Next Article in Journal
Heterogeneous Polymer Dynamics Explored Using Static 1H NMR Spectra
Next Article in Special Issue
Role of Peroxisome Proliferator-Activated Receptors (PPARs) in Trophoblast Functions
Previous Article in Journal
Synthesis, Properties, and Biological Applications of Metallic Alloy Nanoparticles
Previous Article in Special Issue
Immunohistochemical Study on the Expression of G-CSF, G-CSFR, VEGF, VEGFR-1, Foxp3 in First Trimester Trophoblast of Recurrent Pregnancy Loss in Pregnancies Treated with G-CSF and Controls
Review

Early Life Oxidative Stress and Long-Lasting Cardiovascular Effects on Offspring Conceived by Assisted Reproductive Technologies: A Review

1
Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany
2
Department of Obstetrics and Gynecology, University Hospital Augsburg, 86156 Augsburg, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(15), 5175; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155175
Received: 29 June 2020 / Revised: 18 July 2020 / Accepted: 20 July 2020 / Published: 22 July 2020
(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology 2.0)

Abstract

Assisted reproductive technology (ART) has rapidly developed and is now widely practised worldwide. Both the characteristics of ART (handling gametes/embryos in vitro) and the infertility backgrounds of ART parents (such as infertility diseases and unfavourable lifestyles or diets) could cause increased oxidative stress (OS) that may exert adverse influences on gametogenesis, fertilisation, and foetation, even causing a long-lasting influence on the offspring. For these reasons, the safety of ART needs to be closely examined. In this review, from an ART safety standpoint, the origins of OS are reviewed, and the long-lasting cardiovascular effects and potential mechanisms of OS on the offspring are discussed.
Keywords: oxidative stress; long-lasting; cardiovascular; assisted reproductive technologies; offspring oxidative stress; long-lasting; cardiovascular; assisted reproductive technologies; offspring

1. Introduction

The use of assisted reproductive technology (ART) began in 1978. Since then, ART has been widely used worldwide [1]. More than eight million human babies are estimated to have been conceived through ART [2], and the annual increase in this number is estimated to average at 9.1% per year [1]. ART is developing rapidly, and now includes techniques such as intra-uterine insemination (IUI), in vitro fertilisation (IVF), intracytoplasmic sperm injection (ICSI)), accompanied by controlled ovarian hyperstimulation (COH), oocyte retrieval, embryo culture, and embryo transfer, with or without pre-implantation genetic diagnosis or screening (PGD or PGS), gametes or embryos freezing and thawing, surgical sperm retrieval (SSR), and assisted hatching [3,4].
Despite all advances, it is unavoidable that gametes or embryos are handled in vitro. Because ART occurs at the preimplantation period when gametes or embryos are highly sensitive and experience developmental plasticity, the environmental stimuli may alter the embryonic developmental trajectory. According to the ’developmental origins of adult disease’ (DOHaD) hypothesis [5], environmental exposures in early life can exert a long-lasting influence on health and lead to adult-onset chronic non-communicable diseases (NCDs) such as hypertension [6], cardiovascular diseases (CVDs) [7], and type 2 diabetes mellitus (T2DM) [8]. ART can be regarded as an extreme ’exposure’, despite the fact that conclusions of ART safety studies are conflicting, the possible adverse effects have been linked to birth defects [9], epigenetic diseases [10], dysfunction of various body systems (e.g., cardiovascular, metabolic, and neurological systems) [11], and paediatric neoplasms (e.g., leukaemia and Hodgkin’s lymphoma) [12,13]. The observed long-term outcomes of ART, including cardiometabolic and neurological NCDs, are consistent with the DOHaD model [14].
Oxidative stress (OS) is related to an excess of reactive oxygen species (ROS) and a decrease in antioxidant enzymes. This concept was established by Helmut in 1985 [15]. Excess ROS has been proposed to cause severe damage during embryonic development [16], especially in the cardiovascular system, because it is one of the first functional systems to develop. In the ART area, studies on OS have focused on infertile men and their sperm [17,18]. It is now well established that the main cause of male infertility is OS, which can damage sperm DNA, influencing the health of the offspring [19]. Studies have also revealed that OS plays a vital role in ART outcomes. A study found that a reduction in OS improved ART outcomes [20]. Various factors associated with ROS production in an ART setting have been investigated, and the antioxidant strategy in an ART setting has also been explored [20,21]. Several animal models have been applied to study the effect and associated mechanisms of OS on ART offspring [22]. Nevertheless, to the best of our knowledge, no human epidemiological studies have looked at the effect of OS on ART offspring. On the one hand, the health outcome-related follow-up information of ART offspring in the available databases are insufficiently detailed and are even lacking. On the other hand, no databases have recorded the OS status in an ART setting for ART offspring. In fact, in other medical areas, there have been countless studies on OS/ROS, most of which are focused on the negative effects of excessive ROS/OS. Excessive ROS/OS has been implicated in over 100 diseases [23] (e.g., diabetes mellitus [24], CVDs [25], and neurodegenerative diseases [26]), also playing an important role in the pathogenicity of ageing [27].
In this review, from the ART point of view, we describe the origins of OS, provide a timely synthesis of the current evidence on the long-lasting cardiovascular effects of ART-associated OS, and discuss the potential underlying mechanisms. We expect that our review will inform future OS-associated research in the ART area as well as propose suggestions for preventing adverse health outcomes in ART offspring.

2. Origins of OS

2.1. Paternally Derived OS

OS has been linked to a variety of male fertility complications, including leukocytospermia [28], varicocele [29], cryptorchidism [30], spermatic cord torsion [31], male accessory gland infections (MAGI) [32], advanced age [33], obesity [34], diabetes [35], and autoimmune disorders [33]. Infertile men are more likely to possess excessive levels of ROS compared to fertile men [36], which has been identified as one of the few defined aetiologies for male infertility [37]. Recently, male oxidative stress infertility (MOSI) has been proposed to describe infertile men with OS and abnormal semen characteristics. This term includes many patients previously classified as having male idiopathic infertility [38].
In the male genital tract, in addition to the ROS generated from sperm cells [39], other cells may also produce ROS. Among them, leukocytes can produce ROS at levels 1000 times higher than that of sperm at capacitation [40] and may contribute to OS [41]. Further compounding this issue, the plasma membrane of sperm cells contains large quantities of polyunsaturated fatty acids (PUFAs), making them particularly susceptible to elevated ROS levels during OS [42]. OS can also negatively influence other sperm components (i.e., nucleic acids and proteins), inducing sperm DNA fragmentation (SDF) and low sperm motility [43]. Furthermore, compared with somatic cells, there is a lack of cytoplasm and poorer antioxidant capacity in mature spermatozoa, thereby rendering it more vulnerable to OS [44]. Nevertheless, it is entirely possible for sperm suffering from oxidative DNA damage to fertilise an oocyte and thus possibly exert adverse effects on the offspring [45], especially in the context of ICSI [46]. On the other hand, lifestyle and diet factors such as cigarette smoking [47], alcohol abuse [48], psychological stress [49], recreational and illicit drugs use [17,50], malnutrition [51], and excessive physical activity [52]; environmental and occupational exposures such as air pollution [53], radiation [54], heat stress [55], plasticizers (e.g., phthalates) [56], heavy metals (e.g., cadmium) [57], and pesticide/herbicides [33]; and special treatments such as radiation therapy and chemotherapy have been linked with OS [58,59] (as shown in Figure 1).

2.2. Maternally Derived OS

Compared with studies of OS and male sperm, it appears that fewer studies have focused on OS and oocytes/oocyte-cumulus complexes. Nevertheless, it cannot be assumed that this point is less important in oogenesis, fertilisation, pregnancy, and production of healthy offspring. After all, the earliest determinant of life potential is the oocyte. In the female reproductive system, the uterine environment, fallopian tubes, and follicular fluid are the main sources generating ROS [60,61,62]. Normal levels of ROS are responsible for pregnancy establishment in IVF cycles, while excess ROS in the follicular fluid can present a substantial threat to successful assisted reproduction [63].
Recent studies have also shown that OS may cause absence of the oocyte meiotic spindle and may be closely associated with low fertilization rates, compromised embryonic quality, and decreased clinical pregnancy rates [64]. In fact, women attending ART units are usually of advanced age and/or have been diagnosed with other diseases (e.g., endometriosis [65], polycystic ovary syndrome (PCOS) [66], hydrosalpinx [67], and obesity [52]). After pregnancy, women who underwent ART have been reported to be affected by higher incidences of several pregnancy complications (e.g., hypertensive disorders of pregnancy (HDP) [68], gestational diabetes mellitus (GDM) [68], intrauterine growth restriction (IUGR) [69], and preterm birth [68]). All these diseases and pregnancy complications are associated with increased OS, which might exert an influence on the offspring’s development [70]. Specifically, during the maternal ageing process, significantly increased OS occurs in the ovarian and follicular environment, causing impaired oocyte quality and compromised oocyte meiosis [71]. Similar to men, unfavourable lifestyles and diets, adverse environmental and occupational exposures, and special treatments can also contribute to excessive OS in women [52,70,72,73,74,75,76,77,78] (as shown in Figure 2). Different from men, women exert OS on the offspring, not only through the fertilised oocytes, but also through the uterine environment throughout the whole pregnancy.

2.3. ART-Derived OS

ART requires in vitro manipulations of gametes or embryos in a synthetic culture environment. Due to lack of a natural antioxidant system and factors driving ROS production (Figure 3), it is difficult to maintain pro-oxidant/antioxidant balance in vitro, and the resulting increased OS may have an adverse impact on the embryo/offspring. There are various stimuli of OS in the ART setting, including cryopreservation [79,80], gamete or embryo manipulation [81], visible light [82], pH fluctuations [83], temperature fluctuations [84], fluctuating oxygen tension (Pa, O2) [85], centrifugation [86], culture media (especially those containing specific substances, e.g., Fe2+ and Cu2+) [62], and others. For example, in the oviduct and uterus, under certain physiological conditions, gametes or embryos are exposed to O2 concentrations of 2–8 % [87]. During in vitro manipulations, gametes and embryos have a chance of being exposed to higher O2 concentrations (e.g., atmospheric O2 concentrations around 20–21%). The presence of high concentrations of O2 during the incubation stage can activate a variety of cellular oxidase enzymes. This in turn generates excessive ROS, leading to OS [88]. The excess ROS can impact the biological processes of early embryonic development with potentially long-lasting health effects for the offspring.
Collectively, compared with naturally conceived offspring, ART offspring appear to be more likely to suffer from excessive OS. Meanwhile, it should be noted that most of the OS originating from ART parents (e.g., adverse lifestyles and environmental exposures) and ART per se are preventable. For ART-associated OS, the potential management includes oral antioxidant supplements for ART parents [89] and modifications in ART protocols. These include antioxidant supplements to ART culture media [20,89], antioxidant techniques in semen preparation, reduced oocyte-handling time, and minimal exposure of zygotes to atmospheric oxygen concentrations [20]. The ART-associated antioxidants consist of enzymatic antioxidants (e.g., superoxide dismutase, catalase, and the glutathione system), non-enzymatic antioxidants (e.g., Vitamins E, C, and B9 (folic acid), melatonin, coenzyme Q10, and L-carnitine) and combined antioxidants (e.g., Vitamin E + Vitamin C) [89]. Diets containing antioxidant molecules for ART parents may also provide antioxidant benefits [90].

3. OS-Associated Mechanisms in ART

3.1. Formation of OS

Various stress conditions may contribute to OS with increased production of ROS. ROS (e.g., superoxide (O2•−), hydroperoxyl (HO2), hydroxyl (OH), and peroxyl radicals (RO2), and hydrogen peroxide (H2O2) [91]) are generated from the partial reduction of O2 to O2•−, which occurs as a result of oxygen’s preferential acceptance of one electron at the time of redox reactions [92]. ROS are highly active molecules that are continuously generated by mitochondrial electron transport and enzymes (e.g., nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, xanthine oxidase, and lipoxygenase) [93]. ROS that originate intracellularly can be released extracellularly [94], and play vital roles in modulating the signaling pathways in response to intra- and extra-cellular stimuli [95]. Mitochondria are the primary source of ROS, resulting from its role in energy (i.e., ATP) production via oxidative phosphorylation (OXPHOS) [92]. The major sites of ROS emission in the respiratory chain are complex I and complex III [96]. During IVF, selected spermatozoa and oocytes are combined in a petri dish with the fertilisation medium and are checked for fertilization after several hours’ incubation. During this time, ROS can be generated from the oocyte/cumulus cell mass and the spermatozoa, due to the cells’ own metabolism, and the levels of ROS production can be elevated due to the lack of a natural antioxidant defence system and various stimuli. Furthermore, during centrifugation, excess ROS can be derived from the spermatozoa because of the absence of antioxidant-rich seminal plasma and the activation of ROS production [20]. In addition, the external environment that surrounds the cells in an ART setting can also induce OS. For example, even though the composition of the commercial culture media changes over time with various suppliers, most contain serum or serum synthetic replacements, vitamins, albumin, and other components (e.g., heavy metal chelators or buffer). Therefore, the medium itself can be a trigger of OS [97]. Other environmental factors can also contribute to OS as mentioned. In response to various environmental stimuli, cells produce certain mediators and intermediates (mostly ROS) to propagate environmental signals to the cell nucleus, affecting gene regulation and transcription while inducing various phenotypic responses (in the form of inflammation and pathogenesis) [98].

3.2. Epigenetic Modifications Resulting from OS

Epigenetic modifications refer to dynamic and heritable changes in gene expression without DNA sequence changes. These are profoundly involved in OS responses [99] and are regarded as potential mechanisms that influence the developmental origins of CVDs later in adulthood [100]. Maximal epigenetic reprogramming, characterized as ’dynamic’, ’extremely sensitive’, and ’plastic’, occurs during the early stages of life, coinciding with the time that ART procedures take place [101,102]. Both animal studies and follow-up studies of ART children suggest that ART can cause epigenetic perturbation in offspring [10,103], even at the two-cell stage of embryos [104]. It has been proposed that OS during pregnancy may affect the intrauterine foetus and cause cardiovascular dysfunction in later life through epigenetic modifications [105]. Based on these findings, we speculated that ART-associated OS may also influence the offspring through an epigenetic mechanism. In general, ROS can affect epigenetic modifications through both direct and indirect means [106]. For example, OH can directly lead to the transformation from 5-methylcytosine (5-mC, a form of DNA methylation) to 5-hydroxymethylcytosine (5-hmC, an intermediate in active DNA demethylation [107]) [108], which has been suggested to interfere with DNA methyltransferase 1 (DNMT1), preventing the proper inheritance of methylation patterns, thereby causing indirect CpG sites demethylation [109]. ROS can also indirectly affect epigenetic modifications. For example, H2O2-induced OS can impair histone demethylase activity, causing increased global histone methylation of histone H3 lysine 4 (H3K4), histone H3 lysine 27 (H3K27), and histone H3 lysine 9 (H3K9), while H3K4 trimethylation (H3K4me3) appears to be affected most by OS; global acetylation levels show temporary decreases in response to OS and return to normal levels after long-term OS. The activity of DNA demethylases (ten-eleven-translocation (TET) proteins) can also be compromised by OS, inducing global 5-mC increases and 5-hmC decreases [110]. These epigenetic modifications can then regulate gene expression via changes in chromatin accessibility in response to OS [111]. Kietzmann et al. described an ROS-related epigenetic landscape in cardiovascular systems; we direct interested readers to a detailed review [106]. Furthermore, evidence also suggests an interplay between OS and epidemic modifications [112,113]. For example, the down-regulation of SUV39H1 (a H3K9 histone methyltransferase) facilitates the recruitment of SRC-1 (a histone acetyltransferase) and JMJD2C (also known as KDM4C, a H3K9 histone demethylase) with reduced di/trimethylation and acetylation of H3K9 on the promoter of p66Shc (a key driver of mitochondrial OS and vascular damage [114]), which may ultimately drive OS [115].

3.3. Nrf2-Mediated Anti-OS Signaling Pathway

The redox-sensitive transcriptional factor nuclear factor erythroid 2-related factor 2 (Nrf2, also known as NFE2L2) is a well-characterized ’master regulator’ of antioxidant gene expression via its activation of the Nrf2-antioxidant response element (ARE) pathway [116]. Nrf2 dysregulation has been implicated in different aspects of CVDs [117] and multiple types of cancers (e.g., ovarian cancer [118], breast cancer [119], and glioblastoma [120]), while Nrf2 itself has been identified as a promising therapeutic target for these chronic diseases resulting from its role in providing cytoprotection against diverse stress and pathologies [121]. Recent preclinical data have revealed that N-palmitoylethanolamine-oxazoline (PEA-OXA), an antioxidant compound, protects against cardiovascular complication through upregulation of Nrf2 and Nrf2-target genes [122]. Other compounds (e.g., linarin (LIN) [123] and resveratrol (RES) [124]) also provide beneficial effects in myocardial ischemia/reperfusion injury and CVDs by activating Nrf2. In utero, excessive OS can trigger a cascade of molecular events, imperilling the health of offspring [125]. The Nrf2-mediated OS response is one of the most important cytoprotective mechanisms against OS as it transcribes many antioxidative genes and ROS-scavenging proteins [126] that are not only closely associated with embryo survival in in vitro conditions [127], foetal development in utero, and cardiometabolic health in childhood or later life [128], but also involved in maintaining vascular homeostasis [129]. Given this evidence, it is reasonable to assume that Nrf2-mediated antioxidant signaling pathway may also serve as an important mechanism for OS-induced cardiovascular effects in ART offspring. Under redox homeostasis, Nrf2 is bound to its inhibitor, Kelch-like ECH-associated protein 1 (Keap1), and is located in the cytoplasm, where it facilitates the ubiquitin-mediated degradation of Nrf2. However, during OS, Nrf2 is phosphorylated and released from Keap1 and is translocated and accumulated in the nucleus, where it heterodimerizes with small musculoaponeurotic fibrosarcoma (Maf) proteins, binds to ARE, and transcriptionally upregulates antioxidant gene expression [130]. The representative antioxidant genes regulated by Nrf2 are summarized in Table 1.
Collectively, in the ART area, increased OS is one of the major triggers of early life genetic/epigenetic changes in the offspring. From a preventive point of view, the adverse influence of OS can possibly be reversed through timely appropriate interventions (e.g., medical supplements for ART children and ART parents, chemical modification of ART culture media), opening a window for the potential prevention of adverse long-lasting effects on ART offspring.

4. Long-Lasting Cardiovascular Effects

In the human body, ROS act as a ’double-edged sword’, playing a paradoxical role. Normal levels of ROS are important regulators of various transcription factors and signal transduction pathways. Excessive ROS levels can lead to OS, causing damage to cellular components (e.g., proteins, lipids, and DNA), mitochondrial dysfunctions, inhibition of oocyte maturation, delayed embryonic development, and induction of apoptosis in embryos [149]. Several lines of evidence suggest that OS plays a key role in the foetal programming of adulthood CVDs [150,151,152,153]. Studies on mammalian offspring suffering from OS (e.g., hypoxia-reoxygenation) during the gestational period reported that these offspring developed endothelial dysfunction [150,151], enhanced myocardial contractility [151], and hypertension [150,152] in adulthood. Foetal programming-induced alterations are transmissible not only throughout life but also in the subsequent generation [22].
From the maternal point of view, advanced maternal age (AMA) [154,155] and OS-increased ART-associated pregnancy complications (e.g., HDP [156,157], GDM [158], IUGR [159], and preterm birth [100]) are frequently associated with cardiovascular dysfunction in the offspring. For example, AMA/HDP/IUGR have been linked with increased blood pressure and/or altered cardiovascular function in offspring [154,155,156,159], while GDM/preterm birth have been linked with CVDs in offspring [100,158]. Specifically, in a mouse model, it was reported that AMA affects the phenotype of the offspring in a sex-dependent manner: in young adulthood (four months of age), male (but not female) offspring birthed by aged dams presented reperfusion injury and impaired endothelium-dependent relaxation. In mature adulthood (12 months of age), female offspring showed increased systolic blood pressure, whereas male offspring showed decreased ventricular diastolic function and increased vascular sensitivity to methacholine [154,155].
Because of the relative novelty of ART, the follow-up times of relevant studies remain limited, and the debate as to whether the ART techniques cause long-lasting adverse effects on the offspring remains ongoing. Epidemiological studies on ART children and young adults revealed that the ART offspring presented cardiovascular problems (e.g. congenital heart defect [160] and postnatal dysfunctions of the cardiovascular system [161,162,163,164]), despite the fact that one study reported, among 22–35-year-old adults, ART did not correlate with an increase in prevalent cardiovascular risk factors. However, the study population in this study was still in early adulthood and the authors only used non-invasive methods to detect early markers of sub-clinical atherosclerosis; therefore, they did not evaluate the relationships with clinical cardiovascular events (e.g., CVDs) [165]. Several systematic reviews and meta-analyses [166,167,168] have been performed on the cardiovascular profiles of offspring conceived by ART, with the results revealing mild but statistically significant cardiovascular differences in ART offspring. As Guo et al. concluded, ART-conceived children showed mildly but statistically significantly elevated blood pressure with sub-optimal diastolic function, thicker blood vessels, and lower levels of low-density lipoprotein cholesterol (LDL-C) [167].
Despite the limited data on human ART offspring, subclinical cardiometabolic alterations are detectable. Nevertheless, because CVDs are chronic, adult-onset diseases and significant signs of CVDs require years to develop. ART is relatively new; therefore, the follow-up time of epidemiological studies on ART remains limited (i.e., the first ’test-tube baby’, Louise Brown, was born in 1978 [169] and was only 42 years old as of 2020). Therefore, it is too early to form a definite conclusion. More long-term (even life-long) follow-up periods are warranted.

5. Limitations and Prospects of Current Studies

Regarding human ART studies such as those studying the influence of OS in a cohort, it is not clear whether ART is the culprit for OS or whether the infertility factors of ART parents play confounding roles. Moreover, the spectrum of ART-offspring demographic confounders (e.g., lifestyles, dietary habits, familial socio-economic status, adverse childhood experiences, as well as other life experiences), rapidly changing ART protocols, and the various types of culture media make such research more complex. To guarantee a detailed multivariate examination of this kind of study, a large sample size may be key to ensuring adjustments for various confounders. A comprehensive record of clinical and laboratory parameters (independent variables) and a prospective longitudinal design are also necessary.
To independently study the influence of ART on offspring, the ART mouse is an excellent model (i.e., there is no background of infertility; pregnancy and juvenile periods are short; and it is possible to appropriately replicate complications in humans [168]). Human embryonic stem cells (hESC) can also serve as a novel in vitro model to study the effects of OS on the early embryo [170].
In fact, in human assisted reproduction, both the ART procedure and the infertility backgrounds of ART parents may cause increased OS. Increased OS not only is the reason for patients visiting ART clinics, but it is also the outcome of in vitro ART manipulations. Despite increased OS being a prevalent phenomenon in ART, (i) there are no established uniform indicators of OS or standardized cut-off values for ART, ART men, and ART women; (ii) some ART laboratories make no attempt to test for the presence of OS; (iii) neither do the majority of ART clinics analyse their patients’ OS statuses nor pay attention to the clinical causes and sentinel signs of OS, nor do they suggest any changes to OS-related adverse lifestyles or instigate any measures to maintain the redox balance in their patients. Nevertheless, these approaches will not only increase a couple’s chances of natural conception, but will also optimise the efficiency of the ART and the health of ART offspring.

6. Conclusions

OS, which have potentially adverse effects on ART offspring, may derive not only from ART per se but also from the infertility backgrounds of ART parents. OS might exert a long-lasting influences on the offspring’s cardiovascular system via epigenetic and genetic alterations (Figure 4).

Funding

This research received no external funding.

Acknowledgments

Z.M. is supported by the China Scholarship Council (CSC). Z.M. acknowledges the CSC for supporting a visit to Ludwig-Maximilians-University (LMU).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

ARTAssisted reproductive technology
IUIIntra-uterine insemination
IVFIn vitro fertilisation
ICSIIntracytoplasmic sperm injection
COHControlled ovarian hyperstimulation
PGDPre-implantation genetic diagnosis
PGSPre-implantation genetic screening
SSRSurgical sperm retrieval
DOHaDDevelopmental Origins of Adult Disease
NCDsNon-communicable diseases
CVDsCardiovascular diseases
T2DMType 2 diabetes mellitus
OSOxidative stress
ROSReactive oxygen species
MAGIMale accessory gland infections
MOSIMale oxidative stress infertility
PUFAsPolyunsaturated fatty acids
SDFSperm DNA fragmentation
PCOSPolycystic ovary syndrome
HDPHypertensive disorders of pregnancy
GDMGestational diabetes mellitus
IUGRIntrauterine growth restriction
O2Oxygen
O2•−Superoxide
HO2Hydroperoxyl
OHHydroxyl
RO2Peroxyl radicals
H2O2Hydrogen peroxide
NADPHNicotinamide adenine dinucleotide phosphate
OXPHOSOxidative phosphorylation
5-mC5-methylcytosine
5-hmC5-hydroxymethylcytosine
DNMT1DNA methyltransferase 1
H3K4Histone H3 lysine 4
H3K27Histone H3 lysine 27
H3K9Histone H3 lysine 9
H3K4me3H3K4 trimethylation
TETTen-eleven-translocation
Nrf2Nuclear factor erythroid 2-related factor
AREAntioxidant response element
PEA-OXAN-palmitoylethanolamine-oxazoline
LINLinarin
RESResveratrol
Keap1Kelch-like ECH-associated protein 1
MafMusculoaponeurotic fibrosarcoma
AMAAdvanced maternal age
LDL-CLow-density lipoprotein cholesterol
hESCHuman embryonic stem cells

References

  1. Dyer, S.; Chambers, G.M.; De Mouzon, J.; Nygren, K.G.; Zegers-Hochschild, F.; Mansour, R.; Ishihara, O.; Banker, M.; Adamson, G.D. International committee for monitoring assisted reproductive technologies world report: Assisted reproductive technology 2008, 2009 and 2010. Hum. Reprod. 2016, 31, 1588–1609. [Google Scholar] [CrossRef] [PubMed]
  2. Calhaz-Jorge, C.; De Geyter, C. h; Kupka, M.S.; Wyns, C.; Mocanu, E.; Motrenko, T.; Scaravelli, G.; Smeenk, J.; Vidakovic, S.; Goossens, V. Survey on ART and IUI: Legislation, regulation, funding and registries in European countries. Hum. Reprod. Open 2020, 2020, hoz044. [Google Scholar] [CrossRef] [PubMed]
  3. Farquhar, C.; Marjoribanks, J. Assisted reproductive technology: An overview of Cochrane Reviews. Cochrane Database Syst. Rev. 2018, 8, CD010537. [Google Scholar] [CrossRef] [PubMed]
  4. Kushnir, V.A.; Barad, D.H.; Albertini, D.F.; Darmon, S.K.; Gleicher, N. Systematic review of worldwide trends in assisted reproductive technology 2004–2013. Reprod. Biol. Endocrinol. 2017, 15, 6. [Google Scholar] [CrossRef] [PubMed]
  5. Barker, D.J. The developmental origins of chronic adult disease. Acta Paediatr. Suppl. 2004, 93, 26–33. [Google Scholar] [CrossRef]
  6. Eriksson, J.G.; Forsén, T.J.; Kajantie, E.; Osmond, C.; Barker, D.J.P. Childhood growth and hypertension in later life. Hypertension 2007, 49, 1415–1421. [Google Scholar] [CrossRef] [PubMed]
  7. Barker, D.J.P.; Osmond, C.; Forsén, T.J.; Kajantie, E.; Eriksson, J.G. Trajectories of growth among children who have coronary events as adults. N. Engl. J. Med. 2005, 353, 1802–1809. [Google Scholar] [CrossRef]
  8. Hales, C.N.; Barker, D.J.P.; Clark, P.M.S.; Cox, L.J.; Fall, C.; Osmond, C.; Winter, P.D. Fetal and infant growth and impaired glucose tolerance at age 64. Br. Med. J. 1991, 303, 1019–1022. [Google Scholar] [CrossRef]
  9. Yu, H.; Yang, Q.; Sun, X.; Chen, G.; Qian, N.; Cai, R.; Guo, H.; Wang, C. Association of birth defects with the mode of assisted reproductive technology in a Chinese data-linkage cohort. Fertil. Steril. 2018, 109, 849–856. [Google Scholar] [CrossRef]
  10. Uk, A.; Collardeau-Frachon, S.; Scanvion, Q.; Michon, L.; Amar, E. Assisted Reproductive Technologies and imprinting disorders: Results of a study from a French congenital malformations registry. Eur. J. Med. Genet. 2018, 61, 518–523. [Google Scholar] [CrossRef]
  11. Jiang, Z.; Wang, Y.; Lin, J.; Xu, J.; Ding, G.; Huang, H. Genetic and epigenetic risks of assisted reproduction. Best Pract. Res. Clin. Obstet. Gynaecol. 2017, 44, 90–104. [Google Scholar] [CrossRef] [PubMed]
  12. Wainstock, T.; Walfisch, A.; Shoham-Vardi, I.; Segal, I.; Harlev, A.; Sergienko, R.; Landau, D.; Sheiner, E. Fertility treatments and pediatric neoplasms of the offspring: Results of a population-based cohort with a median follow-up of 10 years. Am. J. Obstet. Gynecol. 2017, 216, 314. [Google Scholar] [CrossRef] [PubMed]
  13. Reigstad, M.M.; Larsen, I.K.; Myklebust, T.Å.; Robsahm, T.E.; Oldereid, N.B.; Brinton, L.A.; Storeng, R. Risk of cancer in children conceived by assisted reproductive technology. Pediatrics 2016, 137, e20152061. [Google Scholar] [CrossRef]
  14. Fleming, T.P.; Watkins, A.J.; Velazquez, M.A.; Mathers, J.C.; Prentice, A.M.; Stephenson, J.; Barker, M.; Saffery, R.; Yajnik, C.S.; Eckert, J.J.; et al. Origins of lifetime health around the time of conception: Causes and consequences. Lancet 2018, 391, 1842–1852. [Google Scholar] [CrossRef]
  15. Cadenas, E.; Packer, L.; Traber, M.G. Antioxidants, oxidants, and redox impacts on cell function—A tribute to Helmut Sies. Arch. Biochem. Biophys. 2016, 595, 94–99. [Google Scholar] [CrossRef]
  16. Covarrubias, L.; Hernández-García, D.; Schnabel, D.; Salas-Vidal, E.; Castro-Obregón, S. Function of reactive oxygen species during animal development: Passive or active? Dev. Biol. 2008, 320, 1–11. [Google Scholar] [CrossRef] [PubMed]
  17. Aitken, R.J.; De Iuliis, G.N.; Drevet, J.R. Oxidants, Antioxidants and Impact of the Oxidative Status in Male Reproduction; Academic Press: Cambridge, MA, USA, 2019; pp. 91–100. [Google Scholar]
  18. Tremellen, K. Oxidants, Antioxidants and Impact of the Oxidative Status in Male Reproduction; Academic Press: Cambridge, MA, USA, 2019; pp. 225–235. [Google Scholar]
  19. Aitken, R.J.; Muscio, L.; Whiting, S.; Connaughton, H.S.; Fraser, B.A.; Nixon, B.; Smith, N.D.; De Iuliis, G.N. Analysis of the effects of polyphenols on human spermatozoa reveals unexpected impacts on mitochondrial membrane potential, oxidative stress and DNA integrity; implications for assisted reproductive technology. Biochem. Pharmacol. 2016, 121, 78–96. [Google Scholar] [CrossRef]
  20. Agarwal, A.; Said, TM.; Bedaiwy, M.A.; Banerjee, J.; Alvarez, J.G. Oxidative stress in an assisted reproductive techniques setting. Fertil. Steril. 2006, 86, 503–512. [Google Scholar] [CrossRef]
  21. Gupta, S.; Sekhon, L.; Kim, Y.; Agarwal, A. The Role of Oxidative Stress and Antioxidants in Assisted Reproduction. Curr. Women’s Health Rev. 2010, 6, 227–238. [Google Scholar] [CrossRef]
  22. Sartori, C.; Rimoldi, S.F.; Rexhaj, E.; Allemann, Y.; Scherrer, U. Hypoxia; Springer: New York, NY, USA, 2016; pp. 55–62. [Google Scholar]
  23. Agarwal, A.; Gupta, S.; Sharma, R.K. Role of oxidative stress in female reproduction. Reprod. Biol. Endocrinol. 2005, 3, 28. [Google Scholar] [CrossRef]
  24. Muoio, D.M.; Newgard, C.B. Mechanisms of disease: Molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes. Nat. Rev. Mol. Cell Biol. 2008, 9, 193–205. [Google Scholar] [CrossRef]
  25. Ho, E.; Karimi Galougahi, K.; Liu, C.C.; Bhindi, R.; Figtree, G.A. Biological markers of oxidative stress: Applications to cardiovascular research and practice. Redox Biol. 2013, 1, 483–491. [Google Scholar] [CrossRef] [PubMed]
  26. Lin, M.T.; Beal, M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006, 443, 787–795. [Google Scholar] [CrossRef] [PubMed]
  27. Jacob, K.D.; Noren Hooten, N.; Trzeciak, A.R.; Evans, M.K. Markers of oxidant stress that are clinically relevant in aging and age-related disease. Mech. Ageing Dev. 2013, 134, 139–157. [Google Scholar] [CrossRef] [PubMed]
  28. Mahfouz, R.; Sharma, R.; Thiyagarajan, A.; Kale, V.; Gupta, S.; Sabanegh, E.; Agarwal, A. Semen characteristics and sperm DNA fragmentation in infertile men with low and high levels of seminal reactive oxygen species. Fertil. Steril. 2010, 94, 2141–2146. [Google Scholar] [CrossRef] [PubMed]
  29. Allamaneni, S.S.R.; Naughton, C.K.; Sharma, R.K.; Thomas, A.J.; Agarwal, A. Increased seminal reactive oxygen species levels in patients with varicoceles correlate with varicocele grade but not with testis size. Fertil. Steril. 2004, 82, 1684–1686. [Google Scholar] [CrossRef]
  30. Biçer, Ş.; Gürsul, C.; Sayar, İ.; Akman, O.; Çakarlı, S.; Aydın, M. Role of ozone therapy in preventing testicular damage in an experimental cryptorchid rat model. Med. Sci. Monit. 2018, 24, 5832–5839. [Google Scholar] [CrossRef]
  31. Guimarães, S.B.; Aragão, A.A.; Santos, J.M.V.; Kimura, O.D.S.; Barbosa, P.H.U.; De Vasconcelos, P.R.L. Oxidative stress induced by torsion of the spermatic cord in young rats. Acta Cir. Bras. 2007, 22, 30–33. [Google Scholar] [CrossRef]
  32. La Vignera, S.; Condorelli, R.; D’Agata, R.; Vicari, E.; Calogero, A.E. Semen alterations and flow-citometry evaluation in patients with male accessory gland infections. J. Endocrinol. Investig. 2012, 35, 219–223. [Google Scholar] [CrossRef]
  33. Tremellen, K. Oxidative stress and male infertility—A clinical perspective. Hum. Reprod. Update 2008, 14, 243–258. [Google Scholar] [CrossRef]
  34. Pearce, K.L.; Hill, A.; Tremellen, K.P. Obesity related metabolic endotoxemia is associated with oxidative stress and impaired sperm DNA integrity. Basic Clin. Androl. 2019, 29, 1–9. [Google Scholar] [CrossRef] [PubMed]
  35. Pereira, R.; Sá, R.; Barros, A.; Sousa, M. Major regulatory mechanisms involved in sperm motility. Asian J. Androl. 2017, 19, 5–14. [Google Scholar] [CrossRef] [PubMed]
  36. Pasqualotto, F.F.; Sharma, R.K.; Pasqualotto, E.B.; Agarwal, A. Poor semen quality and ROS-TAC scores in patients with idiopathic infertility. Urol. Int. 2008, 81, 263–270. [Google Scholar] [CrossRef] [PubMed]
  37. Sikka, S.C. Oxidative stress and role of antioxidants in normal and abnormal sperm function. Front. Biosci. 1996, 1, e78–e86. [Google Scholar] [CrossRef]
  38. Agarwal, A.; Parekh, N.; Selvam, M.K.P.; Henkel, R.; Shah, R.; Homa, S.T.; Ramasamy, R.; Ko, E.; Tremellen, K.; Esteves, S.; et al. Male Oxidative Stress Infertility (MOSI): Proposed Terminology and Clinical Practice Guidelines for Management of Idiopathic Male Infertility. World J. Mens Health 2019, 37, 296–312. [Google Scholar] [CrossRef]
  39. Marchetti, C. Study of mitochondrial membrane potential, reactive oxygen species, DNA fragmentation and cell viability by flow cytometry in human sperm. Hum. Reprod. 2002, 17, 1257–1265. [Google Scholar] [CrossRef]
  40. Plante, M.; De Lamirande, E.; Gagnon, C. Reactive oxygen species released by activated neutrophils, but not by deficient spermatozoa, are sufficient to affect normal sperm motility. Fertil. Steril. 1994, 62, 387–393. [Google Scholar] [CrossRef]
  41. Sela, S.; Mazor, R.; Amsalam, M.; Yagil, C.; Yagil, Y.; Kristal, B. Primed polymorphonuclear leukocytes, oxidative stress, and inflammation antecede hypertension in the Sabra rat. Hypertension 2004, 44, 764–769. [Google Scholar] [CrossRef]
  42. Alvarez, J.G.; Storey, B.T. Differential incorporation of fatty acids into and peroxidative loss of fatty acids from phospholipids of human spermatozoa. Mol. Reprod. Dev. 1995, 42, 334–346. [Google Scholar] [CrossRef]
  43. Cannarella, R.; Calogero, A.E.; Condorelli, R.A.; Giacone, F.; Mongioi, L.M.; La Vignera, S. Non-hormonal treatment for male infertility: The potential role of Serenoa repens, selenium and lycopene. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 3112–3120. [Google Scholar] [CrossRef]
  44. Agarwal, A.; Plessis, S.S.D.; Durairajanayagam, D.; Virk, G. Strategies to Ameliorate Oxidative Stress during Assisted Reproduction; Springer: Berlin/Heidelberg, Germany, 2014; p. 7. [Google Scholar]
  45. Bisht, S.; Faiq, M.; Tolahunase, M.; Dada, R. Oxidative stress and male infertility. Nat. Rev. Urol. 2017, 14, 470–485. [Google Scholar] [CrossRef] [PubMed]
  46. Benchaib, M.; Braun, V.; Lornage, J.; Hadj, S.; Salle, B.; Lejeune, H.; Guérin, J.F. Sperm DNA fragentation decreases the pregnancy rate in an assisted reproductive technique. Hum. Reprod. 2003, 18, 1023–1028. [Google Scholar] [CrossRef] [PubMed]
  47. Saleh, R.A.; Agarwal, A.; Sharma, R.K.; Nelson, D.R.; Thomas, A.J. Effect of cigarette smoking on levels of seminal oxidative stress in infertile men: A prospective study. Fertil. Steril. 2002, 78, 491–499. [Google Scholar] [CrossRef]
  48. Aboulmaouahib, S.; Madkour, A.; Kaarouch, I.; Sefrioui, O.; Saadani, B.; Copin, H.; Benkhalifa, M.; Louanjli, N.; Cadi, R. Impact of alcohol and cigarette smoking consumption in male fertility potential: Looks at lipid peroxidation, enzymatic antioxidant activities and sperm DNA damage. Andrologia 2018, 50, e12926. [Google Scholar] [CrossRef] [PubMed]
  49. Eskiocak, S.; Gozen, A.S.; Taskiran, A.; Kilic, A.S.; Eskiocak, M.; Gulen, S. Effect of psychological stress on the L-arginine-nitric oxide pathway and semen quality. Braz. J. Med. Biol. Res. 2006, 39, 581–588. [Google Scholar] [CrossRef]
  50. Nudell, D.M.; Monoski, M.M.; Lipshultz, L.I. Common medications and drugs: How they affect male fertility. Urol. Clin. N. Am. 2002, 29, 965–973. [Google Scholar] [CrossRef]
  51. Ames, B.N. Micronutrient deficiencies. A major cause of DNA damage. Ann. N. Y. Acad. Sci. 1999, 889, 87–106. [Google Scholar] [CrossRef]
  52. Anderson, K.; Nisenblat, V.; Norman, R. Lifestyle factors in people seeking infertility treatment—A review. Aust. N. Z. J. Obstet. Gynaecol. 2010, 50, 8–20. [Google Scholar] [CrossRef]
  53. Rubes, J.; Selevan, S.G.; Evenson, D.P.; Zudova, D.; Vozdova, M.; Zudova, Z.; Robbins, W.A.; Perreault, S.D. Episodic air pollution is associated with increased DNA fragmentation in human sperm without other changes in semen quality. Hum. Reprod. 2005, 20, 2776–2783. [Google Scholar] [CrossRef]
  54. Zhou, D.D.; Hao, J.L.; Guo, K.M.; Lu, C.W.; Liu, X.D. Sperm quality and DNA damage in men from Jilin Province, China, who are occupationally exposed to ionizing radiation. Genet. Mol. Res. 2016, 15, 1–7. [Google Scholar] [CrossRef]
  55. Pérez-Crespo, M.; Pintado, B.; Gutiérrez-Adán, A. Scrotal heat stress effects on sperm viability, sperm DNA integrity, and the offspring sex ratio in mice. Mol. Reprod. Dev. 2008, 75, 40–47. [Google Scholar] [CrossRef] [PubMed]
  56. Wang, Y.X.; Zeng, Q.; Sun, Y.; You, L.; Wang, P.; Li, M.; Yang, P.; Li, J.; Huang, Z.; Wang, C.; et al. Phthalate exposure in association with serum hormone levels, sperm DNA damage and spermatozoa apoptosis: A cross-sectional study in China. Environ. Res. 2016, 150, 557–565. [Google Scholar] [CrossRef]
  57. Xu, D.X.; Shen, H.M.; Zhu, Q.X.; Chua, L.; Wang, Q.N.; Chia, S.E.; Ong, C.N. The associations among semen quality, oxidative DNA damage in human spermatozoa and concentrations of cadmium, lead and selenium in seminal plasma. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 2003, 534, 155–163. [Google Scholar] [CrossRef]
  58. Paoli, D.; Pallotti, F.; Lenzi, A.; Lombardo, F. Fatherhood and sperm DNA damage in testicular cancer patients. Front. Endocrinol. (Lausanne) 2018, 9, 506. [Google Scholar] [CrossRef] [PubMed]
  59. Chibber, S.; Farhan, M.; Hassan, I.; Naseem, I. White light-mediated Cu (II)-5FU interaction augments the chemotherapeutic potential of 5-FU: An in vitro study. Tumor Biol. 2011, 32, 881–892. [Google Scholar] [CrossRef] [PubMed]
  60. Pasqualotto, E.B.; Agarwal, A.; Sharma, R.K.; Izzo, V.M.; Pinotti, J.A.; Joshi, N.J.; Rose, B.I. Effect of oxidative stress in follicular fluid on the outcome of assisted reproductive procedures. Fertil. Steril. 2004, 81, 973–976. [Google Scholar] [CrossRef]
  61. Bedaiwy, M.A.; Falcone, T.; Mohamed, M.S.; Aleem, A.A.N.; Sharma, R.K.; Worley, S.E.; Thornton, J.; Agarwal, A. Differential growth of human embryos in vitro: Role of reactive oxygen species. Fertil. Steril. 2004, 82, 593–600. [Google Scholar] [CrossRef]
  62. Guérin, P.; El Mouatassim, S.; Ménézo, Y. Oxidative stress and protection against reactive oxygen species in the pre-implantation embryo and its surroundings. Hum. Reprod. Update 2001, 7, 175–189. [Google Scholar] [CrossRef]
  63. Oral, O.; Kutlu, T.; Aksoy, E.; Fıçıcıoğlu, C.; Uslu, H.; Tuğrul, S. The effects of oxidative stress on outcomes of assisted reproductive techniques. J. Assist. Reprod. Genet. 2006, 23, 81–85. [Google Scholar] [CrossRef]
  64. Chattopadhayay, R.; Ganesh, A.; Samanta, J.; Jana, S.K.; Chakravarty, B.N.; Chaudhury, K. Effect of follicular fluid oxidative stress on meiotic spindle formation in infertile women with polycystic ovarian syndrome. Gynecol. Obstet. Investig. 2010, 69, 197–202. [Google Scholar] [CrossRef]
  65. Máté, G.; Bernstein, L.R.; Török, A.L. Endometriosis Is a Cause of Infertility. Does Reactive Oxygen Damage to Gametes and Embryos Play a Key Role in the Pathogenesis of Infertility Caused by Endometriosis? Front. Endocrinol. (Lausanne) 2018, 9, 725. [Google Scholar] [CrossRef] [PubMed]
  66. Zhang, D.; Luo, W.Y.; Liao, H.; Wang, C.F.; Sun, Y. The effects of oxidative stress to PCOS. Sichuan Da Xue Xue Bao 2008, 39, 421–423. [Google Scholar] [PubMed]
  67. Bedaiwy, M.A.; Goldberg, J.M.; Falcone, T.; Singh, M.; Nelson, D.; Azab, H.; Wang, X.; Sharma, R. Relationship between oxidative stress and embryotoxicity of hydrosalpingeal fluid. Hum. Reprod. 2002, 17, 601–604. [Google Scholar] [CrossRef] [PubMed]
  68. Qin, J.; Liu, X.; Sheng, X.; Wang, H.; Gao, S. Assisted reproductive technology and the risk of pregnancy-related complications and adverse pregnancy outcomes in singleton pregnancies: A meta-analysis of cohort studies. Fertil. Steril. 2016, 105, 73–85. [Google Scholar] [CrossRef] [PubMed]
  69. Suhag, A.; Berghella, V. Intrauterine Growth Restriction (IUGR): Etiology and Diagnosis. Curr. Obstet. Gynecol. Rep. 2013, 2, 102–111. [Google Scholar] [CrossRef]
  70. Agarwal, A.; Aponte-Mellado, A.; Premkumar, B.J.; Shaman, A.; Gupta, S. The effects of oxidative stress on female reproduction: A review. Reprod. Biol. Endocrinol. 2012, 10, 49. [Google Scholar] [CrossRef]
  71. Mihalas, B.P.; De Iuliis, G.N.; Redgrove, K.A.; McLaughlin, E.A.; Nixon, B. The lipid peroxidation product 4-hydroxynonenal contributes to oxidative stress-mediated deterioration of the ageing oocyte. Sci. Rep. 2017, 7, 6247. [Google Scholar] [CrossRef]
  72. Prasad, S.; Tiwari, M.; Pandey, A.N.; Shrivastav, T.G.; Chaube, S.K. Impact of stress on oocyte quality and reproductive outcome. J. Biomed. Sci. 2016, 23, 36. [Google Scholar] [CrossRef]
  73. Cecchino, G.N.; Seli, E.; Alves da Motta, E.L.; García-Velasco, J.A. The role of mitochondrial activity in female fertility and assisted reproductive technologies: Overview and current insights. Reprod. Biomed. Online 2018, 36, 686–697. [Google Scholar] [CrossRef]
  74. Gudmundsdottir, S.L.; Flanders, W.D.; Augestad, L.B. Physical activity and fertility in women: The North-Trøndelag Health Study. Hum. Reprod. 2009, 24, 3196–3204. [Google Scholar] [CrossRef]
  75. Abir, R.; Nitke, S.; Ben-Haroush, A.; Fisch, B. In vitro maturation of human primordial ovarian follicles: Clinical significance, progress in mammals, and methods for growth evaluation. Histol. Histopathol. 2006, 21, 887–898. [Google Scholar] [CrossRef] [PubMed]
  76. Conklin, K.A. Chemotherapy-associated oxidative stress: Impact on chemotherapeutic effectiveness. Integr. Cancer Ther. 2004, 3, 294–300. [Google Scholar] [CrossRef] [PubMed]
  77. Conforti, A.; Mascia, M.; Cioffi, G.; De Angelis, C.; Coppola, G.; De Rosa, P.; Pivonello, R.; Alviggi, C.; De Placido, G. Air pollution and female fertility: A systematic review of literature. Reprod. Biol. Endocrinol. 2018, 16, 117. [Google Scholar] [CrossRef] [PubMed]
  78. Ruder, E.H.; Hartman, T.J.; Blumberg, J.; Goldman, M.B. Oxidative stress and antioxidants: Exposure and impact on female fertility. Hum. Reprod. Update 2008, 14, 345–357. [Google Scholar] [CrossRef] [PubMed]
  79. Zribi, N.; Feki Chakroun, N.; El Euch, H.; Gargouri, J.; Bahloul, A.; Ammar Keskes, L. Effects of cryopreservation on human sperm deoxyribonucleic acid integrity. Fertil. Steril. 2010, 93, 159–166. [Google Scholar] [CrossRef]
  80. Gualtieri, R.; Iaccarino, M.; Mollo, V.; Prisco, M.; Iaccarino, S.; Talevi, R. Slow cooling of human oocytes: Ultrastructural injuries and apoptotic status. Fertil. Steril. 2009, 91, 1023–1034. [Google Scholar] [CrossRef]
  81. Saeed, Z.; Ali, T.; Hadi, H. Amending in vitro culture condition to overcome oxidative stress in assisted reproduction techniques (ART). J. Paramed. Sci. 2015, 6, 2. [Google Scholar] [CrossRef]
  82. Shahar, S.; Wiser, A.; Ickowicz, D.; Lubart, R.; Shulman, A.; Breitbart, H. Light-mediated activation reveals a key role for protein kinase A and sarcoma protein kinase in the development of sperm hyper-activated motility. Hum. Reprod. 2011, 26, 2274–2282. [Google Scholar] [CrossRef]
  83. Will, M.A.; Clark, N.A.; Swain, J.E. Biological pH buffers in IVF: Help or hindrance to success. J. Assist. Reprod. Genet. 2011, 28, 711–724. [Google Scholar] [CrossRef]
  84. Larkindale, J.; Knight, M.R. Protection against heat stress-induced oxidative damage in Arabidopsis involves calcium, abscisic acid, ethylene, and salicylic acid. Plant Physiol. 2002, 128, 682–695. [Google Scholar] [CrossRef]
  85. Bontekoe, S.; Mantikou, E.; van Wely, M.; Seshadri, S.; Repping, S.; Mastenbroek, S. Low oxygen concentrations for embryo culture in assisted reproductive technologies. Cochrane Database Syst. Rev. 2012, 11, CD008950. [Google Scholar] [CrossRef] [PubMed]
  86. Lampiao, F.; Strijdom, H.; Plessis, S. d. Effects of sperm processing techniques involving centrifugation on nitric oxide, reactive oxygen species generation and sperm function. Open Androl. J. 2010, 2, 1–5. [Google Scholar] [CrossRef]
  87. Calzi, F.; Papaleo, E.; Rabellotti, E.; Ottolina, J.; Vailati, S.; Viganò, P.; Candiani, M. Exposure of embryos to oxygen at low concentration in a cleavage stage transfer program: Reproductive outcomes in a time-series analysis. Clin. Lab. 2012, 58, 997–1003. [Google Scholar] [CrossRef]
  88. Cohen, J.; Gilligan, A.; Esposito, W.; Schimmel, T.; Dale, B. Ambient air and its potential effects on conception in vitro. Hum. Reprod. 1997, 12, 1742–1749. [Google Scholar] [CrossRef] [PubMed]
  89. Agarwal, A.; Durairajanayagam, D.; du Plessis, S.S. Utility of antioxidants during assisted reproductive techniques: An evidence based review. Reprod. Biol. Endocrinol. 2014, 12, 112. [Google Scholar] [CrossRef] [PubMed]
  90. Peritore, A.F.; Siracusa, R.; Crupi, R.; Cuzzocrea, S. Therapeutic efficacy of palmitoylethanolamide and its new formulations in synergy with different antioxidant molecules present in diets. Nutrients 2019, 11, 2175. [Google Scholar] [CrossRef]
  91. Halliwell, B.; Gutteridge, J.M.C. Oxidants, Free Radicals in Biology and Medicine; Oxford University Press: Oxford, UK, 2015; p. 34. [Google Scholar]
  92. Tan, D.Q.; Suda, T. Reactive Oxygen Species and Mitochondrial Homeostasis as Regulators of Stem Cell Fate and Function. Antioxid. Redox Signal. 2018, 29, 149–168. [Google Scholar] [CrossRef]
  93. Ekstrand, M.; Trajkovska, M.G.; Perman-Sundelin, J.; Fogelstrand, P.; Adiels, M.; Johansson, M.; Mattsson-Hultén, L.; Borén, J.; Levin, M. Imaging of intracellular and extracellular ROS levels in atherosclerotic mouse aortas ex vivo: Effects of lipid lowering by diet or atorvastatin. PLoS ONE 2015, 10, e0130898. [Google Scholar] [CrossRef]
  94. Rinaldi, M.; Ceciliani, F.; Lecchi, C.; Moroni, P.; Bannerman, D.D. Differential effects of α1-acid glycoprotein on bovine neutrophil respiratory burst activity and IL-8 production. Vet. Immunol. Immunopathol. 2008, 126, 199–210. [Google Scholar] [CrossRef]
  95. Khandrika, L.; Kumar, B.; Koul, S.; Maroni, P.; Koul, H.K. Oxidative stress in prostate cancer. Cancer Lett. 2009, 282, 125–136. [Google Scholar] [CrossRef]
  96. Lenaz, G. The mitochondrial production of reactive oxygen species: Mechanisms and implications in human pathology. IUBMB Life 2001, 52, 159–164. [Google Scholar] [CrossRef] [PubMed]
  97. Martín-Romero, F.J.; Miguel-Lasobras, E.M.; Domínguez-Arroyo, J.A.; Gonzélez-Carrera, E.; Álvarez, I.S. Contribution of culture media to oxidative stress and its effect on human oocytes. Reprod. Biomed. Online 2008, 17, 652–661. [Google Scholar] [CrossRef]
  98. Vundru, S.S.; Prasad, N.; Patel, R.; Rani, V.; Yadav, U.C.S. Free Radicals in Human Health and Disease; Springer: Berlin/Heidelberg, Germany, 2015; p. 76. [Google Scholar]
  99. Guo, Y.; Yu, S.; Zhang, C.; Kong, A.N.T. Epigenetic regulation of Keap1-Nrf2 signaling. Free Radic. Biol. Med. 2015, 88, 337–349. [Google Scholar] [CrossRef] [PubMed]
  100. Bavineni, M.; Wassenaar, T.M.; Agnihotri, K.; Ussery, D.W.; Lüscher, T.F.; Mehta, J.L. Mechanisms linking preterm birth to onset of cardiovascular disease later in adulthood. Eur. Heart J. 2019, 40, 1107–1112. [Google Scholar] [CrossRef]
  101. Hoeijmakers, L.; Kempe, H.; Verschure, P.J. Epigenetic imprinting during assisted reproductive technologies: The effect of temporal and cumulative fluctuations in methionine cycling on the DNA methylation state. Mol. Reprod. Dev. 2016, 83, 94–107. [Google Scholar] [CrossRef]
  102. Mayneris-Perxachs, J.; Lima, A.A.; Guerrant, R.L.; Leite Á, M.; Moura, A.F.; Lima, N.L.; Swann, J.R. Urinary N-methylnicotinamide and β-aminoisobutyric acid predict catch-up growth in undernourished Brazilian children. Sci. Rep. 2016, 6, 19780. [Google Scholar] [CrossRef]
  103. Kindsfather, A.J.; Czekalski, M.A.; Pressimone, C.A.; Erisman, M.P.; Mann, M.R.W. Perturbations in imprinted methylation from assisted reproductive technologies but not advanced maternal age in mouse preimplantation embryos. Clin. Epigenetics 2019, 11, 162. [Google Scholar] [CrossRef]
  104. Movahed, E.; Soleimani, M.; Hosseini, S.; Akbari Sene, A.; Salehi, M. Aberrant expression of miR-29a/29b and methylation level of mouse embryos after in vitro fertilization and vitrification at two-cell stage. J. Cell Physiol. 2019, 234, 18942–18950. [Google Scholar] [CrossRef]
  105. Rexhaj, E.; Bloch, J.; Jayet, P.Y.; Rimoldi, S.F.; Dessen, P.; Mathieu, C.; Tolsa, J.F.; Nicod, P.; Scherrer, U.; Sartori, C. Fetal programming of pulmonary vascular dysfunction in mice: Role of epigenetic mechanisms. Am. J. Physiol. Heart Circ. Physiol. 2011, 301, H247–H252. [Google Scholar] [CrossRef]
  106. Kietzmann, T.; Petry, A.; Shvetsova, A.; Gerhold, J.M.; Görlach, A. The epigenetic landscape related to reactive oxygen species formation in the cardiovascular system. Br. J. Pharmacol. 2017, 174, 1533–1554. [Google Scholar] [CrossRef]
  107. Booth, M.J.; Ost, T.W.B.; Beraldi, D.; Bell, N.M.; Branco, M.R.; Reik, W.; Balasubramanian, S. Oxidative bisulfite sequencing of 5-methylcytosine and 5-hydroxymethylcytosine. Nat. Protoc. 2013, 8, 1841–1851. [Google Scholar] [CrossRef]
  108. Madugundu, G.S.; Cadet, J.; Wagner, J.R. Hydroxyl-radical-induced oxidation of 5-methylcytosine in isolated and cellular DNA. Nucleic Acids Res. 2014, 42, 7450–7460. [Google Scholar] [CrossRef] [PubMed]
  109. Branco, M.R.; Ficz, G.; Reik, W. Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat. Rev. Genet. 2012, 13, 7–13. [Google Scholar] [CrossRef] [PubMed]
  110. Niu, Y.; Desmarais, T.L.; Tong, Z.; Yao, Y.; Costa, M. Oxidative stress alters global histone modification and DNA methylation. Free Radic. Biol. Med. 2015, 82, 22–28. [Google Scholar] [CrossRef]
  111. Tsankova, N.; Renthal, W.; Kumar, A.; Nestler, E.J. Epigenetic regulation in psychiatric disorders. Nat. Rev. Neurosci. 2007, 8, 355–367. [Google Scholar] [CrossRef] [PubMed]
  112. Saenen, N.D.; Martens, D.S.; Neven, K.Y.; Alfano, R.; Bové, H.; Janssen, B.G.; Roels, H.A.; Plusquin, M.; Vrijens, K.; Nawrot, T.S. Air pollution-induced placental alterations: An interplay of oxidative stress, epigenetics, and the aging phenotype? Clin. Epigenetics 2019, 11, 124. [Google Scholar] [CrossRef] [PubMed]
  113. He, J.; Jiang, B.H. Interplay Between Reactive Oxygen Species and MicroRNAs in Cancer. Curr. Pharmacol. Rep. 2016, 2, 82–90. [Google Scholar] [CrossRef]
  114. Camici, G.G.; Schiavoni, M.; Francia, P.; Bachschmid, M.; Martin-Padura, I.; Hersberger, M.; Tanner, F.C.; Pelicci, P.G.; Volpe, M.; Anversa, P.; et al. Genetic deletion of p66Shc adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress. Proc. Natl. Acad. Sci. USA 2007, 104, 5217–5222. [Google Scholar] [CrossRef]
  115. Costantino, S.; Paneni, F.; Virdis, A.; Hussain, S.; Mohammed, S.A.; Capretti, G.; Akhmedov, A.; Dalgaard, K.; Chiandotto, S.; Pospisilik, J.A.; et al. Interplay among H3K9-editing enzymes SUV39H1, JMJD2C and SRC-1 drives p66 Shc transcription and vascular oxidative stress in obesity. Eur. Heart J. 2019, 40, 383–391. [Google Scholar] [CrossRef]
  116. Shimoyama, Y.; Mitsuda, Y.; Hamajima, N.; Niwa, T. Polymorphisms of Nrf2, an antioxidative gene, are associated with blood pressure in Japanese. Nagoya J. Med. Sci. 2014, 76, 113–120. [Google Scholar] [CrossRef]
  117. Satta, S.; Mahmoud, A.M.; Wilkinson, F.L.; Yvonne Alexander, M.; White, S.J. The Role of Nrf2 in Cardiovascular Function and Disease. Oxid. Med. Cell. Longev. 2017, 2017, 9237263. [Google Scholar] [CrossRef] [PubMed]
  118. Czogalla, B.; Kahaly, M.; Mayr, D.; Schmoeckel, E.; Niesler, B.; Kolben, T.; Burges, A.; Mahner, S.; Jeschke, U.; Trillsch, F. Interaction of ERα and NRF2 impacts survival in ovarian cancer patients. Int. J. Mol. Sci. 2019, 20, 112. [Google Scholar] [CrossRef] [PubMed]
  119. Luo, M.; Shang, L.; Brooks, M.D.; Jiagge, E.; Zhu, Y.; Buschhaus, J.M.; Conley, S.; Fath, M.A.; Davis, A.; Gheordunescu, E.; et al. Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling. Cell Metab. 2018, 28, 69–86. [Google Scholar] [CrossRef] [PubMed]
  120. Schrier, M.S.; Trivedi, M.S.; Deth, R.C. Redox-related epigenetic mechanisms in glioblastoma: Nuclear factor (erythroid-derived 2)-like 2, cobalamin, and dopamine receptor subtype 4. Front. Oncol. 2017, 7, 46. [Google Scholar] [CrossRef]
  121. Cuadrado, A.; Rojo, A.I.; Wells, G.; Hayes, J.D.; Cousin, S.P.; Rumsey, W.L.; Attucks, O.C.; Franklin, S.; Levonen, A.L.; Kensler, T.W.; et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat. Rev. Drug Discov. 2019, 18, 295–317. [Google Scholar] [CrossRef] [PubMed]
  122. Impellizzeri, D.; Siracusa, R.; Cordaro, M.; Crupi, R.; Peritore, A.F.; Gugliandolo, E.; D’Amico, R.; Petrosino, S.; Evangelista, M.; Di Paola, R.; et al. N-Palmitoylethanolamine-oxazoline (PEA-OXA): A new therapeutic strategy to reduce neuroinflammation, oxidative stress associated to vascular dementia in an experimental model of repeated bilateral common carotid arteries occlusion. Neurobiol. Dis. 2019, 125, 77–91. [Google Scholar] [CrossRef]
  123. Yu, Q.; Li, X.; Cao, X. Linarin could protect myocardial tissue from the injury of Ischemia-reperfusion through activating Nrf-2. Biomed. Pharmacother. 2017, 90, 1–7. [Google Scholar] [CrossRef]
  124. Bonnefont-Rousselot, D. Resveratrol and cardiovascular diseases. Nutrients 2016, 8, 250. [Google Scholar] [CrossRef]
  125. Wan, J.; Winn, L.M. In utero-initiated cancer: The role of reactive oxygen species. Birth Defects Res. Part C Embryo Today Rev. 2006, 78, 326–332. [Google Scholar] [CrossRef]
  126. Giudice, A.; Arra, C.; Turco, M.C. Review of molecular mechanisms involved in the activation of the Nrf2-ARE signaling pathway by chemopreventive agents. Methods Mol. Biol. 2010, 647, 37–74. [Google Scholar] [CrossRef]
  127. Amin, A. NRF2 Mediated Oxidative Stress Response Activity During Early In Vitro Bovine Embryo Development. Ph.D. Thesis, Universitäts-und Landesbibliothek Bonn, Bonn, Germany, 2015. [Google Scholar]
  128. Chapple, S.J.; Puszyk, W.M.; Mann, G.E. Keap1-Nrf2 regulated redox signaling in utero: Priming of disease susceptibility in offspring. Free Radic. Biol. Med. 2015, 88, 212–220. [Google Scholar] [CrossRef] [PubMed]
  129. Mann, G.E.; Niehueser-Saran, J.; Watson, A.; Gao, L.; Ishii, T.; de Winter, P.; Siow, R.C. Nrf2/ARE regulated antioxidant gene expression in endothelial and smooth muscle cells in oxidative stress: Implications for atherosclerosis and preeclampsia. Sheng Li Xue Bao 2007, 59, 117–127. [Google Scholar] [PubMed]
  130. Kensler, T.W.; Wakabayashi, N.; Biswal, S. Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway. Annu. Rev. Pharmacol. Toxicol. 2007, 47, 89–116. [Google Scholar] [CrossRef] [PubMed]
  131. Hayes, J.D.; Dinkova-Kostova, A.T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci. 2014, 39, 199–218. [Google Scholar] [CrossRef] [PubMed]
  132. Kwak, M.K.; Wakabayashi, N.; Itoh, K.; Motohashi, H.; Yamamoto, M.; Kensler, T.W. Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway: Identification of novel gene clusters for cell survival. J. Biol. Chem. 2003, 278, 8135–8145. [Google Scholar] [CrossRef] [PubMed]
  133. Macleod, A.K.; Mcmahon, M.; Plummer, S.M.; Higgins, L.G.; Penning, T.M.; Igarashi, K.; Hayes, J.D. Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: Demonstration that the KEAP1-NRF2 pathway, and not the BACH1-NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds. Carcinogenesis 2009, 30, 1571–1580. [Google Scholar] [CrossRef] [PubMed]
  134. Li, J.; Lee, J.M.; Johnson, J.A. Microarray analysis reveals an antioxidant responsive element-driven gene set involved in conferring protection from an oxidative stress-induced apoptosis in IMR-32 cells. J. Biol. Chem. 2002, 277, 388–394. [Google Scholar] [CrossRef]
  135. Song, D.; Cheng, Y.; Li, X.; Wang, F.; Lu, Z.; Xiao, X.; Wang, Y. Biogenic Nanoselenium Particles Effectively Attenuate Oxidative Stress-Induced Intestinal Epithelial Barrier Injury by Activating the Nrf2 Antioxidant Pathway. ACS Appl. Mater. Interfaces 2017, 9, 14724–14740. [Google Scholar] [CrossRef]
  136. Singh, A.; Rangasamy, T.; Thimmulappa, R.K.; Lee, H.; Osburn, W.O.; Brigelius-Flohé, R.; Kensler, T.W.; Yamamoto, M.; Biswal, S. Glutathione peroxidase 2, the major cigarette smoke-inducible isoform of GPX in lungs, is regulated by Nrf2. Am. J. Respir. Cell Mol. Biol. 2006, 35, 639–650. [Google Scholar] [CrossRef]
  137. Cho, H.Y.; Reddy, S.P.; DeBiase, A.; Yamamoto, M.; Kleeberger, S.R. Gene expression profiling of NRF2-mediated protection against oxidative injury. Free Radic. Biol. Med. 2005, 38, 325–343. [Google Scholar] [CrossRef]
  138. Okawa, H.; Motohashi, H.; Kobayashi, A.; Aburatani, H.; Kensler, T.W.; Yamamoto, M. Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Biochem. Biophys. Res. Commun. 2006, 339, 79–88. [Google Scholar] [CrossRef] [PubMed]
  139. Banning, A.; Deubel, S.; Kluth, D.; Zhou, Z.; Brigelius-Flohé, R. The GI-GPx Gene Is a Target for Nrf2. Mol. Cell. Biol. 2005, 25, 4914–4923. [Google Scholar] [CrossRef] [PubMed]
  140. Habeos, I.G.; Ziros, P.G.; Chartoumpekis, D.; Psyrogiannis, A.; Kyriazopoulou, V.; Papavassiliou, A.G. Simvastatin activates Keap1/Nrf2 signaling in rat liver. J. Mol. Med. 2008, 86, 1279–1285. [Google Scholar] [CrossRef] [PubMed]
  141. Reisman, S.A.; Yeager, R.L.; Yamamoto, M.; Klaassen, C.D. Increased Nrf2 activation in livers from keap1-knockdown mice Increases expression of cytoprotective genes that detoxify electrophiles more than those that detoxify reactive oxygen species. Toxicol. Sci. 2009, 108, 35–47. [Google Scholar] [CrossRef]
  142. Rangasamy, T.; Cho, C.Y.; Thimmulappa, R.K.; Zhen, L.; Srisuma, S.S.; Kensler, T.W.; Yamamoto, M.; Petrache, I.; Tuder, R.M.; Biswal, S. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J. Clin. Investig. 2004, 114, 1248–1259. [Google Scholar] [CrossRef]
  143. Thimmulappa, R.K.; Mai, K.H.; Srisuma, S.; Kensler, T.W.; Yamamoto, M.; Biswal, S. Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res. 2002, 62, 5196–5203. [Google Scholar]
  144. Yates, M.S.; Kwak, M.K.; Egner, P.A.; Groopman, J.D.; Bodreddigari, S.; Sutter, T.R.; Baumgartner, K.J.; Roebuck, B.D.; Liby, K.T.; Yore, M.M.; et al. Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1, 9(11)-dien-28-oyl]imidazole. Cancer Res. 2006, 66, 2488–2494. [Google Scholar] [CrossRef]
  145. Hu, R.; Xu, C.; Shen, G.; Jain, M.R.; Khor, T.O.; Gopalkrishnan, A.; Lin, W.; Reddy, B.; Chan, J.Y.; Kong, A.N.T. Gene expression profiles induced by cancer chemopreventive isothiocyanate sulforaphane in the liver of C57BL/6J mice and C57BL/6J/Nrf2(−/−) mice. Cancer Lett. 2006, 243, 170–192. [Google Scholar] [CrossRef]
  146. Hayes, J.D.; Dinkova-Kostova, A.T. Epigenetic Control of NRF2-Directed Cellular Antioxidant Status in Dictating Life-Death Decisions. Mol. Cell 2017, 68, 5–7. [Google Scholar] [CrossRef]
  147. Chowdhury, I.; Mo, Y.; Gao, L.; Kazi, A.; Fisher, A.B.; Feinstein, S.I. Oxidant stress stimulates expression of the human peroxiredoxin 6 gene by a transcriptional mechanism involving an antioxidant response element. Free Radic. Biol. Med. 2009, 46, 146–153. [Google Scholar] [CrossRef]
  148. Mahaffey, C.M.; Zhang, H.; Rinna, A.; Holland, W.; Mack, P.C.; Forman, H.J. Multidrug-resistant protein-3 gene regulation by the transcription factor Nrf2 in human bronchial epithelial and non-small-cell lung carcinoma. Free Radic. Biol. Med. 2009, 46, 1650–1657. [Google Scholar] [CrossRef] [PubMed]
  149. Youle, R.J.; Van Der Bliek, A.M. Mitochondrial fission, fusion, and stress. Science 2012, 337, 1062–1065. [Google Scholar] [CrossRef]
  150. Rodford, J.L.; Torrens, C.; Siow, R.C.M.; Mann, G.E.; Hanson, M.A.; Clough, G.F. Endothelial dysfunction and reduced antioxidant protection in an animal model of the developmental origins of cardiovascular disease. J. Physiol. 2008, 586, 4709–4720. [Google Scholar] [CrossRef] [PubMed]
  151. Giussani, D.A.; Camm, E.J.; Niu, Y.; Richter, H.G.; Blanco, C.E.; Gottschalk, R.; Blake, E.Z.; Horder, K.A.; Thakor, A.S.; Hansell, J.A.; et al. Developmental programming of cardiovascular dysfunction by prenatal hypoxia and oxidative stress. PLoS ONE 2012, 7, e31017. [Google Scholar] [CrossRef]
  152. Do Franco, M.C.P.; Dantas, A.P.V.; Akamine, E.H.; Kawamoto, E.M.; Fortes, Z.B.; Scavone, C.; Tostes, R.C.A.; Carvalho, M.H.C.; Nigro, D. Enhanced oxidative stress as a potential mechanism underlying the programming of hypertension in utero. J. Cardiovasc. Pharmacol. 2002, 40, 501–509. [Google Scholar] [CrossRef] [PubMed]
  153. Da Liao, X.; Wang, L.; Huang, X.; Li, Y.; Dasgupta, C.; Zhang, L. Protective effect of antenatal antioxidant on Nicotine-induced heart ischemia-sensitive phenotype in rat offspring. PLoS ONE 2016, 11, e0150557. [Google Scholar] [CrossRef]
  154. Cooke, C.L.M.; Shah, A.; Kirschenman, R.D.; Quon, A.L.; Morton, J.S.; Care, A.S.; Davidge, S.T. Increased susceptibility to cardiovascular disease in offspring born from dams of advanced maternal age. J. Physiol. 2018, 596, 5807–5821. [Google Scholar] [CrossRef]
  155. Shah, A.; Cooke, C.L.M.; Kirschenman, R.D.; Quon, A.L.; Morton, J.S.; Care, A.S.; Davidge, S.T. Sex-specific effects of advanced maternal age on cardiovascular function in aged adult rat offspring. Am. J. Physiol. Heart Circ. Physiol. 2018, 315, H1724–H1734. [Google Scholar] [CrossRef]
  156. Fox, R.; Kitt, J.; Leeson, P.; Aye, C.Y.L.; Lewandowski, A.J. Preeclampsia: Risk Factors, Diagnosis, Management, and the Cardiovascular Impact on the Offspring. J. Clin. Med. 2019, 8, 1625. [Google Scholar] [CrossRef]
  157. Tripathi, R.R.; Rifas-Shiman, S.L.; Hawley, N.; Hivert, M.F.; Oken, E. Hypertensive disorders of pregnancy and offspring cardiometabolic health at midchildhood: Project viva findings. J. Am. Heart Assoc. 2018, 7, e007426. [Google Scholar] [CrossRef]
  158. Yu, Y.; Arah, O.A.; Liew, Z.; Cnattingius, S.; Olsen, J.; Sørensen, H.T.; Qin, G.; Li, J. Maternal diabetes during pregnancy and early onset of cardiovascular disease in offspring: Population based cohort study with 40 years of follow-up. BMJ 2019, 367, l6398. [Google Scholar] [CrossRef] [PubMed]
  159. Kuo, A.H.; Li, C.; Huber, H.F.; Clarke, G.D.; Nathanielsz, P.W. Intrauterine growth restriction results in persistent vascular mismatch in adulthood. J. Physiol. 2018, 596, 5777–5790. [Google Scholar] [CrossRef] [PubMed]
  160. Wen, S.W.; Leader, A.; White, R.R.; Léveillé, M.C.; Wilkie, V.; Zhou, J.; Walker, M.C. A comprehensive assessment of outcomes in pregnancies conceived by in vitro fertilization/intracytoplasmic sperm injection. Eur. J. Obstet. Gynecol. Reprod. Biol. 2010, 150, 160–165. [Google Scholar] [CrossRef]
  161. Liu, H.; Zhang, Y.; Gu, H.T.; Feng, Q.L.; Liu, J.Y.; Zhou, J.; Yan, F. Association between assisted reproductive technology and cardiac alteration at age 5 years. JAMA Pediatr. 2015, 169, 603–605. [Google Scholar] [CrossRef]
  162. Meister, T.A.; Rimoldi, S.F.; Soria, R.; von Arx, R.; Messerli, F.H.; Sartori, C.; Scherrer, U.; Rexhaj, E. Association of Assisted Reproductive Technologies with Arterial Hypertension During Adolescence. J. Am. Coll. Cardiol. 2018, 72, 1267–1274. [Google Scholar] [CrossRef] [PubMed]
  163. Von Arx, R.; Allemann, Y.; Sartori, C.; Rexhaj, E.; Cerny, D.; De Marchi, S.F.; Soria, R.; Germond, M.; Scherrer, U.; Rimoldi, S.F. Right ventricular dysfunction in children and adolescents conceived by assisted reproductive technologies. J. Appl. Physiol. 2015, 118, 1200–1206. [Google Scholar] [CrossRef] [PubMed]
  164. Scherrer, U.; Rimoldi, S.F.; Rexhaj, E.; Stuber, T.; Duplain, H.; Garcin, S.; De Marchi, S.F.; Nicod, P.; Germond, M.; Allemann, Y.; et al. Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies. Circulation 2012, 125, 1890–1896. [Google Scholar] [CrossRef]
  165. Juonala, M.; Lewis, S.; McLachlan, R.; Hammarberg, K.; Kennedy, J.; Saffery, R.; McBain, J.; Welsh, L.; Cheung, M.; Doyle, L.W.; et al. American Heart Association ideal cardiovascular health score and subclinical atherosclerosis in 22-35-year-old adults conceived with and without assisted reproductive technologies. Hum. Reprod. 2020, 35, 232–239. [Google Scholar] [CrossRef]
  166. Hart, R.; Norman, R.J. The longer-term health outcomes for children born as a result of ivf treatment: Part i-general health outcomes. Hum. Reprod. Update 2013, 19, 232–243. [Google Scholar] [CrossRef]
  167. Guo, X.Y.; Liu, X.M.; Jin, L.; Wang, T.T.; Ullah, K.; Sheng, J.Z.; Huang, H.F. Cardiovascular and metabolic profiles of offspring conceived by assisted reproductive technologies: A systematic review and meta-analysis. Fertil. Steril. 2017, 107, 622–631. [Google Scholar] [CrossRef]
  168. Vrooman, L.A.; Bartolomei, M.S. Can assisted reproductive technologies cause adult-onset disease?. Evidence from human and mouse. Reprod. Toxicol. 2017, 68, 72–84. [Google Scholar] [CrossRef] [PubMed]
  169. Steptoe, P.C.; Edwards, R.G. Birth after the reimplantation of a human embryo. Lancet 1978, 2, 366. [Google Scholar] [CrossRef]
  170. Barandalla, M.; Colleoni, S.; Lazzari, G. Differential response of human embryonic stem and somatic cells to non-cytotoxic hydrogen peroxide exposure: An attempt to model in vitro the effects of oxidative stress on the early embryo. Cell Dev. Biol. 2016, 5, 177. [Google Scholar] [CrossRef] [PubMed]
Figure 1. This figure shows the origins of paternally derived OS. The origins of OS that could affect fathers and their gametes mainly derive from four causes: male fertility complications, lifestyle/diet, environmental/occupational exposures, and special treatments. OS, oxidative stress; MAGI, male accessory gland infections; MOSI, male oxidative stress infertility.
Figure 1. This figure shows the origins of paternally derived OS. The origins of OS that could affect fathers and their gametes mainly derive from four causes: male fertility complications, lifestyle/diet, environmental/occupational exposures, and special treatments. OS, oxidative stress; MAGI, male accessory gland infections; MOSI, male oxidative stress infertility.
Ijms 21 05175 g001
Figure 2. This figure shows the origins of maternally derived OS. The origins of OS that could affect the mothers, gametes, and their pregnancies mainly derive from five aspects: female fertility complications, lifestyle/diet, environmental/occupational exposures, special treatments and pregnancy complications. PCOS, polycystic ovary syndrome; HDP, hypertensive disorders of pregnancy; GDM, gestational diabetes mellitus; IUGR, intrauterine growth restriction.
Figure 2. This figure shows the origins of maternally derived OS. The origins of OS that could affect the mothers, gametes, and their pregnancies mainly derive from five aspects: female fertility complications, lifestyle/diet, environmental/occupational exposures, special treatments and pregnancy complications. PCOS, polycystic ovary syndrome; HDP, hypertensive disorders of pregnancy; GDM, gestational diabetes mellitus; IUGR, intrauterine growth restriction.
Ijms 21 05175 g002
Figure 3. This figure shows the origins of ART-derived OS. During ART, several factors might lead to elevated OS. ART, assisted reproductive technology.
Figure 3. This figure shows the origins of ART-derived OS. During ART, several factors might lead to elevated OS. ART, assisted reproductive technology.
Ijms 21 05175 g003
Figure 4. This figure shows the early-life OS exert long-lasting effects on offspring conceived by ART. ncRNAs, non-coding RNAs; miRNAs, micro-RNAs; lncRNAs, long non-coding RNAs.
Figure 4. This figure shows the early-life OS exert long-lasting effects on offspring conceived by ART. ncRNAs, non-coding RNAs; miRNAs, micro-RNAs; lncRNAs, long non-coding RNAs.
Ijms 21 05175 g004
Table 1. Antioxidant genes regulated by Nrf2.
Table 1. Antioxidant genes regulated by Nrf2.
Gene Protein EncodedSynonymsSpecies 1Refs
GSH-based antioxidant genes
GCLCGlutamate-cysteine ligase catalytic subunitGCS, GLCL, GLCLCm, h[131,132,133]
GCLMGlutamate-cysteine ligase modifier subunitGLCLRm, h[131,132,133,134]
GGT1Gamma-glutamyltransferase 1CD224, D22S672, D22S732, GGTh[131]
GLRXGlutaredoxinGRX, GRX1h[131]
GLSGlutaminaseGLS1, KIAA0838h[131]
GPX1Glutathione peroxidase 1-m[135,136]
GPX2Glutathione peroxidase 2GSHPX-GIm, h[131,137,138,139,140]
GPX4Glutathione peroxidase 4MCSP, PHGPxm[131]
GSRGlutathione-disulfide reductase-m, h[133,134]
GSTA1Glutathione S-transferase alpha 1-m[131,141,142,143]
GSTA2Glutathione S-transferase alpha 2-m[132,142,143]
GSTA3Glutathione S-transferase alpha 3-m[141,142,143]
GSTA4Glutathione S-transferase alpha 4-m[144]
GSTM1Glutathione S-transferase mu 1GST1, H-B, MUm[131,132,143,144]
GSTM2Glutathione S-transferase mu 2GST4m[132,143,144]
GSTM3Glutathione S-transferase mu 3GST5m, h[132,134,143,144]
GSTM4Glutathione S-transferase mu 4-m[144]
GSTM5Glutathione S-transferase mu 5-m[145]
GSTM6Glutathione S-transferase mu 6-m[144]
GSTP1Glutathione S-transferase pi 1FAEES3, GST3, GSTPm[131]
MGST1icrosomal glutathione S-transferase 1GST12, MGST-Im, h[131]
MGST2Microsomal glutathione S-transferase 2MGST-IIm[143]
MGST3Microsomal glutathione S-transferase 3GST-IIIm[132,143]
SLC6A9Solute carrier family 6 member 9GLYT1m[131]
SLC7A11Solute carrier family 7 member 11xCTm, h[131,146]
TXN-based antioxidant genes
PRDX1Peroxiredoxin 1NKEFA, PAGA)m[131,138,142]
PRDX6Peroxiredoxin 61-Cys, aiPLA2, AOP2, KIAA0106, MGC46173, NSGPx, p29, PRXh[131,147]
SRXN1Sulfiredoxin 1C20orf139, dJ850E9.2, Npn3, SRX1, YKL086Wm, h[131]
TXNThioredoxinTRXm, h[131,132,135]
TXNRD1Thioredoxin reductase 1GRIM-12, Trxr1, TXNRm, h[131,135,144]
ATP-binding-based antioxidant genes
ABCB6ATP binding cassette subfamily B member 6EST45597, MTABC3, umatm, h[131]
ABCC1ATP binding cassette subfamily C member 1GS-X, MRP, MRP1m, h[131]
ABCC2ATP binding cassette subfamily C member 2CMOAT, cMRP, DJS, MRP2m, h[131,141]
ABCC3ATP binding cassette subfamily C member 3cMOAT2, EST90757, MLP2, MOAT-D, MRP3m, h[131,141,148]
ABCC4ATP binding cassette subfamily C member 4EST170205, MOAT-B, MOATB, MRP4m[131]
ABCC5ATP binding cassette subfamily C member 5EST277145, MOAT-C, MRP5, SMRPm[131]
Heme/iron metabolism-associated antioxidant genes
BLVRABiliverdin reductase ABLVRh[131]
BLVRBBiliverdin reductase BFLR, SDR43U1m, h[131]
FTH1Ferritin heavy chain 1FHC, FTH, FTHL6, PIG15, PLIFm, h[131]
FTLFerritin light chainMGC71996, NBIA3m, h[131]
HMOX1Heme oxygenase 1bK286B10, HO-1m, h[131,133,134,135,140,145]
UDP glucuronosyltransferase-associated antioxidant genes
UGT1A1UDP glucuronosyltransferase family 1 member A1GNT1, UGT1, UGT1Ah[131]
UGT1A6UDP glucuronosyltransferase family 1 member A6GNT1, HLUGP, UGT1Fm[138]
UGT2B1UDP glucuronosyltransferase family 2 member B1-m[141]
UGT2B5UDP glucuronosyltransferase family 2 member B5-m[132,143]
UGT2B7UDP glucuronosyltransferase family 2 member B7UGT2B9m, h[131]
Other antioxidant genes
ADH7Alcohol dehydrogenase 7 (class IV), mu or sigma polypeptideADH-4m[131]
AKR1A1Aldo-keto reductase family 1 member A1ALR, DD3h[132,143]
AKR1B1Aldo-keto reductase family 1 member B1ALDR1, ARm, h[131]
AKR1B8Aldo-keto reductase family 1 member B8-m[142,143]
AKR1C1Aldo-keto reductase family 1 member C1DD1, DDH, DDH1, HAKRC, MBABh[131]
ALDH1A1ldehyde dehydrogenase 1 family member A1ALDH1, PUMB1, RALDH1m[131]
ALDH3A1Aldehyde dehydrogenase 3 family member A1ALDH3m, h[131]
ALDH7A1Aldehyde dehydrogenase 7 family member A1ATQ1, EPD, PDEm[131]
CATCatalase-m[137,141]
CBR1Carbonyl reductase 1CBR, SDR21C1h[131]
CYP1B1Cytochrome P450 family 1 subfamily B member 1CP1B, GLC3Am[131]
CYP2B9Cytochrome P450 family 2 subfamily B member 9-m[131]
G6PDGlucose-6-phosphate dehydrogenaseG6PD1m, h[131]
IDH1Isocitrate dehydrogenase (NADP(+)) 1, cytosolic-m[131]
ME1Malic enzyme 1-m, h[131]
NQO1NAD(P)H quinone dehydrogenase 1DHQU, DIA4, DTD, NMOR1, QR1m, h[131,132,134,135,142,143]
PGDPhosphogluconate dehydrogenase-m, h[131]
PTGR1Prostaglandin reductase 1LTB4DH, ZADH3h[131]
SOD1Superoxide dismutase 1ALS, ALS1, IPOAm[141]
SOD2Superoxide dismutase 2-m[141]
SOD3Superoxide dismutase 3EC-SODm[142]
TALDO1Transaldolase 1-m, h[131]
UGDHUDP-glucose 6-dehydrogenase-h[131]
1 The species means the gene has been identified in mouse (m) and/or human (h). Nrf2, nuclear factor erythroid 2-related factor; GSH, glutathione; UDP, uridine diphosphate. The GSH and TXN antioxidant pathways are two important downstream pathways of Nrf2 [117].
Back to TopTop