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Allegra, A.; Caserta, S.; Genovese, S.; Pioggia, G.; Gangemi, S. Sex Differences in Oxidative Stress and Neoplastic Diseases. Encyclopedia. Available online: (accessed on 19 June 2024).
Allegra A, Caserta S, Genovese S, Pioggia G, Gangemi S. Sex Differences in Oxidative Stress and Neoplastic Diseases. Encyclopedia. Available at: Accessed June 19, 2024.
Allegra, Alessandro, Santino Caserta, Sara Genovese, Giovanni Pioggia, Sebastiano Gangemi. "Sex Differences in Oxidative Stress and Neoplastic Diseases" Encyclopedia, (accessed June 19, 2024).
Allegra, A., Caserta, S., Genovese, S., Pioggia, G., & Gangemi, S. (2023, June 13). Sex Differences in Oxidative Stress and Neoplastic Diseases. In Encyclopedia.
Allegra, Alessandro, et al. "Sex Differences in Oxidative Stress and Neoplastic Diseases." Encyclopedia. Web. 13 June, 2023.
Sex Differences in Oxidative Stress and Neoplastic Diseases

Genetic, developmental, biochemical, and environmental variables interact intricately to produce sex differences. The significance of sex differences in cancer susceptibility is being clarified by numerous studies. Epidemiological research and cancer registries have revealed over the past few years that there are definite sex variations in cancer incidence, progression, and survival. However, oxidative stress and mitochondrial dysfunction also have a significant impact on the response to treatment of neoplastic diseases. Young women may be more protected from cancer than men because most of the proteins implicated in the regulation of redox state and mitochondrial function are under the control of sexual hormones. 

gender differences cancer oxidative stress estrogens testosterone antioxidant reactive oxygen species sex hormones

1. Glioma, Oxidative Stress, and Gender Differences

Although it is the second most common cancer in children, brain cancer is an uncommon condition in comparison with other cancer types [1]. Men are twice as likely to develop medulloblastoma, ependymoma, and gliomas than women, according to epidemiologic research [2]. In addition, a recent study found that women outlived males and responded better to standard treatment, identifying transcriptome signatures for glioblastomas in women [3].
Since oxidative stress and inflammation are also involved in the onset and progression of brain cancer, substances able to modify oxidative stress such as phytoestrogens have been considered good candidates for brain cancer prevention due to their antioxidant and anti-inflammatory properties. In fact, consuming foods containing phytoestrogens, particularly daidzein, appears to have a protective effect against gliomagenesis, according to an epidemiologic study conducted in 2006 [4]. Additionally, new research has shown that the phytoestrogens formononetin or biochanin A and the cytotoxic drug temozolomide combined have an enhanced anticancer effect in glioblastoma multiforme cells, with greater inhibition of cell signaling and invasion pathways and restoration of mitochondrial function [5][6].
Furthermore, long-term research has been conducted on the effects of gender on oxidative stress in the brain, including free radical generation, oxidative damage, and antioxidant enzyme levels and/or activity [7]. According to certain studies [8][9][10][11][12][13][14][15][16][17], male rats have greater DNA, protein, and lipid oxidative damage than female rats. The increased ROS generation in male rats [18][19] and the decreased levels and/or activities of antioxidant enzymes [20][21][22][23][24] are the causes of this oxidative damage. However, although these studies suggest that female rats have better redox homeostasis than male rats, other reports [25][26][27][28] have found no differences.
In terms of sex hormones, 17-estradiol (E2) and progesterone, which are produced by females, have neuroprotective effects in vivo and in vitro at physiological concentrations [29][30][31][32], but androgens and testosterone, which are produced by males, typically have neurotoxic effects [33]. The ability of some neurons and glial cells to create neurosteroids—sex hormones that are often produced de novo and independently of peripheral tissues—is particularly intriguing. These neurosteroids are equivalent to circulating steroids in both chemical and biological terms [34][35].
Along with oxidative stress, brain tumorigenesis has also been linked to decreased responses from nonenzyme (reduced glutathione, GSH) and enzyme antioxidant systems (SOD, catalase, and GPx) [36]. Since the central nervous system (CNS) is extremely susceptible to free radical damage, an imbalance between the production of free radicals and the effectiveness of the antioxidant defense systems is able to initiate the neoplastic process [37]. This theory is supported by numerous research works. For instance, research has shown that subcutaneous administration of hydroxytyrosol, but not oleuropein or a combination of both compounds, resulted in a significant inhibition of tumor growth through mechanisms involving endogenous enzymatic and nonenzymatic antioxidant defense systems [38][39][40].
Thus, the existence of gender differences in processes related to brain tumors, such as the management of redox status, suggested that research on brain cancer should take gender differences into account in preclinical studies, screening, and prevention programs, as well as in therapeutic approaches.

2. Liver Cancer, Oxidative Stress, and Gender Differences

Liver cancer is currently the second most common cancer type [41]. The 5-year survival rate for people with liver cancer only oscillates by 10%, despite the use of intensive treatments [42]. In total, 90% of liver cancer cases are caused by hepatocellular carcinoma (HCC).
Even after accounting for variations in exposure to risk factors, there is a two- to four-fold higher incidence of liver cancer in men than in women in humans [43][44]. Additionally, males predominate in transgenic mouse models of hepatitis virus infection and models of liver tumor induction in mice after exposure to chemical carcinogens such as AFB1, 4-aminobiphenyl (ABP), and diethylnitrosamine (DEN) [45]. Additionally, numerous human and animal studies on HCC confirmed sexual dimorphism during the onset and development of alcohol liver disease (ALD). It is likely that variations in the expression of genes that code for ethanol-metabolizing enzymes have an impact on the development and progression of ALD and liver cancer [46]. Alcohol dehydrogenase (ADH) activity varies between sexes; it is lower in men than in women, which leads to less acetaldehyde build-up. Additionally, studies reveal that estrogens positively affect CYP2E1 and ADH, indicating that ethanol should be metabolized more quickly in females than in males [47].
Some studies demonstrated that male mice are more vulnerable than female mice to HCC [48].
It should be mentioned that lipid peroxide levels in the liver and serum are decreased by estradiol and its derivatives, which are potent endogenous antioxidants [49][50]. The loss of SOD and glutathione peroxidase activity, as well as iron (ferric nitrilotriacetate)-induced ROS production, lipid peroxidation, activation of AP-1 and NF-B, are all suppressed by estradiol in cultured rat hepatocytes, according to recent research [51][52]. In isolated rat liver mitochondria, estradiol also reduces the lipid peroxidation brought on by iron [51]. These results imply that the inhibitory impact of estradiol on AP-1 and NF-B activation may result from scavenging ROS and/or from lowering intracellular ROS generation by inducing antioxidant enzymes.
Male sex, like the viral risk factor for hepatic fibrosis, is a significant risk factor for HCC [53], while it is unknown whether males and females differ in their susceptibility to the integration of viral DNA, which causes the malignant transformation of hepatocytes. In contrast, premenopausal women are least susceptible to HCC because they lack the risk factors of older age and male sex. In a study, 901 individuals with HBV-associated HCC had their age-specific male-to-female ratios looked at. The younger group had a smaller percentage of females (10.5%) than the older group when the subjects were split into two age groups based on whether they were younger or older than the menopausal age of 50 years.
The differences in hepatic damage were connected to alterations in cellular GSH, ROS production, and cell REDOX status brought on by the metabolism of ethanol. The imbalance between acetaldehyde and ALDH is accentuated by CYP2E1 induction, which also leads to the production of ROS, the subsequent depletion of GSH, and oxidative damage [48]. Similar results were obtained employing a different experimental model exposing mice to aminobiphenyl (ABP) [54][55][56][57].
In contrast, levels of the hepatotoxicity biomarker alanine aminotransferase (ALT) were acutely two-fold higher in male adult mice exposed to ABP, DEN, or carbon tetrachloride (CCl4) than in female adult mice [58], while levels of the inflammatory biomarker interleukin-6 (IL-6) did not differ based on sex. While CCl4 produced a 40-fold ALT elevation but without sex differences, treatment of immature mice with either ABP or DEN using conventional tumor-inducing postnatal exposure protocols did not result in an increase in serum ALT or IL-6 levels in either males or females. There was no sex difference in the baseline expression of Ggt1 or Hmox1, but adult females expressed the NRF2-responsive gene Nqo1 at higher levels than adult males. Animals that were still developing sexually revealed no sex difference in the three genes’ baseline expression. While CCl4 slightly increased the expression of Ggt1 in both males and females and Nqo1 only in females, postnatal DEN exposure slightly increased the expression of Ggt1 only in male mice and Nqo1 in both sexes. Together, these findings rule out the possibility that postnatal carcinogen exposure in mice results in acute hepatotoxic, inflammatory, or NRF2-activated gene responses that are responsible for the male predominance in liver tumor growth [58]. These results also imply that when extrapolating putative processes to liver carcinogenesis models that frequently employ postnatally exposed mice, acute toxicity studies conducted in adult mice should be read with caution. However, the various experimental setups used could be the cause of the disparate results found in the various studies.
Aflatoxin B1 (AFB1) is a strong hepatotoxin and hepatocarcinogen for humans and most other mammalian species, although adult mice are remarkably resistant to it [59]. Aspergillus flavus, a mold that develops on groundnuts, grain, and maize that mice frequently consume, produces AFB1. Cytochrome P450 (CYP) transforms AFB1 in both humans and mice into a reactive AFB1-epoxide that can damage DNA by attaching to the N-7 atom of guanine [60]. Once produced, the glutathione S-transferase (GST) enzymes in the cytosol can catalyze the conjugation of the AFB1-epoxide with reduced glutathione to detoxify it. Water-soluble aflatoxin mercapturic acids (AFB1-NAC) are eliminated in urine as glutathione conjugates of AFB1-epoxides [61]. Mice’s inherent resistance to AFB1 may be due to CYP isoenzymes’ poor capacity to produce reactive epoxides and/or GST isoenzymes’ great capacity to produce glutathione conjugates.
The important function of GSTA3 in AFB1 resistance was confirmed by a study that produced glutathione S-transferase (GST) A3 knockout (KO) mice. GSTA3 KO mice are vulnerable to the acute cytotoxic and genotoxic effects of AFB1 [62]. In contrast to the known higher incidence of liver cancer in males in humans, this research shows that initial vulnerability to AFB1 is greater in female mice and that oval cell response and GSTA3 peroxidase activity may affect susceptibility to cancer development.
Other information supports the notion that oxidative stress plays a part in the different onset of liver cancer in the two sexes. According to a study, age-related TBARS accumulation in the liver may be sex-related, because it was more noticeable in old male mice compared with old female mice. Gonadotropic hormones, particularly estrogens, may be the cause of these sex-related variations in the TBARS level [63]. The connection between estrogens and liver oxidative damage has been shown by numerous in vitro investigations [64]. Since females at that age are in a reproductive decline stage, hormonal changes alone cannot account for the fact that TBARS in 18-month-old females were higher than in males of the same age. The growth of tumors seen in aged male mice may be linked to gender-specific changes in TBARS. These findings are consistent with some published studies that link declining lipid peroxidation (LPO) levels to increasing tumor size [65].
Researchers have studied the activities of total superoxide dismutase (tSOD), Gpx, and catalase (CAT). LPO, quantified in terms of TBARS, was determined by the authors to be a marker of liver oxidative damage. LPO increased with aging in both sexes. In both mouse sexes, tSOD appears to be a dormant antioxidative enzyme. The principal alterations in the liver’s antioxidant capacity of aging mice were connected to sex-related increases in CAT and Gpx that were only seen in males. Surprisingly, hepatic tumors developed in more than 60% of 18-month-old men (but not girls), which first appeared at 10 months. The findings indicate that increased liver antioxidant capacity of CAT and Gpx in male mice may be an indication of oxidative stress; increases in CAT and Gpx activities in male mice are strongly correlated with the incidence of hepatic tumors; and significantly increased SOD activity in tumor-bearing mice may have been caused by damage from accumulated hydrogen peroxide H2O2 [66].
The varied ways that oxidative stress behaves in the two sexes is also intriguing. An experiment revealed that during male senescence, CAT and Gpx significantly changed. In contrast to this, there was little to no change in CAT activity and no appreciable change in Gpx activity in female mice. In general, CAT and Gpx activity were 50% and 85% higher in males than in females. Tumor-bearing mice displayed elevated tSOD activity in contrast to the antioxidant enzyme status of tumor-free mice (inert tSOD activity). Antioxidant enzyme activities are typically thought to vary during or after tumor development [67]. Most past investigations have suggested that cancer has poor antioxidant enzyme activity [68]. However, most of them used cell lines, and in some of them, conclusions were reached based on blood sample activity measurements that did not accurately reflect the enzyme levels in the tumor or the affected organ. Manganese superoxide dismutase (MnSOD) expression has been shown to be high in many human cancers and, in some tumors, the level of MnSOD is directly correlated with the tumor grade [69]. Additionally, Manna et al. demonstrated that MnSOD overexpression in tumors may give tumor cells a survival advantage [70]. Another author’s theory is that tumor cells produce a significant amount of H2O2 [71], and research showing that tSOD overexpression promotes H2O2 generation supports this idea. To fulfil the demands of the increased LPO and H2O2 build-up brought on by the increased SOD activity, these facts may explain why males generally have higher CAT and Gpx activities [72].
Numerous studies have demonstrated that oxidative stress restricts the ability of cells to undergo mitosis, suggesting that oxidative stress may also condition a different proliferative capacity of cancerous cells [73]. Based on higher antioxidant enzyme levels and the oxidative stress situation prevalent in men, it is possible to infer that cell division favoring clonal growth can occur. Such a phenomenon might aid in the development of cancer. Similar findings have been published from Gonzales, where higher antioxidant levels have been linked to a faster rate of cell division [74]. Like the gender difference in the incidence of liver cancer in humans, postnatal exposure of mice to ABP causes a higher incidence of liver tumors in males than in females. ABP-DNA adducts that start tumor growth are produced because of first N-hydroxylation that is initially mediated by CYP1A2, according to a conventional theory of ABP carcinogenesis. CYP2E1 was found to be a key ABP N-hydroxylating enzyme in isozyme-selective inhibition tests employing liver microsomes from wild-type and genetically engineered mice. Oxidative stress was brought on by the N-hydroxylation of ABP by transiently expressed CYP2E1 in cultured mouse hepatoma cells. Male wild-type mice exposed postnatally to a tumor-causing dosage of ABP also experienced oxidative stress, but neither male Cyp2e1(/) mice nor female mice did. However, females showed a stronger NRF2-associated antioxidant response [75]. These results imply that CYP2E1 is a novel ABP-N-oxidizing enzyme and that sex differences in tumor incidence and cell proliferation may be related to sex differences in oxidative stress and antioxidant responses to ABP.
Finally, a particularly exciting area of research focuses on the relationships between gender differences, obesity, oxidative stress, and liver cancers. Recent population-based studies have repeatedly demonstrated that obese men are far more likely to acquire HCC. Men with a BMI of 35 kg/m2 showed a severe 4.52-fold increase in relative risk of mortality from liver cancer, although women only showed a small 1.68-fold increase, according to prospective research involving more than 900,000 persons [76]. The large gender-based variation in HCC incidence has been further validated by a cohort study of 5.24 million persons in the UK [77]. According to the studies, BMI and HCC in males were correlated [77], and increased and disordered ROS production in extra adipose tissue during obesity may increase oxidative stress and the likelihood of developing HCC [78]. In contrast to subcutaneous fat accumulation, visceral fat deposition is substantially higher in males than in females [79]. In numerous datasets [80][81], men were found to have larger visceral fat and liver fat contents than women, despite having similar total fat and BMI values. Liver cancer is facilitated by visceral fat, which actively secretes carcinogenic adipokines that cause persistent inflammation. High androgen receptor density may be the root cause of the differences between liver cancer and visceral fat accumulation [82]. As people get older, their visceral body fat increases, while their subcutaneous body fat decreases, which is correlated with an increase in the incidence of HCC [83].

3. Colorectal Cancer, Oxidative Stress, and Gender Differences

Colorectal cancer (CRC) is the second most prevalent cause of cancer mortality among men and women globally [84]. Drug resistance and adverse reactions continue to hinder the success of treatment, despite the fact that the overall survival rate of CRC patients has increased because of advancements in treatment methods such as chemotherapy.
According to certain research, the disease affects people of various sexes at different rates, and this could be due to oxidative stress. For instance, neutrophils and monocytes both contain the lysosomal enzyme myeloperoxidase (MPO) [85]. Hypochlorous acid, a potent oxidant produced by MPO for its microbicidal function, can target proteins, nucleic acids, and unsaturated lipids by simultaneously releasing ROS [86]. A-463 G>A transition, which is situated in the consensus binding location of the SP1 transcription factor, is a frequently occurring polymorphism in the MPO gene promoter region. In vitro, the MPO G wild-type allele confers approximately twenty-five times more transcriptional activation than the -463 A variant. According to reports, this polymorphism raises the likelihood of developing laryngeal, lung, breast, and stomach cancers [87][88][89][90][91]. According to a study, those with the genotype GA/AA were considerably less likely to get colorectal cancer than people with the GG genotype. The reduced risk was particularly significant among men according to the stratified analysis. For male individuals with the GA/AA genotype compared with GG genotype, the adjusted OR was 0.47. However, among women, the OR was not statistically significant. The possibility that estrogen-induced increased MPO-463 A promoter activity is the cause of the MPO-463 A variant’s lack of protective effect in female patients is therefore plausible [92].
Oxidative stress and cancer have been linked in other research. Bilirubin is more than only the byproduct of heme catabolism. It is now thought to be an essential blood component that forms endogenously and has anti-inflammatory and antioxidant activities [93][94][95][96][97][98]. Recent research has indicated that bilirubin, particularly unconjugated bilirubin (UCB), may provide protection against oxidative stress-related illnesses such as CRC. In vitro research outcomes also demonstrated that UCB has antimutagenic qualities [99], which may be especially pertinent for gut health. Tetrapyrroles, a family of bile pigments that are abundant in the intestine, reduced the genotoxicity brought on by poly-/heterocyclic amines and triggered apoptosis in cancer cells [100][101][102]. Higher circulating UCB concentrations were positively linked with CRC risk in males and negatively associated with risk in women, according to a study that examined relationships between UCB and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study [103]. According to one study, every one standard deviation increase in log-UCB was associated with a lower risk of CRC in males and a higher risk in women (heterogeneity = 0.4 for differences between men and women) [104]. Finally, it has been demonstrated that UCB may easily cross cell membranes in vivo, infiltrate colon cancer cells to stop tumor cell growth [105], trigger death in cancer cells in vitro [106], and control gene transcription (via ERK, p53, and p27) [107]. Strogen, lower NADPH-oxidase activity, or other previously described mechanisms may make women less susceptible to oxidative stress [108].

4. Lung Cancer, Oxidative Stress, and Gender Differences

Lung cancer is the most common cancer in the world [109][110]. There may be gender disparities in lung cancer incidence, according to epidemiologic data [111][112][113]. Agreeing to several studies, women may be more likely than men to acquire lung and colon cancer from smoking cigarettes [114][115].
The expression of genes relevant to cancer and the immune system is altered by genetic and epigenetic alterations, as well as by the abnormal expression of noncoding RNAs, which predisposes the lung epithelium to carcinogenesis. Smoking-related oxidative stress contributes to decreased genomic integrity and promotes epithelial–mesenchymal transition and the creation of a chronic inflammatory milieu. Although not all smokers develop lung cancer, this results in abnormal immune reactions that support the development of cancer. Females are more likely to accumulate oxidative stress damage due to gender differences in the metabolism of cigarette smoke, which increases their risk of developing lung cancer [116]. Additionally, ROS and RNS can activate signaling molecules such as HIF1, which is a key regulator of angiogenesis and a driving force behind the development of tumors [117]. Furthermore, it has been demonstrated that the byproducts of ROS and inflammation can inactivate PTEN, a tumor suppressor gene that is frequently altered in lung cancer, by creating an intramolecular disulfide bond [118][119].
Large epidemiological studies have demonstrated that for every pack-year of smoking, women are two to three times more likely to die from COPD than males [120] and are 50% more likely to develop COPD than men. One explanation is that because women’s lungs are smaller than men’s with comparable smoking histories, the harm from oxidative stress is more obvious in women [120]. Another is sex variations in the metabolism of tobacco: women have higher liver CYP1A1 and CYP1B1 activity levels, which activate specific tobacco smoke components to create ROS [121]. Strogen’s role in activating CYP enzyme-related pathways is a contributing factor in the enhanced CYP expression in females [122]. For instance, a study of smokers who developed lung cancer showed that females had higher levels of CYP1A1 expression and a commensurate rise in DNA adducts, even in lung tissue that was not cancerous [123]. Additionally, studies on animals showed that the injection of naphthalene—a substance found in tobacco smoke—caused more airway damage in female mice than in male mice. This was due to increased CYP enzyme expression and the production of metabolites, which led to a more severe inflammatory response in the airways and produced more ROS than in male mice [124]. Because women are more frequently exposed to biomass smoke, exposure to indoor and outdoor air pollution is also a significant risk factor for the development of lung cancer in nonsmokers [125][126].
The varied ways that oxidative stress affects the incidence of pulmonary neoplasia in the two sexes could be explained by other processes, as reported in studies performed employing a class of pervasive environmental pollutants known as polycyclic aromatic hydrocarbons (PAHs) [127][128][129].
A study identified sixteen environmental PAHs in workplaces and assessed that women who worked in the office, next to the coke oven, or on its bottom or side, respectively, had significantly higher urine 8-OHdG and 8-isoPGF2a levels and lymphocytic micronucleus frequencies than men who worked in those locations. Gender and BPDE-Alb adducts had a strong impact on rising micronucleus frequencies. The foregoing gender disparities were more pronounced in the median- and high-exposure groups, according to authors who further stratified all workers based on the tertiles of urinary ROH-PAHs or plasma BPDE-Alb adducts [130]. As a result, women were more vulnerable than males to the oxidative stress and chromosomal damage caused by PAHs, which could be additional evidence for gender differences in PAH-exposure-related lung carcinogenesis.

5. Melanoma, Oxidative Stress, and Gender Differences

Since the middle of the 1950s, malignant melanoma prognoses for cases with advanced metastases have remained dismal [131][132]. Gender has been shown to be an independent prognostic factor of melanoma survival in numerous studies, as it remains significant after adjusting for nearly all known prognostic indicators, including age, Breslow thickness, Clark level of invasion, body site, histological subtype, and recently, emerged prognostic indicators, such as ulceration, sentinel node status, and mitotic rate [133][134]. Both the incidence and survival of malignant melanoma differ significantly across gender. Male patients advance more quickly to stage III [135] and maybe even stage IV melanoma [136][137]; male original melanomas appear to grow more quickly than those in females; and men present with nodal and visceral metastases more frequently than women [133]. Instead, women are more likely to present with tumors that are in an earlier stage, have longer survival times, and experience better outcomes [138][139][140][141][142].
More and more evidence points to the involvement of oxidative stress, which is brought on by high amounts of ROS, such as superoxide anions and hydrogen peroxide, in the development of melanoma [143][144]. When compared with nearby tissues or melanocytes, melanoma cells produce a lot of ROS, which they then excrete into extracellular space [145]. Additionally, melanoma cells have elevated intracellular ROS levels [146].
High amounts of oxidative stress are known to exist in the initial melanoma tumor environment [147][148][149]; tumor-related immune cells release ROS [150], and ultraviolet (UV) radiation further intensifies oxidative stress in the skin and melanocytes [151]. In contrast to surrounding nontumor tissue, benign melanocytic nevi, and control subject skin, Sander et al. discovered a considerable upregulation in antioxidant enzymes in human melanoma biopsies, indicating that the melanoma cells were responding to increasing oxidative stress [148].
According to a different study, the advantage that females have in terms of melanoma survival is likely due to sex differences in the capacity to counteract the oxidative stress brought on by ROS [147]. In fact, it appears that the oxidative environment in the skin of male and female mice has different baseline characteristics; UV-induced oxidative stress amplifies these differences. In comparison with female hairless mice, the skin of males had a lower baseline level of antioxidant enzymes and a roughly 10-fold lower antioxidant functional capacity. In comparison with levels found in the skin of male mice exposed to UVB radiation, the skin of female mice showed a significantly higher induction in antioxidant level, greater antioxidant functional capacity, and lower levels of 8-oxo-deoxyguanosine, the most common type of DNA damage caused by ROS [152]. These findings were supported by an experiment that looked at gender differences in the development of cancer linked to UV-induced chronic inflammation [153]. According to the finding’s, photoaging damage was present in both male and female mice at the ninth week. However, only male mice in the third week developed skin tumors. Additionally, UV increased the expression of the p65, p-p65, IL-6, and TNF proteins in skin, and these factors were more elevated in the male mouse model. The parameters of blood systemic inflammation were altered to variable degrees in the model groups, according to hematology data, whereas the internal organs of both model groups revealed varying degrees of inflammatory cell infiltration, according to pathology results. These findings suggest that UV-induced skin inflammation, carcinogenesis, and systemic damage differ between the sexes.
Additionally, it is possible that men’s higher ROS levels encourage the selection of ROS-resistant melanoma cells. Consequently, ROS can promote melanoma cells’ capacity for metastatic spread. Additionally, because men have weaker antioxidant defenses, the ROS that melanoma cells produce damage surrounding healthy tissues more severely, which promotes metastasis. As a result, ROS could account for the reported disparities in melanoma survival between males and females [147].
After menopause, according to some researchers, the female advantage vanishes [134]. Others, however, discovered that females continue to live longer even after menopause [154]. In female rats, ovariectomies boosted peroxide generation in liver cells to levels seen in male cells, decreased antioxidant enzyme levels to those found in male cells, and restored both peroxide and antioxidant enzyme levels in female cells to the control female levels [108]. This team discovered that 17-b-estradiol decreased hydrogen peroxide production when isolated mitochondrion was incubated with it [155].
The effect of antioxidant supplementation on the incidence of melanoma has also been studied; however, due to the small number of events in the trials, no significant effect [156], or even a negative effect [157], was discovered. More importantly, the effect of antioxidants varied by gender in each of these studies, affecting both the incidence of melanoma [157] and all cancers [158]. This strongly implies that gender has a role in the relationship between melanoma and ROS.

6. Non-Hodgkin Lymphoma, Oxidative Stress, and Gender Differences

The Swedish Lymphoma Register was used in a population-based cohort study that looked at gender differences in the incidence of lymphoma subtypes and excess mortality among people diagnosed between 2000 and 2019 [159]. Poisson regression was used to predict the male-to-female incidence rate ratios (IRRs) and excess mortality ratios (EMRs) after adjusting for age. They discovered 36,795 instances of lymphoma, 20,738 (56.4%) of which were in men and 16,057 (43.6%) in women. Incidence rate ratios (IRRs) ranged from 1.15 in follicular lymphoma to 5.95 in hairy cell leukemia, with men being considerably more at risk for 14 of the 16 subtypes of lymphoma. Although only statistically significant for classical Hodgkin lymphoma 1.26, aggressive lymphoma not otherwise specified 1.29, and small lymphocytic lymphoma 1.52, EMRs > 1 was seen in 13 out of 16 lymphoma subtypes, indicating higher mortality in men. Similar findings were obtained from a related analysis utilizing information from the Danish Lymphoma Register [159]. In conclusion, researchers found that for the majority of lymphoma subtypes, men had a significantly greater incidence and a tendency toward higher death rates.
The differing levels of oxidative stress experienced by the two sexes may contribute to the development and spread of lymphomas. For instance, a study in [160] examined the idea that lymphomagenesis following low-dose radiation is aided by mitochondrial malfunction and elevated superoxide levels in thymocytes overexpressing Bax (Lck-Bax1 and Lck-Bax38&1). Single whole-body doses of 10 or 100 cGy of 137Cs, iron ions, or silicon ions, were administered to Lck-Bax1 single-transgenic and Lck-Bax38&1 double-transgenic mice. In female Lck-Bax1 mice, a 10 cGy dosage of 137Cs markedly increased the incidence and development of thymic lymphomas. In contrast to silicon ions, a 100 cGy dosage of high-LET iron ions significantly and dose-dependently accelerated lymphomagenesis in both male and female Lck-Bax38&1 mice. Lck-Bax38&1 overexpressing animals were bred with Sirtuin 3 knockouts, a mitochondrial protein deacetylase that controls superoxide metabolism, to ascertain the contribution of mitochondrial oxidative metabolism. Significant increases in thymocyte superoxide levels and accelerated lymphomagenesis were seen in Sirt3//Lck-Bax38&1 animals [160]. These findings demonstrate that radiation exposure increases lymphomagenesis in Bax overexpressing animals in a manner that depends on both LET and gender. These results are consistent with the hypothesis that in Lck-Bax transgenic mice, mitochondrial dysfunction increases superoxide levels and speeds up lymphomagenesis.


  1. Torre, L.A.; Siegel, R.L.; Ward, E.M.; Jemal, A. Global cancer incidence and mortality rates and trends—An update. Cancer Epidemiol. Biomark. Prev. 2016, 25, 16–27.
  2. Sun, T.; Plutynski, A.; Ward, S.; Rubin, J.B. An integrative view on sex differences in brain tumors. Cell. Mol. Life Sci. 2015, 72, 3323–3342.
  3. Yang, W.; Warrington, N.M.; Taylor, S.J.; Whitmire, P.; Carrasco, E.; Singleton, K.W.; Wu, N.; Lathia, J.D.; Berens, M.E.; Kim, A.H.; et al. Sex differences in GBM revealed by analysis of patient imaging, transcriptome, and survival data. Sci. Transl. Med. 2019, 11, eaao5253.
  4. Tedeschi-Blok, N.; Lee, M.; Sison, J.D.; Miike, R.; Wrensch, M. Inverse association of antioxidant and phytoestrogen nutrient intake with adult glioma in the San Francisco Bay Area: A case-control study. BMC Cancer 2006, 6, 148.
  5. Desai, V.; Jain, A.; Shaghaghi, H.; Summer, R.; Lai, J.C.K.; Bhushan, A. Combination of Biochanin A and Temozolomide Impairs Tumor Growth by Modulating Cell Metabolism in Glioblastoma Multiforme. Anticancer Res. 2019, 39, 57–66.
  6. Zhang, X.; Ni, Q.; Wang, Y.; Fan, H.; Li, Y. Synergistic anticancer effects of formononetin and temozolomide on glioma C6 cells. Biol. Pharm. Bull. 2018, 41, 1194–1202.
  7. Ruszkiewicz, J.A.; Miranda-Vizuete, A.; Tinkov, A.A.; Skalnaya, M.G.; Skalny, A.V.; Tsatsakis, A.; Aschner, M. Sex-Specific Differences in Redox Homeostasis in Brain Norm and Disease. J. Mol. Neurosci. 2019, 67, 312–342.
  8. Candeias, E.; Duarte, A.I.; Sebastião, I.; Fernandes, M.A.; Plácido, A.I.; Carvalho, C.; Correia, S.; Santos, R.X.; Seiça, R.; Santos, M.S.; et al. Middle-Aged Diabetic Females and Males Present Distinct Susceptibility to Alzheimer Disease-like Pathology. Mol. Neurobiol. 2017, 54, 6471–6489.
  9. Chakraborti, A.; Gulati, K.; Banerjee, B.D.; Ray, A. Possible involvement of free radicals in the differential neurobehavioral responses to stress in male and female rats. Behav. Brain Res. 2007, 179, 321–325.
  10. Cole, T.B.; Coburn, J.; Dao, K.; Roqué, P.; Chang, Y.C.; Kalia, V.; Guilarte, T.R.; Dziedzic, J.; Costa, L.G. Sex and genetic differences in the effects of acute diesel exhaust exposure on inflammation and oxidative stress in mouse brain. Toxicology 2016, 374, 1–9.
  11. Guevara, R.; Santandreu, F.M.; Valle, A.; Gianotti, M.; Oliver, J.; Roca, P. Sex-dependent differences in aged rat brain mitochondrial function and oxidative stress. Free Radic. Biol. Med. 2009, 46, 169–175.
  12. Katalinic, V.; Modun, D.; Music, I.; Boban, M. Gender differences in antioxidant capacity of rat tissues determined by 2,2′-azinobis (3-ethylbenzothiazoline 6-sulfonate; ABTS) and ferric reducing antioxidant power (FRAP) assays. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 2005, 140, 47–52.
  13. Silva, T.L.A.; Braz, G.R.F.; Silva, S.C.A.; Pedroza, A.A.D.S.; Freitas, C.M.; Ferreira, D.J.S.; da Silva, A.I.; Lagranha, C.J. Serotonin transporter inhibition during neonatal period induces sex-dependent effects on mitochondrial bioenergetics in the rat brainstem. Eur. J. Neurosci. 2018, 48, 1620–1634.
  14. Sobočanec, S.; Balog, T.; Kušić, B.; Šverko, V.; Šarić, A.; Marotti, T. Differential response to lipid peroxidation in male and female mice with age: Correlation of antioxidant enzymes matters. Biogerontology 2008, 9, 335–343.
  15. Guevara, R.; Gianotti, M.; Roca, P.; Oliver, J. Age and sex-related changes in rat brain mitochondrial function. Cell. Physiol. Biochem. 2011, 27, 201–206.
  16. Jung, M.E.; Metzger, D.B. A sex difference in oxidative stress and behavioral suppression induced by ethanol withdrawal in rats. Behav. Brain Res. 2016, 314, 199–214.
  17. Uzun, H.; Kayali, R.; Çakatay, U. The chance of gender dependency of oxidation of brain proteins in aged rats. Arch. Gerontol. Geriatr. 2010, 50, 16–19.
  18. Khalifa, A.R.; Abdel-Rahman, E.A.; Mahmoud, A.M.; Ali, M.H.; Noureldin, M.; Saber, S.H.; Mohsen, M.; Ali, S.S. Sex-specific differences in mitochondria biogenesis, morphology, respiratory function, and ROS homeostasis in young mouse heart and brain. Physiol. Rep. 2017, 5, e13125.
  19. Lloret, A.; Badía, M.C.; Mora, N.J.; Ortega, A.; Pallardó, F.V.; Alonso, M.D.; Atamna, H.; Viña, J. Gender and age-dependent differences in the mitochondrial apoptogenic pathway in Alzheimer’s disease. Free Radic. Biol. Med. 2008, 44, 2019–2025.
  20. Dkhil, M.A.; Al-Shaebi, E.M.; Lubbad, M.Y.; Al-Quraishy, S. Impact of sex differences in brain response to infection with Plasmodium berghei. Parasitol. Res. 2016, 115, 415–422.
  21. Ehrenbrink, G.; Hakenhaar, F.S.; Salomon, T.B.; Petrucci, A.P.; Sandri, M.R.; Benfato, M.S. Antioxidant enzymes activities and protein damage in rat brain of both sexes. Exp. Gerontol. 2006, 41, 368–371.
  22. Krolow, R.; Noschang, C.G.; Arcego, D.; Andreazza, A.C.; Peres, W.; Gonçalves, C.A.; Dalmaz, C. Consumption of a palatable diet by chronically stressed rats prevents effects on anxiety-like behavior but increases oxidative stress in a sex-specific manner. Appetite 2010, 55, 108–116.
  23. Mármol, F.; Rodríguez, C.A.; Sánchez, J.; Chamizo, V.D. Anti-oxidative effects produced by environmental enrichment in the hippocampus and cerebral cortex of male and female rats. Brain Res. 2015, 1613, 120–129.
  24. Noschang, C.; Krolow, R.; Arcego, D.M.; Toniazzo, A.P.; Huffell, A.P.; Dalmaz, C. Neonatal handling affects learning, reversal learning and antioxidant enzymes activities in a sex-specific manner in rats. Int. J. Dev. Neurosci. 2012, 30, 285–291.
  25. Brocardo, P.S.; Boehme, F.; Patten, A.; Cox, A.; Gil-Mohapel, J.; Christie, B.R. Anxiety and depression-like behaviors are accompanied by an increase in oxidative stress in a rat model of fetal alcohol spectrum disorders: Protective effects of voluntary physical exercise. Neuropharmacology 2012, 62, 1607–1618.
  26. Charradi, K.; Mahmoudi, M.; Bedhiafi, T.; Kadri, S.; Elkahoui, S.; Limam, F.; Aouani, E. Dietary supplementation of grape seed and skin flour mitigates brain oxidative damage induced by a high-fat diet in rat: Gender dependency. Biomed. Pharmacother. 2017, 87, 519–526.
  27. Giménez-Llort, L.; García, Y.; Buccieri, K.; Revilla, S.; Suñol, C.; Cristofol, R.; Sanfeliu, C. Gender-specific neuroimmunoendocrine response to treadmill exercise in 3xTg-AD mice. Int. J. Alzheimer Dis. 2010, 2010, 128354.
  28. Harish, G.; Venkateshappa, C.; Mahadevan, A.; Pruthi, N.; Srinivas Bharath, M.M.; Shankar, S.K. Effect of premortem and postmortem factors on the distribution and preservation of antioxidant activities in the cytosol and synaptosomes of human brains. Biopreserv. Biobanking 2012, 10, 253–265.
  29. Engler-Chiurazzi, E.B.; Brown, C.M.; Povroznik, J.M.; Simpkins, J.W. Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury. Prog. Neurobiol. 2017, 157, 188–211.
  30. Liu, M.; Kelley, M.H.; Herson, P.S.; Hurn, P.D. Neuroprotection of sex steroids. Minerva Endocrinol. 2010, 35, 127–143.
  31. Siddiqui, A.N.; Siddiqui, N.; Khan, R.A.; Kalam, A.; Jabir, N.R.; Kamal, M.A.; Firoz, C.K.; Tabrez, S. Neuroprotective Role of Steroidal Sex Hormones: An Overview. CNS Neurosci. Ther. 2016, 22, 342–350.
  32. Spychala, M.S.; Honarpisheh, P.; McCullough, L.D. Sex differences in neuroinflammation and neuroprotection in ischemic stroke. J. Neurosci. Res. 2017, 95, 462–471.
  33. Quillinan, N.; Deng, G.; Grewal, H.; Herson, P.S. Androgens and stroke: Good, bad or indifferent? Exp. Neurol. 2014, 259, 10–15.
  34. Reddy, D.S.; Bakshi, K. Neurosteroids: Biosynthesis, molecular mechanisms, and neurophysiological functions in the human brain. Horm. Signal. Biol. Med. 2020, 69–82.
  35. Yilmaz, C.; Karali, K.; Fodelianaki, G.; Gravanis, A.; Chavakis, T.; Charalampopoulos, I.; Alexaki, V.I. Neurosteroids as regulators of neuroinflammation. Front. Neuroendocrinol. 2019, 55, 100788.
  36. Illan-Cabeza, N.A.; Garcia-Garcia, A.R.; Martinez-Martos, J.M.; Ramirez-Exposito, M.J.; Pena-Ruiz, T.; Moreno-Carretero, M.N. A potential antitumor agent, (6-amino-1-methyl-5-nitrosouracilato-N3)-triphenylphosphinegold(I): Structural studies and in vivo biological effects against experimental glioma. Eur. J. Med. Chem. 2013, 64, 260–272.
  37. Ramirez-Exposito, M.J.; Martinez-Martos, J.M. The Delicate Equilibrium between Oxidants and Antioxidants in Brain Glioma. Curr. Neuropharmacol. 2019, 17, 342–351.
  38. Martínez-Martos, J.M.; Mayas, M.D.; Carrera, P.; Arias de Saavedra, J.M.; Sánchez-Agesta, R.; Marcela Arrazola, M.; Ramírez-Expósito, M.J. Phenolic compounds oleuropein and hydroxytyrosol exert differential effects on glioma development via antioxidant defense systems. J. Funct. Food 2014, 11, 221–234.
  39. Ramírez-Expósito, M.J.; Carrera-González, M.P.; Mayas, M.D.; Martínez-Martos, J.M. Gender differences in the antioxidant response of oral administration of hydroxytyrosol and oleuropein against N-ethyl-N-nitrosourea (ENU)-induced glioma. Food Res. Int. 2021, 140, 110023.
  40. Ramírez-Expósito, M.J.; Mayas, M.D.; Carrera-González, M.P.; Martínez-Martos, J.M. Gender Differences in the Antioxidant Response to Oxidative Stress in Experimental Brain Tumors. Curr. Cancer Drug Targets 2019, 19, 641–654.
  41. Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 2015, 136, E359–E386.
  42. Villanueva, A.; Llovet, J.M. Liver cancer in 2013: Mutational landscape of HCC-the end of the beginning. Nat. Rev. Clin. Oncol. 2014, 11, 73–74.
  43. El-Serag, H.B. Hepatocellular carcinoma. N. Engl. J. Med. 2011, 365, 1118–1127.
  44. Guy, J.; Peters, M.G. Liver disease in women: The influence of gender on epidemiology, natural history, and patient outcomes. Gastroenterol. Hepatol. 2013, 9, 633–639.
  45. Vesselinovitch, S.D.; Mihailovich, N.; Wogan, G.N.; Lombard, L.S.; Rao, K.V.; Sugamori, K.S.; Brenneman, D.; Sanchez, O.; Doll, M.A.; Hein, D.W.; et al. Reduced 4-aminobiphenyl-induced liver tumorigenicity but not DNA damage in arylamine N-acetyltransferase null mice. Cancer Lett. 2012, 318, 206–213.
  46. Gramenzi, A.; Caputo, F.; Biselli, M.; Kuria, F.; Loggi, E.; Andreone, P.; Bernardi, M. Review article: Alcoholic liver disease—Pathophysiological aspects and risk factors. Aliment. Pharmacol. Ther. 2006, 24, 1151–1161.
  47. Harada, S. Classification of alcohol metabolizing enzymes and polymorphisms–specificity in Japanese. Nihon Arukoru Yakubutsu Igakkai Zasshi 2001, 36, 85–106. (In Japanese)
  48. Brandon-Warner, E.; Walling, T.L.; Schrum, L.W.; McKillop, I.H. Chronic ethanol feeding accelerates hepatocellular carcinoma progression in a sex-dependent manner in a mouse model of hepatocarcinogenesis. Alcohol. Clin. Exp. Res. 2012, 36, 641–653.
  49. Yoshino, K.; Komura, S.; Watanabe, I.; Nakagawa, Y.; Yagi, K. Effect of estrogens on serum and liver lipid peroxide levels in mice. J. Clin. Biochem. Nutr. 1987, 3, 233–239.
  50. Lacort, M.; Leal, A.M.; Liza, M.; Martín, C.; Martínez, R.; Ruiz-Larrea, M.B. Protective effect of estrogens and catecholestrogens against peroxidative membrane damage in vitro. Lipids 1995, 30, 141–146.
  51. Omoya, T.; Shimizu, I.; Zhou, Y.; Okamura, Y.; Inoue, H.; Lu, G.; Itonaga, M.; Honda, H.; Nomura, M.; Ito, S. Effects of idoxifene and estradiol on NF-kappaB activation in cultured rat hepatocytes undergoing oxidative stress. Liver 2001, 21, 183–191.
  52. Inoue, H.; Shimizu, I.; Lu, G.; Itonaga, M.; Cui, X.; Okamura, Y.; Shono, M.; Honda, H.; Inoue, S.; Muramatsu, M.; et al. Idoxifene and estradiol enhance antiapoptotic activity through estrogen receptor-beta in cultured rat hepatocytes. Dig. Dis. Sci. 2003, 48, 570–580.
  53. Tanaka, Y.; Mukaide, M.; Orito, E.; Yuen, M.F.; Ito, K.; Kurbanov, F.; Sugauchi, F.; Asahina, Y.; Izumi, N.; Kato, M.; et al. Specific mutations in enhancer II/core promoter of hepatitis B virus subgenotypes C1/C2 increase the risk of hepatocellular carcinoma. J. Hepatol. 2006, 45, 646–653.
  54. Slocum, S.L.; Kensler, T.W. Nrf2: Control of sensitivity to carcinogens. Arch. Toxicol. 2011, 85, 273–284.
  55. Kitamura, Y.; Umemura, T.; Kanki, K.; Kodama, Y.; Kitamoto, S.; Saito, K.; Itoh, K.; Yamamoto, M.; Masegi, T.; Nishikawa, A.; et al. Increased susceptibility to hepatocarcinogenicity of Nrf2-deficient mice exposed to 2-amino-3-methylimidazo quinoline. Cancer Sci. 2007, 98, 19–24.
  56. Thimmulappa, R.K.; Lee, H.; Rangasamy, T.; Reddy, S.P.; Yamamoto, M.; Kensler, T.W.; Biswal, S. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J. Clin. investig. 2006, 116, 984–995.
  57. Wruck, C.J.; Streetz, K.; Pavic, G.; Götz, M.E.; Tohidnezhad, M.; Brandenburg, L.O.; Varoga, D.; Eickelberg, O.; Herdegen, T.; Trautwein, C.; et al. Nrf2 induces interleukin-6 (IL-6) expression via an antioxidant response element within the IL-6 promoter. J. Biol. Chem. 2011, 286, 4493–4499.
  58. Hanna, D.; Riedmaier, A.E.; Sugamori, K.S.; Grant, D.M. Influence of sex and developmental stage on acute hepatotoxic and inflammatory responses to liver procarcinogens in the mouse. Toxicology 2016, 373, 30–40.
  59. Shupe, T.; Sell, S. Low hepatic glutathione S-transferase and increased hepatic DNA adduction contribute to increased tumorigenicity of aflatoxin B1 in newborn and partially hepatectomized mice. Toxicol. Lett. 2004, 148, 1–9.
  60. Eaton, D.L.; Gallagher, E.P. Mechanisms of aflatoxin carcinogenesis. Annu. Rev. Pharmacol. Toxicol. 1994, 34, 135–172.
  61. Egner, P.A.; Groopman, J.D.; Wang, J.S.; Kensler, T.W.; Friesen, M.D. Quantification of aflatoxin-B1-N7-Guanine in human urine by high-performance liquid chromatography and isotope dilution tandem mass spectrometry. Chem. Res. Toxicol. 2006, 19, 1191–1195.
  62. Crawford, D.R.; Ilic, Z.; Guest, I.; Milne, G.L.; Hayes, J.D.; Sell, S. Characterization of liver injury, oval cell proliferation and cholangiocarcinogenesis in glutathione S-transferase A3 knockout mice. Carcinogenesis 2017, 38, 717–727.
  63. Fu, D.; Hornick, C.A. Modulation of lipid metabolism at rat hepatic subcellular sites by female sex hormones. Biochim. Biophys. Acta 1995, 1254, 267–273.
  64. Chen, J.; Li, Y.; Lavigne, J.A.; Trush, M.A.; Yager, J.D. Increased mitochondrial superoxide production in rat liver mitochondria, rat hepatocytes, and HepG2 cells following ethinyl estradiol treatment. Toxicol. Sci. 1999, 52, 224–235.
  65. Gerber, M.; Astre, C.; Segala, C.; Saintot, M.; Scali, J.; Simony Lafontaine, J.; Grenier, J.; Pujol, H. Tumor progression and oxidant-antioxidant status. Cancer Lett. 1997, 114, 211–214.
  66. Sverko, V.; Sobocanec, S.; Balog, T.; Marotti, T. Age and gender differences in antioxidant enzyme activity: Potential relationship to liver carcinogenesis in male mice. Biogerontology 2004, 5, 235–242.
  67. Coto-Montes, A.; Boga, J.A.; Tomas-Zapico, C.; Rodriguez Colunga, M.J.; Martinez-Fraga, J.; Tolivia-Cadrecha, D.; Manendez, G.; Herdeband, R.; Tolivia, D. Physiological oxidative stress model: Syrian hamster harderian gland-sex differences in antioxidant enzymes. Free Radic. Biol. Med. 2001, 30, 785–792.
  68. Oberley, L.W.; Oberley, T.D. Role of antioxidant enzymes in cell immortalization and transformation. Mol. Cell. Biochem. 1988, 84, 147–153.
  69. Janssen, A.M.; Bosman, C.B.; Sier, C.F.; Griffioen, G.; Kubben, F.J.; Lamers, C.B.; van Krieken, J.H.; van de Velde, C.J.; Verspaget, H.W. Superoxide dismutase in relation to the overall survival of colorectal cancer patients. Br. J. Cancer 1998, 78, 1051–1057.
  70. Manna, S.K.; Zhang, H.J.; Yan, T.; Oberley, L.W.; Aggarwal, B.B. Overexpression of manganese superoxide dismutase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-jB and activated protein-1. J. Biol. Chem. 1998, 273, 13245–13254.
  71. Szatrowski, T.P.; Nathan, C.F. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 1991, 51, 794–798.
  72. Gardner, R.; Salvador, A.; Moradas-Ferreira, P. Why does SOD overexpression sometimes enhance, sometimes decrease, hydrogen peroxide production? A minimalist explanation. Free Radic. Biol. Med. 2022, 32, 1352–1357.
  73. Pigeolet, E.; Corbisier, P.; Houbion, A.; Lambert, D.; Michiels, C.; Raes, M.; Zachary, M.D.; Remacle, J. Glutathione peroxidase, superoxide dismutase and catalase inactivation by peroxides and oxygen-derived free radicals. Mech. Ageing Dev. 1990, 51, 283–297.
  74. Gonzales, M.J. Lipid peroxidation and tumor growth: An inverse relationship. Med. Hypotheses 1992, 38, 106–110.
  75. Wang, S.; Sugamori, K.S.; Tung, A.; McPherson, J.P.; Grant, D.M. N-hydroxylation of 4-aminobiphenyl by CYP2E1 produces oxidative stress in a mouse model of chemically induced liver cancer. Toxicol. Sci. 2015, 144, 393–405.
  76. Calle, E.E.; Rodriguez, C.; Walker-Thurmond, K.; Thun, M.J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 2003, 348, 1625–1638.
  77. Bhaskaran, K.; Douglas, I.; Forbes, H.; dos-Santos-Silva, I.; Leon, D.A.; Smeeth, L. Body-mass index and risk of 22 specific cancers: A population-based cohort study of 5.24 million UK adults. Lancet 2014, 384, 755–765.
  78. Świątkiewicz, I.; Wróblewski, M.; Nuszkiewicz, J.; Sutkowy, P.; Wróblewska, J.; Woźniak, A. The Role of Oxidative Stress Enhanced by Adiposity in Cardiometabolic Diseases. Int. J. Mol. Sci. 2023, 24, 6382.
  79. Ibrahim, M.M. Subcutaneous and visceral adipose tissue: Structural and functional differences. Obes. Rev. 2010, 11, 11–18.
  80. Setiawan, V.W.; Lim, U.; Lipworth, L.; Lu, S.C.; Shepherd, J.; Ernst, T.; Wilkens, L.R.; Henderson, B.E.; Le Marchand, L. Sex and ethnic differences in the association of obesity with risk of hepatocellular carcinoma. Clin. Gastroenterol. Hepatol. 2016, 14, 309–316.
  81. Chang, Y.; Jung, H.S.; Cho, J.; Zhang, Y.; Yun, K.E.; Lazo, M.; Pastor-Barriuso, R.; Ahn, J.; Kim, C.W.; Rampal, S.; et al. Metabolically healthy obesity and the development of nonalcoholic fatty liver disease. Am. J. Gastroenterol. 2016, 111, 1133–1140.
  82. Freedland, E.S. Roles of critical visceral adipose tissue threshold in metabolic syndrome: Implications for controlling dietary carbohydrates: A review. Nutr. Metab. 2004, 1, 12.
  83. Björntorp, P. Endocrine abnormalities in obesity. Metabolism. 1995, 44 (Suppl. 3), 21–23.
  84. He, J.; Gu, D.; Wu, X.; Reynolds, K.; Duan, X.; Yao, C.; Wang, J.; Chen, C.S.; Chen, J.; Wildman, R.P.; et al. Major causes of death among men and women in China. N. Engl. J. Med. 2005, 353, 1124–1134.
  85. Riley, G.F.; Potosky, A.L.; Lubitz, J.D.; Kessler, L.G. Medicare payments from diagnosis to death for elderly cancer patients by stage at diagnosis. Med. Care 1995, 33, 828–841.
  86. Ohnishi, S.; Murata, M.; Kawanishi, S. DNA damage induced by hypochlorite and hypobromite with reference to inflammation-associated carcinogenesis. Cancer Lett. 2002, 178, 37–42.
  87. Kiyohara, C.; Yoshimasu, K.; Takayama, K.; Nakanishi, Y. NQO1, MPO, and the risk of lung cancer: A HuGE review. Genet. Med. 2005, 7, 463–478.
  88. Yang, M.; Choi, Y.; Hwangbo, B.; Lee, J.S. Combined effects of genetic polymorphisms in six selected genes on lung cancer susceptibility. Lung Cancer 2007, 57, 135–142.
  89. Yang, J.; Ambrosone, C.B.; Hong, C.C.; Ahn, J.; Rodriguez, C.; Thun, M.J.; Calle, E.E. Relationships between polymorphisms in NOS3 and MPO genes, cigarette smoking and risk of post-menopausal breast cancer. Carcinogenesis 2007, 28, 1247–1253.
  90. Steenport, M.; Eom, H.; Uezu, M.; Schneller, J.; Gupta, R.; Mustafa, Y.; Villanueva, R.; Straus, E.W.; Raffaniello, R.D. Association of polymorphisms in myeloperoxidase and catalase genes with precancerous changes in the gastric mucosa of patients at inner-city hospitals in New York. Oncol. Rep. 2007, 18, 235–240.
  91. Cascorbi, I.; Henning, S.; Brockmöller, J.; Gephart, J.; Meisel, C.; Müller, J.M.; Loddenkemper, R.; Roots, I. Substantially reduced risk of cancer of the aerodigestive tract in subjects with variant--463A of the myeloperoxidase gene. Cancer Res. 2000, 60, 644–649.
  92. Li, Y.; Qin, Y.; Wang, M.L.; Zhu, H.F.; Huang, X.E. The myeloperoxidase-463 G>A polymorphism influences risk of colorectal cancer in southern China: A case-control study. Asian Pac. J. Cancer Prev. 2011, 12, 1789–1793.
  93. Otero Regino, W.; Velasco, H.; Sandoval, H. The protective role of bilirubin in human beings. Rev. Colomb. Gastroenterol. 2009, 24, 293–301.
  94. Wagner, K.H.; Wallner, M.; Molzer, C.; Gazzin, S.; Bulmer, A.C.; Tiribelli, C.; Vitek, L. Looking to the horizon: The role of bilirubin in the development and prevention of age-related chronic diseases. Clin. Sci. 2015, 129, 1–25.
  95. Sedlak, T.W.; Saleh, M.; Higginson, D.S.; Paul, B.D.; Juluri, K.R.; Snyder, S.H. Bilirubin and glutathione have complementary antioxidant and cytoprotective roles. Proc. Natl. Acad. Sci. USA 2009, 106, 5171–5176.
  96. Rodrigues, C.M.; Sola, S.; Brito, M.A.; Brites, D.; Moura, J.J. Bilirubin directly disrupts membrane lipid polarity and fluidity, protein order, and redox status in rat mitochondria. J. Hepatol. 2002, 36, 335–341.
  97. Hansen, T.W.; Mathiesen, S.B.; Walaas, S.I. Bilirubin has widespread inhibitory effects on protein phosphorylation. Pediatr. Res. 1996, 39, 1072–1077.
  98. Fevery, J. Bilirubin in clinical practice: A review. Liver Int. 2008, 28, 592–605.
  99. Bulmer, A.C.; Ried, K.; Coombes, J.S.; Blanchfield, J.T.; Toth, I.; Wagner, K.H. The anti-mutagenic and antioxidant effects of bile pigments in the Ames Salmonella test. Mutat. Res. 2007, 629, 122–132.
  100. Molzer, C.; Huber, H.; Diem, K.; Wallner, M.; Bulmer, A.C.; Wagner, K.H. Extracellular and intracellular anti-mutagenic effects of bile pigments in the Salmonella typhimurium reverse mutation assay. Toxicol. Int. J. Public Assoc. BIBRA 2013, 27, 433–437.
  101. Molzer, C.; Huber, H.; Steyrer, A.; Ziesel, G.; Ertl, A.; Plavotic, A.; Wallner, M.; Bulmer, A.C.; Wagner, K.H. In vitro antioxidant capacity and antigenotoxic properties of protoporphyrin and structurally related tetrapyrroles. Free Radic. Res. 2012, 46, 1369–1377.
  102. Molzer, C.; Huber, H.; Steyrer, A.; Ziesel, G.V.; Wallner, M.; Hong, H.T.; Blanchfield, J.T.; Bulmer, A.C.; Wagner, K.H. Bilirubin and related tetrapyrroles inhibit food-borne mutagenesis: A mechanism for antigenotoxic action against a model epoxide. J. Nat. Prod. 2013, 76, 1958–1965.
  103. Seyed Khoei, N.; Jenab, M.; Murphy, N.; Banbury, B.L.; Carreras-Torres, R.; Viallon, V.; Kühn, T.; Bueno-de-Mesquita, B.; Aleksandrova, K.; Cross, A.J.; et al. Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses. BMC Med. 2020, 18, 229.
  104. Seyed Khoei, N.; Anton, G.; Peters, A.; Freisling, H.; Wagner, K.H. The Association between Serum Bilirubin Levels and Colorectal Cancer Risk: Results from the Prospective Cooperative Health Research in the Region of Augsburg (KORA) Study in Germany. Antioxidants 2020, 9, 908.
  105. Ollinger, R.; Kogler, P.; Troppmair, J.; Hermann, M.; Wurm, M.; Drasche, A.; Konigsrainer, I.; Amberger, A.; Weiss, H.; Ofner, D.; et al. Bilirubin inhibits tumor cell growth via activation of ERK. Cell Cycle 2007, 6, 3078–3085.
  106. Keshavan, P.; Schwemberger, S.J.; Smith, D.L.; Babcock, G.F.; Zucker, S.D. Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization. Int. J. Cancer 2004, 112, 433–445.
  107. Grant, D.J.; Bell, D.A. Bilirubin UDP-glucuronosyltransferase 1A1 gene polymorphisms: Susceptibility to oxidative damage and cancer? Mol. Carcinogen. 2000, 29, 198–204.
  108. Kander, M.C.; Cui, Y.; Liu, Z. Gender difference in oxidative stress: A new look at the mechanisms for cardiovascular diseases. J. Cell. Mol. Med. 2017, 21, 1024–1032.
  109. Zhang, T.; Joubert, P.; Ansari-Pour, N.; Zhao, W.; Hoang, P.H.; Lokanga, R.; Moye, A.L.; Rosenbaum, J.; Gonzalez-Perez, A.; Martínez-Jiménez, F.; et al. Genomic and Evolutionary Classification of Lung Cancer in Never Smokers. Nat. Genet. 2021, 53, 1348–1359.
  110. Adib, E.; Nassar, A.H.; Abou Alaiwi, S.; Groha, S.; Akl, E.W.; Sholl, L.M.; Michael, K.S.; Awad, M.M.; Jänne, P.A.; Gusev, A.; et al. Variation in Targetable Genomic Alterations in Non-Small Cell Lung Cancer by Genetic Ancestry, Sex, Smoking History, and Histology. Genome Med. 2022, 14, 39.
  111. Gasperino, J.; Rom, W.N. Gender and lung cancer. Clin Lung Cancer 2004, 5, 353–359.
  112. Thomas, L.; Doyle, L.A.; Edelman, M.J. Lung cancer in women: Emerging differences in epidemiology, biology, and therapy. Chest 2005, 128, 370–381.
  113. Kiyohara, C.; Ohno, Y. Sex differences in lung cancer susceptibility: A review. Gend Med. 2010, 7, 381–401.
  114. Henschke, C.I.; Yip, R.; Miettinen, O.S. Women’s susceptibility to tobacco carcinogens and survival after diagnosis of lung cancer. J. Am. Med. Assoc. 2006, 296, 180–184.
  115. Parajuli, R.; Bjerkaas, E.; Tverdal, A.; Selmer, R.; Le Marchand, L.; Weiderpass, E.; Gram, I.T. The increased risk of colon cancer due to cigarette smoking may be greater in women than men. Cancer Epidemiol. Biomarkers Prev. 2013, 22, 862–871.
  116. Forder, A.; Zhuang, R.; Souza, V.G.P.; Brockley, L.J.; Pewarchuk, M.E.; Telkar, N.; Stewart, G.L.; Benard, K.; Marshall, E.A.; Reis, P.P.; et al. Mechanisms Contributing to the Comorbidity of COPD and Lung Cancer. Int. J. Mol. Sci. 2023, 24, 2859.
  117. Dewhirst, M.W.; Cao, Y.; Moeller, B. Cycling Hypoxia and Free Radicals Regulate Angiogenesis and Radiotherapy Response. Nat. Rev. Cancer 2008, 8, 425–437.
  118. Covey, T.M.; Edes, K.; Coombs, G.S.; Virshup, D.M.; Fitzpatrick, F.A. Alkylation of the Tumor Suppressor PTEN Activates Akt and β-Catenin Signaling: A Mechanism Linking Inflammation and Oxidative Stress with Cancer. PLoS ONE 2010, 5, e13545.
  119. Cai, B.; Liu, M.; Li, J.; Xu, D.; Li, J. Cigarette Smoke Extract Amplifies NADPH Oxidase-Dependent ROS Production to Inactivate PTEN by Oxidation in BEAS-2B Cells. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2021, 150, 112050.
  120. Shukla, S.D.; Shastri, M.D.; Jha, N.K.; Gupta, G.; Chellappan, D.K.; Bagade, T.; Dua, K. Female Gender as a Risk Factor for Developing COPD. EXCLI J. 2021, 20, 1290–1293.
  121. Ben-Zaken Cohen, S.; Paré, P.D.; Man, S.F.P.; Sin, D.D. The Growing Burden of Chronic Obstructive Pulmonary Disease and Lung Cancer in Women: Examining Sex Differences in Cigarette Smoke Metabolism. Am. J. Respir. Crit. Care Med. 2007, 176, 113–120.
  122. Meireles, S.I.; Esteves, G.H.; Hirata, R.J.; Peri, S.; Devarajan, K.; Slifker, M.; Mosier, S.L.; Peng, J.; Vadhanam, M.V.; Hurst, H.E.; et al. Early Changes in Gene Expression Induced by Tobacco Smoke: Evidence for the Importance of Estrogen within Lung Tissue. Cancer Prev. Res. 2010, 3, 707–717.
  123. Mollerup, S.; Ryberg, D.; Hewer, A.; Phillips, D.H.; Haugen, A. Sex Differences in Lung CYP1A1 Expression and DNA Adduct Levels among Lung Cancer Patients. Cancer Res. 1999, 59, 3317–3320.
  124. Van Winkle, L.S.; Gunderson, A.D.; Shimizu, J.A.; Baker, G.L.; Brown, C.D. Gender Differences in Naphthalene Metabolism and Naphthalene-Induced Acute Lung Injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 2002, 282, L1122–L1134.
  125. Soriano, J.B.; Kendrick, P.J.; Paulson, K.R.; Gupta, V.; Abrams, E.M.; Adedoyin, R.A.; Adhikari, T.B.; Advani, S.M.; Agrawal, A.; Ahmadian, E.; et al. Prevalence and Attributable Health Burden of Chronic Respiratory Diseases, 1990-2017: A Systematic Analysis for the Global Burden of Disease Study 2017. Lancet Respir. Med. 2020, 8, 585–596.
  126. Ramírez-Venegas, A.; Sansores, R.H.; Pérez-Padilla, R.; Regalado, J.; Velázquez, A.; Sánchez, C.; Mayar, M.E. Survival of Patients with Chronic Obstructive Pulmonary Disease Due to Biomass Smoke and Tobacco. Am. J. Respir. Crit. Care Med. 2006, 173, 393–397.
  127. Armstrong, B.G.; Gibbs, G. Exposure-response relationship between lung cancer and polycyclic aromatic hydrocarbons (PAHs). Occup. Environ. Med. 2009, 66, 740–746.
  128. Veglia, F.; Matullo, G.; Vineis, P. Bulky DNA adducts and risk of cancer: A meta-analysis. Cancer Epidemiol. Biomarkers Prev. 2003, 12, 157–160.
  129. Bostrom, C.E.; Gerde, P.; Hanberg, A.; Jernstrom, B.; Johansson, C.; Kyrklund, T.; Rannug, A.; Tornqvist, M.; Victorin, K.; Westerholm, R. Cancer risk assessment, indicators, and guidelines for polycyclic aromatic hydrocarbons in the ambient air. Environ. Health Perspect. 2002, 110 (Suppl. 3), 451–488.
  130. Guo, H.; Huang, K.; Zhang, X.; Zhang, W.; Guan, L.; Kuang, D.; Deng, Q.; Deng, H.; Zhang, X.; He, M.; et al. Women are more susceptible than men to oxidative stress and chromosome damage caused by polycyclic aromatic hydrocarbons exposure. Environ. Mol. Mutagen. 2014, 55, 472–481.
  131. Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics. CA Cancer J. Clin. 2013, 63, 11–30.
  132. Balch, C.M.; Gershenwald, J.E.; Soong, S.J.; Thompson, J.F.; Atkins, M.B.; Byrd, D.R.; Buzaid, A.C.; Cochran, A.J.; Coit, D.G.; Ding, S.; et al. Final version of 2009 AJCC melanoma staging and classification. J. Clin. Oncol. 2009, 27, 6199–6206.
  133. De Vries, E.; Nijsten, T.E.; Visser, O.; Bastiaannet, E.; Van Hattem, S.; Janssen-Heijnen, M.L.; Coebergh, J.W. Superior survival of females among 10,538 Dutch melanoma patients is independent of Breslow thickness, histologic type and tumor site. Ann. Oncol. 2008, 19, 583–589.
  134. Lasithiotakis, K.; Leiter, U.; Meier, F.; Eigentler, T.; Metzler, G.; Moehrle, M.; Breuninger, H.; Garbe, C. Age and gender are significant independent predictors of survival in primary cutaneous melanoma. Cancer 2008, 112, 1795–1804.
  135. Richardson, B.; Price, A.; Wagner, M.; Williams, V.; Lorigan, P.; Browne, S.; Miller, J.G.; Mac Neil, S. Investigation of female survival benefit in metastatic melanoma. Br. J. Cancer 1999, 80, 2025–2033.
  136. Kemeny, M.M.; Busch, E.; Stewart, A.K.; Menck, H.R. Superior survival of young women with malignant melanoma. Am. J. Surg. 1998, 175, 437–444; discussion 444–445.
  137. Daryanani, D.; Plukker, J.T.; De Jong, M.A.; Haaxma-Reiche, H.; Nap, R.; Kuiper, H.; Hoekstra, H.J. Increased incidence of brain metastases in cutaneous head and neck melanoma. Melanoma Res. 2005, 15, 119–124.
  138. Scoggins, C.R.; Ross, M.I.; Reintgen, D.S.; Noyes, R.D.; Goydos, J.S.; Beitsch, P.D.; Urist, M.M.; Ariyan, S.; Sussman, J.J.; Edwards, M.J.; et al. Gender-related differences in outcome for melanoma patients. Ann. Surg. 2006, 243, 693–698; discussion 698–700.
  139. Joosse, A.; Collette, S.; Suciu, S.; Nijsten, T.; Lejeune, F.; Kleeberg, U.R.; Coebergh, J.W.; Eggermont, A.M.; de Vries, E. Superior outcome of women with stage I/II cutaneous melanoma: Pooled analysis of four European Organisation for Research and Treatment of Cancer phase III trials. J. Clin. Oncol. 2012, 30, 2240–2247.
  140. Joosse, A.; de Vries, E.; Eckel, R.; Nijsten, T.; Eggermont, A.M.; Hölzel, D.; Coebergh, J.W.; Engel, J.; Munich Melanoma Group. Gender differences in melanoma survival: Female patients have a decreased risk of metastasis. J. investig. Dermatol. 2011, 131, 719–726.
  141. Sondak, V.K.; Swetter, S.M.; Berwick, M.A. Gender disparities in patients with melanoma: Breaking the glass ceiling. J. Clin. Oncol. 2012, 30, 2177–2178.
  142. Gamba, C.S.; Clarke, C.A.; Keegan, T.H.; Tao, L.; Swetter, S.M. Melanoma survival disadvantage in young, non-Hispanic white males compared with females. JAMA Dermatol. 2013, 149, 912–920.
  143. Fruehauf, J.P.; Trapp, V. Reactive oxygen species: An Achilles’ heel of melanoma? Expert Rev. Anticancer Ther. 2008, 8, 1751–1757.
  144. Liu, J.; Zheng, R.; Zhang, Y.; Jia, S.; He, Y.; Liu, J. The Cross Talk between Cellular Senescence and Melanoma: From Molecular Pathogenesis to Target Therapies. Cancers 2023, 15, 2640.
  145. Bittinger, F.; Gonzalez-Garcia, J.L.; Klein, C.L.; Brochhausen, C.; Offner, F.; Kirkpatrick, C.J. Production of superoxide by human malignant melanoma cells. Melanoma Res. 1998, 8, 381–387.
  146. Meyskens, F.L., Jr.; Chau, H.V.; Tohidian, N.; Buckmeier, J. Luminol-enhanced chemiluminescent response of human melanocytes and melanoma cells to hydrogen peroxide stress. Pigment Cell Res. 1997, 10, 184–189.
  147. Joosse, A.; De Vries, E.; van Eijck, C.H.; Eggermont, A.M.; Nijsten, T.; Coebergh, J.W. Reactive oxygen species and melanoma: An explanation for gender differences in survival? Pigment Cell Melanoma Res. 2010, 23, 352–364.
  148. Sander, C.S.; Hamm, F.; Elsner, P.; Thiele, J.J. Oxidative stress in malignant melanoma and non-melanoma skin cancer. Br. J. Dermatol. 2003, 148, 913–922.
  149. Meyskens, F.L., Jr.; McNulty, S.E.; Buckmeier, J.A.; Tohidian, N.B.; Spillane, T.J.; Kahlon, R.S.; Gonzalez, R.I. Aberrant redox regulation in human metastatic melanoma cells compared to normal melanocytes. Free Radic. Biol. Med. 2001, 31, 799–808.
  150. Nishikawa, M. Reactive oxygen species in tumor metastasis. Cancer Lett. 2008, 266, 53–59.
  151. Trouba, K.J.; Hamadeh, H.K.; Amin, R.P.; Germolec, D.R. Oxidative stress and its role in skin disease. Antioxid. Redox Signal. 2002, 4, 665–673.
  152. Thomas-Ahner, J.M.; Wulff, B.C.; Tober, K.L.; Kusewitt, D.F.; Riggenbach, J.A.; Oberyszyn, T.M. Gender differences in UVB-induced skin carcinogenesis, inflammation, and DNA damage. Cancer Res. 2007, 67, 3468–3474.
  153. Zhong, Q.Y.; Lin, B.; Chen, Y.T.; Huang, Y.P.; Feng, W.P.; Wu, Y.; Long, G.H.; Zou, Y.N.; Liu, Y.; Lin, B.Q.; et al. Gender differences in UV-induced skin inflammation, skin carcinogenesis and systemic damage. Environ. Toxicol. Pharmacol. 2021, 81, 103512.
  154. Masback, A.; Olsson, H.; Westerdahl, J.; Ingvar, C.; Jonsson, N. Prognostic factors in invasive cutaneous malignant melanoma: A population-based study and review. Melanoma Res. 2001, 11, 435–445.
  155. Borrás, C.; Gambini, J.; López-Grueso, R.; Pallardó, F.V.; Viña, J. Direct antioxidant and protective effect of estradiol on isolated mitochondria. Biochim. Biophys. Acta 2010, 1802, 205–211.
  156. Duffield-Lillico, A.J.; Reid, M.E.; Turnbull, B.W.; Combs, G.F., Jr.; Slate, E.H.; Fischbach, L.A.; Marshall, J.R.; Clark, L.C. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: A summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol. Biomarkers Prev. 2002, 11, 630–639.
  157. Hercberg, S.; Ezzedine, K.; Guinot, C.; Preziosi, P.; Galan, P.; Bertrais, S.; Estaquio, C.; Briançon, S.; Favier, A.; Latreille, J.; et al. Antioxidant supplementation increases the risk of skin cancers in women but not in men. J. Nutr. 2007, 137, 2098–2105.
  158. Hercberg, S.; Galan, P.; Preziosi, P.; Bertrais, S.; Mennen, L.; Malvy, D.; Roussel, A.M.; Favier, A.; Briancon, S. The SU. VI. MAX Study: A randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch. Intern. Med. 2004, 164, 2335–2342.
  159. Radkiewicz, C.; Bruchfeld, J.B.; Weibull, C.E.; Jeppesen, M.L.; Frederiksen, H.; Lambe, M.; Jakobsen, L.; El-Galaly, T.C.; Smedby, K.E.; Wästerlid, T. Sex differences in lymphoma incidence and mortality by subtype: A population-based study. Am. J. Hematol. 2023, 98, 23–30.
  160. Jacobus, J.A.; Duda, C.G.; Coleman, M.C.; Martin, S.M.; Mapuskar, K.; Mao, G.; Smith, B.J.; Aykin-Burns, N.; Guida, P.; Gius, D.; et al. Low-dose radiation-induced enhancement of thymic lymphomagenesis in Lck-Bax mice is dependent on LET and gender. Radiat. Res. 2013, 180, 156–165.
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