significant increase in DNA oxidation noted in hyperbilirubinemic patients. Similarly, El-Abdin et al. (2012) reported that high bilirubin levels (14.3 ± 4.3 mg/dL) are associated with DNA damage in newborns with hyperbilirubinemia. Karadag et al. (2009) suggested that total bilirubin levels higher than 10 mg/dL are hazardous to chromosomes. ...
Hyperbilirubinemia is one of the most common diseases in neonates. Slight elevations in bilirubin levels exert antioxidant effects but high levels may cause oxidative damage in newborns. We assessed the effects of hyperbilirubinemia on DNA damage and total oxidant and antioxidant status in newborns receiving phototherapy. A total of 68 term newborn infants exhibiting idiopathic unconjugated hyperbilirubinemia (UCH) requiring phototherapy and 27 age-matched healthy controls were enrolled in the study. Plasma 8-hydroxy-2 deoxy-guanosine (8-OH-dG) levels, total oxidant status (TOS), and total antioxidant status (TAS) were compared between newborns with UCH requiring phototherapy and age-matched healthy controls. The extent of DNA damage, the TOS, and the TAS were significantly higher in the study group than the control group (p < 0.01). The extent of DNA damage and the TOS increased at lower bilirubin levels; this became significant at bilirubin levels >16 mg/dL. A significant increase in TAS was observed even at low bilirubin levels, and the TAS was positively correlated with the bilirubin level to 30 mg/dL. At slightly elevated levels bilirubin serves as a physiological antioxidant. However, the high bilirubin levels evident in the present study increased DNA damage and oxidative stress.
... [9] It has also been seen that PT causes an additive effect on DNA damage in newborn with jaundice. [31] Furthermore, Koç et al. (1999) reported that PT causes degenerative changes in the rat's testes, however, they did not observe any changes in fertilization rates. ...
Ultrastructural Study of Rat Testis Following Conventional Phototherapy during Neonatal Period
Hare Krishna, Asha Changil,1 M. Srinivas,2 Tara Sankar Roy, and Tony George Jacob
Introduction:
Phototherapy is the most common treatment for neonatal jaundice. This study sought to determine ultrastructural changes in testis, at different time-points, after 48 hours of conventional phototherapy was given to newborn rats.
Methods:
Newborn male Wistar rats (n = 36) were divided into two groups as follows – group 1 (G1), control (without phototherapy) and group 2 (G2), exposure to conventional phototherapy for 48 h. Six animals from each group were sacrificed on postnatal days (PND) 70, 100 and 130. The testes were dissected out and processed for Transmission Electron Microscopy (TEM).
Results:
TEM showed that G2 on PND 70 and 100 showed damaged organelles, including nuclei, mitochondria, endoplasmic reticulum, vacuoles and electron dense bodies in the testes. Seminiferous Tubule on PND130 showed lesser damage. On PND70 ST wall thickness (STWT) of G2 was significantly higher (P < 0.001) than G1 STWT of G2 was significantly lower than G1 on PND100 (P = 0.047) and on PND130 (P < 0.001). Mitochondrial diameter in spermatogonia was significantly higher in G2 on PND70 (P = 0.001), PND100 (P = 0.031) and PND130 (P = 0.028). Primary spermatocytes in G2 also had larger mitochondria on PND70 (P < 0.001), PND100 (P = 0.007) and PND130 (P = 0.008). Further, spermatids had larger mitochondria in G2 on PND70 (P < 0.001), PND100 (P = 0.044) and PND130 (P < 0.001).
Conclusion:
Phototherapy causes degenerative changes in rat testis on PND70 and 100 that partially recover by PND 130.
Keywords: Mitochondria, neonatal jaundice, seminiferous tubule, spermatocyte, spermatogonium, transmission electron microscopy
