770
Views & Citations10
Likes & Shares
Background
and purpose: As in many countries, Colorectal
Cancer (CRC) incidence and mortality in Uruguay show increasing trends among
men but relative stability among women. Dietary iron has shown inconsistencies
regarding the CRC risk. Based on iron contents in representative foods, we
carried out the present study, in order to accurately analyzing dietary iron
and its role in CRC risk.
Subjects/methods: A case-control study was performed on 611 CRC incident cases and
2394 controls, using a specific multi-topic questionnaire including a food
frequency questionnaire. The sample included 1937 men and 1068 women. Controls
were matched by sex and age (± 5 years) to cases. Food-derived nutrients were
calculated from available databases. Dietary iron was calculated according to
its heme or non-heme source, additionally adjusted by energy. Odds Ratios (OR)
was calculated through unconditional logistic regression, adjusting for
potential confounders. Animal/plant and heme/non-heme (H/NH) ratios were
created for analysis purposes.
Results: Total iron intake was inversely associated with CRC risk among men
(OR=0.65 for 3rd vs. 1st tertile). Heme-iron was
inversely associated among women (OR=0.47). Plant-based and non-heme-iron
showed an inverse association among men (OR=0.62 and OR=0.60, respectively).
Animal-based iron lacked risk association, suggesting opposite trends between
sexes. The Animal/Plant iron ratio was directly associated with CRC risk among
men (OR=1.77) and inversely associated among women (OR=0.51). The same occurred
to the H/NH ratio, whose risks increased among men (OR=1.53) but decreased
among women (OR=0.53).
Conclusion: Dietary iron showed different associations with CRC risk, regarding
iron source and sex. The available iron type, due to its wide hormonal, red-ox,
and metabolic interactions, might play also different roles linked to
colorectal carcinogenesis. Nevertheless, the different associations observed
for each sex demand further studies to clarify this point.
Keywords:
Aromatase, Chelation, Colorectal cancer, Estrogens, Heme, Ilex paraguariensis, Iron, Non-heme
INTRODUCTION
Colorectal cancer (CRC) is the most frequent malignancy
in the Uruguayan population, taking into account both sexes combined [1]. The
age-adjusted incidence and mortality rates locate Uruguayan men at top of the
list in America and very high in the world’s ranking [2]. However, mortality
trends change annually in +0.3% among men but a -0.5% among women through
1990-2017 [1].
Processed and red meats are considered as major risk
factors for CRC [3,4] and base their implication in colorectal carcinogenesis
on some of their own or added components like fats, Heterocyclic Amines (HCA),
nitrosodimethylamine and heme-iron [3,5,6]. Although Uruguay is a developing
country, its average diet is meat-based, with the world's highest per capita
beef intake [7]. Meat and its role in the CRC risk were thoroughly analyzed in
Uruguayan studies [8-14].
Total iron intake was reported as a risk
factor for rectal cancer in Uruguay [9]. Reports on iron intake and CRC showed
some inconsistency [15,16], but heme-iron is a major participant in the
meat-induced promotion of CRC without additive or synergistic effects of HCA
and endogenous N-nitroso compounds [17,18]. Heme-iron potentially affects
homeostasis and colonic epithelial cell renewal and promotes the formation of
mutagenic and carcinogenic agents, also linked to the development of adenomas
[19]. The gut microbiota seems to influence the activation of enterocyte genes
involved in the initiation and progression of colorectal carcinogenesis
[20-22]. Iron supplements beyond certain limits were found as a risk factor for
CRC [23]. Recently, a case-control study found different associations of iron
types and CRC risk, depending on the source [24]: the iron intakes from red
meat and heme-iron were positively associated, iron from white meat and plants
were inversely associated, and no significant association was found for total
dietary iron, non-heme-iron, and iron from meat.
Iron is essential for many biological
processes. Heme-iron is absorbed ~30% and non-heme-iron ~10% [25], therefore
most dietary iron is excreted and the human colon contains large amounts [26].
Because humans lack a mechanism for controlled iron excretion, regulatory
systems controlling iron absorption, systemic transport and cellular uptake and
storage [27], enable the body to reduce pathogenesis [28,29], depending on the
organ, tissue or cell type affected [30]. Iron accumulation during lifespan
poses a disadvantage for men because women can balance dietary iron excesses
with their menses (periodical iron losses) during the reproductive years.
Assuming similar dietary styles in both sexes, different body iron levels can
be expected close to age 50.
Higher CRC incidence rates among men than
women raised a possibility that estrogen and/or progesterone may confer
protection against CRC [31]; however, the evidence remains inconclusive [32].
Estrogen acts on non-reproductive, secretory and absorptive tissues (e.g.
colon, respiratory tract) expressing Estrogen Receptors (ERs), modulating the
electrolyte and fluid balance. The colonic epithelium expresses both ERα and ERβ: in the crypts of the proximal
colon, ERα is
expressed more highly at the base of the crypt while ERβ expression prevails in its
mid-section and the lumen surface cells [33].
Recently important ERβ features were described, linking
them to colorectal carcinogenesis [34]: ERβ -the predominant ERs expressed
in both normal and malignant colonic epithelium co-exist- with limited or no
expression of ERα in the colon, and are responsible for tumor-suppressive functions in
CRC. Estrogen signaling has an anti-tumorigenic role in the colonic mucosa,
through selective activation of pro-apoptotic ERβ-mediated signaling, inhibition
of inflammatory
signals and modulation of the tumor microenvironment and different immune
surveillance mechanisms [34,35].
Hormone Replacement Therapy (HRT) reduces
postmenopausal CRC incidence [36,37]. Nevertheless, although estrogen was
initially protective, once CRC had developed, exogenous estrogens augmented the
growth. This could be explained by ERβ expression, which is selectively lost during tumor progression through
methylation-dependent gene silencing [38]. Aromatase is usually overexpressed
in colon carcinoma, more than in normal tissues of both sexes [39]. Since
aromatase has a place for heme-iron in its molecular structure, women may have
a higher demand of it at the colorectal level, to build more aromatases, which
in turn synthesize more estrogens needed by women.
Besides, there is a staple beverage in
temperate South America known as “mate”, an infusion made from the herb Ilex
paraguariensis. Uruguayans are the world’s highest consumers (~400
L/person/year of infusion) [40]. Although “mate” drinking was classified
in 1991 by the International Agency for Research on Cancer as 2A [41], due to
the presence of several pro-carcinogenic substances [42,43], it will be
reassessed because it contains several antioxidant and anti-carcinogenic
compounds (e.g. polyphenols, chlorogenic acids) [44,45].
Saponins from “mate” leave prevent
colorectal carcinogenesis by suppressing inflammation and promoting apoptosis
[46]. “Mate” is a rich source of oleanolic acid and ursolic acid (UA) [47]. UA
has several intra- and extra-cellular targets playing a role in apoptosis,
metastasis, angiogenesis and inflammation [48,49]. These “mate” components and
theaflavins from black tea exert an aromatase-inhibitory activity [50]. UA can
suppress ERα through
down-regulation of estrogen-responsive genes expression in response to exposure
to estradiol [51], showing a dose-dependent inhibition capability, comparable
to phytoestrogens [47]. Moreover, “mate” iron-chelating capabilities were
already demonstrated [52-55]. Our previous study on CRC showed an inverse
association of “mate” intake among women, but lack of association among men
[56].
There is strong evidence for a role of inflammation, oxidative stress, and
metabolic dysfunction as underlying, interactive mechanisms in CRC [57].
Dietary iron and its metabolism are linked to several items, as the intake of
processed meats, red meats, alcoholic drinks, and smoking [26,58,59], as well
as to hormonal [60,61] and microbiota [20-22] features. Interestingly, the
identified risk factors do not make equivalent contributions to CRC development
in men and women [62].
The aforementioned epidemiologic links among
iron, red/processed meat, “mate” infusion and CRC, justified doing additional
studies following the recommended identification of the iron source to clarify
the relationship between its intake and CRC [63]. Therefore, we conducted a
case-control study on dietary iron and CRC risk, applying a similar methodology
as in previous studies [64-66]. To our knowledge, this is the first Latin
American epidemiologic study focusing on dietary iron sources and CRC risk.
PATIENTS AND METHODS
Selection of cases
and controls
During 1992-2004, all the newly diagnosed,
microscopically confirmed CRC cases were collected from the major public
hospitals in Montevideo (Oncología, Clínicas, Maciel, Pasteur), which catch a
large fraction of patients from the public healthcare system for diagnosis and/or
treatment of cancer. From the initial 625 patients, only 14 (2.3%) refused the
interview (response rate 97.7%), finally leaving 611 cases. The former version
of International Diseases Code for Oncology was used to classify lesions as
colon (153.0 to 153.9) or rectum (154.0 to 154.9).
In the same period and hospitals, 2.460
patients afflicted with non-neoplastic diseases not related to tobacco smoking
or alcohol drinking and without recent dietary changes were considered as
eligible for the study. Sixty-six (66, 2.7%) of them refused the interview,
leaving a final number of 2.394 controls (response rate 97.3%). These controls
had the following diseases: skin diseases (357 patients, 14.9%), eye disorders
(349, 14.6%), ear disorders (309, 12.9%), abdominal hernia (258, 10.8%),
fractures (184, 7.7%), hydatid cysts (151, 6.3%), lipoma (101, 4.2%),
osteoarticular diseases (100, 4.2%), varicose veins (91, 3.8%), injuries (92,
3.9%), urinary stones (73, 3.1%), goiter (62, 2.6%) and other acute diseases (267,
11.1%).
Interviews and questionnaire
Two trained
social workers, unaware of the study objectives, worked at the hospitals in two
phases: First, they looked for newly diagnosed cancer patients, working with
the collaboration of Medical Records personnel. Second, they contacted patients
who were eligible to be matched by the age-frequencies of the cases. After
looking for their will to cooperate with the study, all the participants were
face-to-face interviewed in the hospitals. Proxy interviews were not accepted
in our study.
A structured
questionnaire was applied to all participants. It included the following
sections: socio-demographic variables; history of cancer in first- and
second-degree relatives; self-reported height and weight 5 years before the interview;
menstrual and reproductive events; tobacco smoking (average number of
cigarettes/day); alcohol drinking (average amount of alcohol/day and beverage
type); “mate”, tea and coffee drinking (daily intake). The age at starting and
quitting was asked for these 5 habits.
Finally, we included a detailed
semi-quantitative food–frequency questionnaire (FFQ) on 64 items representative
of the Uruguayan diet, which asked about food consumption 5 years before
diagnosis in cases and before to the interview in controls. The FFQ was not
validated but was tested for reproducibility, having high correlations [67]. It
allowed the estimation of individual total energy intake. All dietary questions
were open-ended. Each amount was converted to times/year. To obtain nutritional
information about foods, we used foreign tables coming from a neighboring
country with similar habits [68].
Estimation
of iron and nutrients intake
We estimated heme-iron intake using our FFQ
and following previous studies [16,69,70], by using its percentage of total
iron in the following foods: 69% for beef, 39% for ham, bacon, mortadella,
salami, hot dogs, saucisson and sausage, 26% for chicken, fish, eggs and milk and 21% for the
liver. Mean daily heme-iron intake was calculated by multiplying consumption
frequency by the amount of total iron and the quoted percentages. Estimations
were made irrespective of the cooking method and doneness of meats since so
accurate data [71] were not available at the time of the study design.
Non-heme-iron intake was calculated subtracting heme-iron from total iron.
Animal-based iron was calculated by addition of estimations from all animal
foods; plant-based iron derived from subtracting animal-based iron from total
iron. For the present study, we estimated the non-heme component of animal
iron, by using the formula: (animal iron) – (heme-iron) [65].
For analysis
purposes, based on the original iron variables, an Animal/Plant Iron Ratio
(APIR) and a Heme/Non-Heme Ratio (H/NH) were created. To calculate energy and
daily nutrients, an analysis program was compiled: it made the sum of all
individual values, each one obtained after multiplying the number of
servings/year by the ratio nutrient content or calories of the serving/100 g of
each, divided by 365 days. Most typical or average servings of solid foods are
within the range of 100-150 g. Since iron intake showed a high correlation with
energy, we calculated an iron density expressed as daily mg of iron/1000 KCal.
STATISTICAL
ANALYSIS
Descriptive statistics, means, frequencies
and percentages were used to show the distribution of patients’ features. Most
questionnaire variables were originally continuous. They were categorized into
tertiles or quartiles or dichotomized for analysis purposes. Odds Ratios (ORs)
and 95% confidence intervals (95% CI) were calculated by unconditional logistic
regression [72]. Potential confounders were included in the multivariate
analyses. All equations included terms for age, sex, education, years of urban
residence, history of cancer in 1st-2nd degree relatives,
body mass index, smoking status and intakes of alcohol, total energy, red meat,
processed meat, total plant foods, infusions (tea, “mate”, coffee), dietary
calcium and total HCA. The best regression models included continuous and categorized
variables. Menopausal status was included for analyses in women.
Likelihood-ratio tests were performed to explore possible heterogeneities in
the stratified analyses. All calculations were done with STATA software
(Release 10, StataCorp LP, College Station, TX, 2007).
RESULTS
Table 1 shows the
distribution of general features among cases and controls. Although there was
not a perfect matching, distribution of age groups was adequate (p=0.42).
Neither urban/rural status nor residence displayed significant differences
(p=0.53 and p=0.23, respectively). Whereas “mate” intake was highly prevalent
(~86% ever consumers), tea (~19%) and coffee (~15%) were less frequently
consumed. All infusions tended to be more consumed by the control population
than by cancer cases, in spite of statistical differences. Finally, dietary
energy showed highly significant differences (p<0.001).
The mean values
of iron intake and other selected dietary items are presented in Table 2, with two comparisons, between
cases/controls and men/women. Most iron variables displayed significant
differences in both comparisons. Cases had higher intakes of animal-based and
heme-iron, while their plant and non-heme-iron intakes were lower. Regarding
comparisons by sex, men showed higher intakes in the quoted four sources, they
showed higher intake of energy, red meat and processed meat, while women had a
higher intake of white meat, vegetables and pulses.
Table 3 shows the adjusted
ORs of CRC for all iron variables, including estimates for each sex.
Considering the whole sample, none of the eight iron variables were associated
to CRC risk, neither comparing the highest vs. lowest tertile, nor the p-values
for trend for each one of the analyzed variables. A significant inverse
association was found for total dietary iron among men (OR=0.65, ptrend=0.005),
but not among women. Animal-based iron displayed inverse associations between
sexes, but both were non-significant: a positive one among men and a negative
one among women. Conversely, plant-based iron was significantly associated
reducing the risk among men (OR=0.62, ptrend=0.003), and marginally
increasing the risk among women (OR=1.56, ptrend=0.07). Heme-iron
was not associated among men, but marginally inversely associated among women
(OR=0.47, ptrend=0.06). Estimates of non-heme-iron were different:
they displayed a highly significant association among men (OR=0.60, ptrend=0.001),
but they were not significantly associated among women, tending to a risk
increase. The animal non-heme-iron did not show a risk association. Finally,
the calculated ratios displayed risk associations among men and protective
associations among women. Both estimations were significant for the latter
subset. Regarding the iron types, all likelihood ratio tests for heterogeneity
between sexes were significant.
Table 4 shows the
continuous ORs as estimates derived from stratified analysis of “mate” intake
and by sex. Considering the differences between “mate” intake (12%
non-drinkers, 88% ever drinkers), and despite the significance level, the Table
displays two different risk trends, each one for each sex in the Ever drinkers
column: while the ORs tended to a slight increase among men, they tended to a
slight, but stronger, decrease among women. Ever drinkers improved the
significance of trends compared to those presented in Table 3. Of 16 calculated trends for ever-drinkers, there are 8
significant and 3 marginally significant ones.
Table 5 displays the estimates
derived from stratified analysis of tumor site and by sex, as continuous ORs.
Regarding colon cancer, significant risk reductions were found for heme-iron,
APIR and H/NH ratio and only among women. A direct and marginally significant
association (ptrend=0.07) for plant iron was also found among women.
Rectal cancer, conversely, displayed all significant risk associations among
men: Total, plant-based and non-heme-iron was inversely associated, whereas
APIR and H/NH ratios were directly associated. Except for total iron, all
likelihood ratio tests for heterogeneity between sexes were significant for
both tumor sites.
Figure 1 displays a
graphic representation of the data shown in Table 4. Stratified by never/ever “mate” drinking, the continuous
ORs for each iron type reveals different associations for each sex. Whereas the
ORs tend to increase slightly among drinker men, the ORs tend to decrease among
drinker women. The quoted trends also reflect changes in drinkers according to
different iron types: among men, the inverse associations of plant and
non-heme-iron tend to be stronger, whereas, among women, inverse risk
associations emerge of animal and heme-iron.
Figure 2 shows a graphic
representation of the data shown in Table
5. Stratified by tumor sub-site and by sex, the continuous ORs for each
dietary iron display different associations for each sex. On one hand, the risk
associations derived from the intakes of certain iron types among women are
supported by stronger effects in the colon but not in the rectum. On the other
hand, the risk associations found among men are supported by stronger effects
in the rectum but not in colon.
DISCUSSION
Concerning the
associations between CRC risk and iron intake, we found significant
heterogeneity between sexes. Total iron, plant-based and non-heme-iron showed
inverse associations with CRC risk among men (OR=0.65, OR=0.62 and OR=0.60,
respectively for 3rd vs. 1st tertile). Heme-iron was
inversely associated among women (OR=0.47). Animal-based iron lacked risk
association, suggesting opposite trends between sexes. Regarding APIR and H/NH
ratio, both were positively associated with CRC risk among men (OR=1.77 and
OR=1.53, respectively) and inversely associated among women (OR=0.51 and
OR=0.53, respectively).
Previous findings on total
dietary iron and CRC risk are inconsistent and controversial. Some case-control
studies showed increased risks with high intake of total iron [9,73,74], but
others did not [24,75]. Most prospective studies showed a non-significant
relationship between dietary iron and CRC incidence [76]. The controversial results
might be partially explained by the different dietary styles and their iron
intake among different populations.
Regarding stratified analysis by sex, the
present study shows some similarities with a recent case-control study [24]:
they found positive associations of heme-iron, iron from meat and iron from red
meat and CRC risk among males but not in females. A straightforward explanation
for the inverse associations we found between heme-iron and CRC risk among
women is hard to find, since heme, but not non-heme-iron, is responsible for
intestinal N-nitrosation arising from red meat [77]. The dietary patterns of
each sex, usually featured by higher meat/lower vegetable intakes among men
compared to women, were recognized as different [78]. According to these
authors, different combinations of food groups or nutrients might have also
different effects on health outcomes.
Concerning red meat, a recent Uruguayan
study showed elevated risks among men, but not among women [14]. Those
differences by sex resulted in a significant heterogeneity. Heme-iron could
partially explain the differences found in the former study [16]. As women need
more iron due to menstrual losses, and heme-iron is more easily absorbed than
non-heme-iron, more iron from heme is absorbed in women, and less heme is
available during lifetime up to menopause to form cytotoxic factors in the
colorectum [16]. Non-heme-iron can react with dissolved oxygen or with
peroxides to give Reactive Oxygen Species (ROS) [79]. Besides, a possible role
for zinc could be considered. Because zinc and heme-iron food sources are
similar (e.g. meats), combined effects of prooxidant iron and antioxidant zinc
may attenuate associations between cancer and consumption of those foods [15].
Iron probably exerts different effects on different cancer sites and in women,
among whom iron-induced carcinogenesis likely involves a complex interplay with
reproductive/hormonal factors [80,81].
As most dietary iron is excreted rather than
absorbed, the human colon contains large amounts of iron, however,
non-heme-iron might prevail as the remaining iron in women’s colorectum.
Despite a higher presence of chlorophyll as an iron chelator in several foods
containing non-heme-iron, increasing dietary iron was experimentally shown to
increase the number of colonic free radicals, the amount of subsequent lipid
peroxidation, and the number of aberrant crypt foci recognized as a
pre-malignant change [82]. Dietary chlorophylls might act as interceptor
molecules of food-borne carcinogens and mutagens [83]. Several epidemiological
studies have demonstrated that a magnesium-rich diet, including dark green
leafy vegetables (rich in chlorophyll), may reduce the colon cancer occurrence
[84]. Magnesium deficiency has therefore been proposed as a risk factor for
some human cancers.
Recently, heme-iron intake was positively
associated with CRC and colon adenoma risk in a prospective cohort study
[18,19]. Heme-iron from meat plays a role promoting experimental CRC,
associated with enhanced luminal lipoperoxidation and leading to the subsequent
formation of α-β-unsaturated aldehydes
(alkenals), such as 4-hydroxynonenal (HNE) from Ω-6 fatty acids [85,86]. A
defective mucosal barrier in response to heme exposure, facilitates access to
the mucosa for both deleterious luminal heme-induced compounds and
opportunistic pathogens, able to promote changes in permeability [87,88],
inflammation [89] and genotoxicity [90,91], which are correlated with luminal
heme and lipoperoxidation markers and closely associated with a shift in the
gut microbiome [92]. Limiting heme-iron bioavailability can prevent these
changes [93]. Trapping of luminal heme-induced aldehydes normalized cellular
genotoxicity, permeability and ROS formation [59,94,95]. HNE from heme-induced
lipoperoxidation selects adenomatous polyposis coli (Apc, a frequently mutated
gene in colorectal carcinogenesis)-mutated cells and enhances cancer promotion
[96]. The reduction of gut microbiota by antibiotics, preventing a heme-induced
lipoperoxidation, suggests a role of the microbiota in the heme-induced
formation of aldehydes [97].
Nitrites are harmful because they: a) allow
an endogenous intestinal nitrosation; b) can react with hemoglobin and
myoglobin to form N-nitroso compounds, and; c) can nitrosylate heme-iron.
Cooking red meat causes the release from myoglobin of nitrosyl heme, formed by
nitrites, with the production of free nitrosyl-heme [20]. Free nitrosyl-heme
from processed meat can be more toxic than native heme (presented as
hemoprotein) from fresh meat because the former has a greater ability to induce
nitrosamine synthesis and to increase the formation of mucin depleted foci
(MDF, precancerous lesions with defective mucus production) [98]. MDF may
explain why processed meat is associated with a higher CRC risk than is fresh
red meat.
In addition to an elevated breast cancer
risk, nuns were also more likely to develop colon cancer, suggesting that
lifetime exposure to high endogenous estrogens levels may lead to a greater CRC
incidence [99]. Recent research found reported that reproductive factors- all
surrogate markers for lifetime estrogen exposure- are linked with colorectal
tumorigenesis, suggesting that a greater lifetime endogenous estrogen exposure
may increase CRC risk in postmenopausal women. [100] Aromatase activity was
reported in human colon epithelial and carcinoma tissue (in several cell lines)
[101,102]. Newer results also suggested that aromatase was frequently
overexpressed in human colon adenocarcinoma [39]. These authors consider that
circulating testosterone is reasonably postulated as a major precursor
substrate of local estradiol production by aromatase in colon carcinoma. Since
heme-iron is a component of the aromatase complex, iron overload may enhance
estrogen synthesis [103].
Experimental models indicate genomic actions
mediated by ER-estrogen binding. During development, part of CRC shifts towards
an increasingly estrogenic genotype by down- or up-regulating specific steroid
enzymes. Estrogen signaling has an anti-tumorigenic role in the colonic mucosa,
through selective activation of pro-apoptotic signaling mediated by ERβ, inhibition of inflammatory signals and modulation
of the tumor microenvironment and different immune surveillance mechanisms
[34]. Indeed, ERβ (the most abundant colonic ER), was identified as a tumor suppressor in
CRC and selectively lost its expression by methylation-dependent gene silencing
during tumor progression [31,37]. This absence of ERβ expression is associated with
disrupted tight-junction formation and abnormal colonic architecture.
Large doses of exogenous estrogens reduced
the hepatic insulin and IGF-1 production, probably attenuating their
cancer-promoting effects [104]. HRT in women was protective of the CRC risk
[37]. Although initially protective, exogenous estrogens augment the growth
once CRC has developed. ERβ functions as a dominant regulator when both receptors are co-expressed
and promotes apoptotic and anti-proliferative effects [62]. These authors
suggested that the estrogen anti-secretory effect is gender-specific. A
selective ERα antagonism
decreases inflammation in
cancer cells, inhibits proliferation and promotes apoptosis in human CRC cells
[105]. According to the literature, inhibition of ERα enhancement of ERβ activity seems logical to be
taken into account for CRC [106,107]. ERβ mRNA levels were reduced in
animal and human studies models of colitis, supporting a protective effect of
ERβ [108] and
suggesting that the regulation of colonic epithelial permeability might be ERβ-mediated. Other researchers
found that ERβ levels were
significantly
reduced in CRC of men (p<0.001) and women (p<0.04) compared with normal
colonic mucosa; this reduction in ERβ level was greater in men vs. women (p<0.04) [109]. Also, hepcidin levels
are lower in women than in men, and premenopausal women have lower serum
hepcidin concentrations than postmenopausal ones [61]. While the observation of
higher CRC incidence rates among men than women suggested that estrogen and/or
progesterone may protect against CRC, the evidence remains inconclusive [32].
Polycyclic Aromatic Hydrocarbons (PAHs) are
environmental contaminants because of their toxic, carcinogenic and putative
estrogenic or anti-estrogenic properties in the human body. Human exposure to
PAHs mainly occurs through oral uptake of charcoal-broiled, grilled and smoked
meats [110] and through ingestion of poorly cleaned vegetables. Several PAH
metabolites structurally resemble steroidal hormones that bind the human ERs.
Human intestinal microbiota can also bioactivate PAHs, tending to estrogenic
metabolites. Whereas colon digests of PAH compounds displayed estrogenicity,
stomach and small intestine digestions of benzo(a)pyrene showed no estrogenic
effects [111]. In our opinion, women might have an enhanced transformation of
PAH (mainly derived from meat) to the estrogen biosynthesis, compared to men.
Those estrogens could bind preferentially to ERβ.
Intestinal microbiota genes sets can produce
estrogen-metabolizing enzymes [112,113]. The gut microbiota deconjugates
estrogens into their active forms, through β-glucuronidase secretion,
increasing their intestinal reabsorption and enabling them to bind to ERs
[114,115]. A diminished deconjugation due to dysbiosis results in reduced
circulating estrogens. Besides, the gut microbiome is influenced by estrogens, which
modulate inflammatory
pathways and decrease the concentration of pathogenic bacteria [116,117]. Male
and female microbiota respond differently to diet: the latter may be more
susceptible to dietary manipulation [118,119].
The gut microbiota composition is
susceptible to the quality and quantity of ingested carbohydrates [120]. A
western diet (high in meat, fat and sugar) can cause dysbiosis by increasing
certain strains and decreasing others as Bifidobacteria. Conversely,
vegetarians and individuals consuming a high proportion of fruits and
vegetables and a low proportion of meat increase the Prevotella. Nevertheless,
supplementary iron induced decreased levels of Bifidobacteriaceae and Lactobacillaceae,
while it caused higher levels of Prevotella [93]. A vegetarian dietary style,
therefore, could partially influence the gut microbiota similar to
supplementary iron does. Although our results in women subset could be linked
to these facts, the picture is complex.
Most polyphenols found in antioxidant-rich
plant foods also may chelate iron. Observations suggest that when subjects have
a regular diet low in plant-based foods, pro-carcinogenic compounds of “mate”
infusion could overcome its potential antioxidant compounds. Other “mate”
components, as ferrozine and chlorogenic acid, can also contribute with
chelation [53,54]. Recent research on healthy subjects receiving ferrous
sulfate showed that “mate” infusion reduced ~76% its absorption [52].
Coffee components as caffeic acid,
chlorogenic acid and tocotrienols have a preferential binding to ERβ, which has
anti-proliferative action [121-123]. Also, caffeine reduces the ERα expression,
possibly explaining an inverse association of coffee intake and CRC found only
among men [56]. Dietary iron might be also influenced by the infusion.
Colorectal adenoma recurrence has been inversely associated with iron intake,
but there was very low meat intake in the study population and iron intake was
highly correlated with dietary fiber, which may explain the inverse association
[124]. That study suggested potential benefits if dietary iron is derived from
plants as opposed to meat, or perhaps the benefit is purely supported on the
absorption decrease caused by fiber.
Data in Figure
1 suggest different risk associations for each sex. The ORs increase
slightly among drinker men but decrease among drinker women. Nevertheless, the
quoted trends also reflect different effects of “mate” drinking according to
different iron types: the inverse associations of plant and non-heme-iron tend
to be stronger among men, whereas among women emerge inverse associations of
animal and heme-iron. The differential effects of the infusion on CRC risk in
each sex add complexity to the global picture, probably linked to the
antioxidant, anti-estrogenic and iron-chelating properties of “mate”.
Given the different meat, plants, and iron intakes reported by each sex, the scenario appears advantageous for women, despite their lesser “mate” intake compared to men. A CRC risk reduction for heme-iron among women remains only in their “mate” drinker’s subset. Also, the inverse association with heme-iron is slightly stronger than animal iron’s, which reflects the associations seen with non-heme-iron. Therefore, the antioxidant capabilities of the infusion could be highlighted in front of iron intake.
Our work shares some limitations and
strengths, as other case-control studies. Among the limitations, we recognize
the lack of validation of the questionnaire, although the instrument was tested
for reproducibility and showed high correlations [67]. The validation was
projected to be done but was never performed due to budgetary cuts in
2002-reflecting a severe national economy crisis-. Epidemiologic research on
cancer in Uruguay continued with the remaining databases-like the one used for
the present study-, without additional funds.
Another limitation was related to iron intake
estimations: while based on average serving sizes but not on actual food sizes,
they might not be highly accurate. Recall bias could be a problem in the
present study, by leading to misclassification. We cannot exclude neither the
possibility of confounding by unmeasured factors like physical activity,
closely related to the CRC risk nor the possibility of confounding by dietary
factors, such as other constituents of animal foods or the effects of cooking
methods, which can influence the contents of iron types. The total iron
concentration increases with cooking and with the doneness level heme-iron is
degraded at higher temperatures, however, different results have been reported
[71]. The present study did not ask iron from supplements, therefore it was not
part of the exposure.
As the strengths of the study, the analyzed
population included subsets coming from the whole country, and times of data
collection were coincident. The age distribution was adequate; distribution by
urban/rural status and country region gave homogeneity to the sample. The
potential for selection bias does exist, as in any case-control study, but it
is unlikely to have substantially affected our results due to the high
participation achieved (~97%). Since the data collection was performed before
2005, no effect from wheat flour fortification with ferrous sulfate (legally
established in 2005 in 30 mg/kg of flour) is expected in our study. Although it
is unlikely to completely avoid any kind of bias, we think that the results of
the present study were not chance findings.
CONCLUSION
In conclusion, our study shows certain
associations between dietary iron and CRC risk. This applies for total iron and
also for heme and non-heme subtypes, suggesting different, even opposite,
effects for each sex. Further epidemiologic and mechanistic research is needed
to disentangle complex nutritional and biochemical interrelationships linked to
the disease.
ETHICS
APPROVAL
The study was conducted after receiving the
approval of each Medical Director of the participant hospitals, following an
ethical approval from each institution. For this type of studies and during the
years when interviews were performed, patients have not given an informed
consent, since it was not mandatory for interviewers to request it. The study
was always accepted under the obvious condition of confidentiality for
individual data assured for the interviews.
CONFLICT OF
INTEREST
The authors declare no conflict of interest.
1.
Registro Nacional de Cáncer de Uruguay Situacion
epidemiologica del Uruguay en relacion al cancer. Incidencia del cancer en
2011-2015 y tendencia de la mortalidad por cancer 1990-2017. In: http://www.comisioncancer.org.uy/uc_513_1.html
2.
Bray F, Ferlay F, Soerjomataram I, Siegel RL, Torre LA,
et al. (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence
and mortality worldwide for 36 cancers in 185 countries. CA Cancer Clin 68:
394-424.
3.
Gunter MJ, Alhomoud S, Arnold M, Brenner H, Burn J, et
al. (2019) Meeting report from the joint IARC-NCI international cancer seminar
series: A focus on colorectal cancer. Ann Oncol 30: 510-519.
4.
Bouvard V, Loomis D, Guyton KZ, Grosse Y, El Ghissassi F,
et al. (2015) Carcinogenicity of consumption of red and processed meat. Lancet
Oncol 16: 1599-1600.
5.
World Cancer Research Fund/American Institute for Cancer
Research (2007) Food, nutrition, physical activity and the prevention of
cancer: A global perspective Washington DC: AICR.
6.
Fonseca-Nunes A, Jakszyn P, Agudo A (2014) Iron and
cancer risk - A systematic review and meta-analysis of the epidemiological
evidence. Cancer Epidemiol Biomark Prev 23: 12-31.
7.
http://www.fao.org/faostat/en/#data/CL
8.
De Stefani E, Deneo-Pellegrini H, Mendilaharsu M, Ronco
AL (1997) Meat intake, heterocyclic amines and risk of colorectal cancer: A
case-control study in Uruguay. Int J Oncol 10: 573-580.
9.
Deneo-Pellegrini H, De Stefani E, Boffetta P, Ronco A,
Mendilaharsu M (1999) Dietary iron and cancer or the rectum: A case-control
study in Uruguay. Eur J Cancer Prev 8: 501-508.
10.
Deneo-Pellegrini H, Boffetta P, De Stefani E, Ronco AL,
Correa P, et al. (2005) Meat consumption and risk of colorectal cancer: A
case-control study in Uruguay. Cancer Ther 2005: 193-200.
11.
De Stefani E, Deneo-Pellegrini H, Ronco AL, Correa P,
Boffetta P, et al. (2011) Dietary patterns and risk of colorectal cancer: A
factor analysis in Uruguay. Asian Pac J Cancer Prev 12: 753-759.
12.
De Stefani E, Ronco AL, Boffetta P, Deneo-Pellegrini H,
Correa P, et al. (2012) Nutrient-derived dietary patterns and risk of
colorectal cancer: A factor analysis in Uruguay. Asian Pac J Cancer Prev 13:
231-235.
13.
De Stefani E, Boffetta P, Ronco AL, Deneo-Pellegrini H,
Correa P, et al. (2012) Processed meat consumption and risk of cancer: A
multisite case-control study in Uruguay. Br J Cancer 107: 1584-1588.
14.
De Stefani E, Boffetta P, Ronco AL, Deneo-Pellegrini H,
Mendilaharsu M, et al. (2016) Meat consumption and risk of colorectal cancer: A
case-control study in Uruguay emphasizing the role of gender. Cancer Res Oncol
2: CROOA-2-015.
15.
Lee DH, Anderson KE, Harnack LJ, Folsom AR, Jacobs DR
(2004) Heme iron, zinc, alcohol consumption and colon cancer: Iowa Women's
Health Study. J Natl Cancer Inst 96: 403-407.
16.
Balder HF, de Vogel J, Jansen MCJ, Weijenberg MP, van den
Brandt PA, et al. (2006) Heme and chlorophyll intake and risk of colorectal
cancer in the Netherlands Cohort Study. Cancer Epidemiol Biomarkers Prev 15:
717-725.
17.
Bastide NM, Pierre FH, Corpet DE (2011) Heme iron from
meat and risk of colorectal cancer: A meta-analysis and a review of the
mechanisms involved. Cancer Prev Res (Phila) 4: 177-184.
18.
Bastide NM, Chenni F, Audebert M, Santarelli RL, Taché S,
et al. (2015) A central role for heme iron in colon carcinogenesis associated
with red meat intake. Cancer Res 75: 870-879.
19.
Bastide N, Morois S, Cadeau C, Kangas S, Serafini M, et
al. (2016) Heme iron intake, dietary antioxidant capacity and risk of colorectal
adenomas in a large cohort study of French women. Cancer Epidemiol Biomarkers
Prev 25: 640-647.
20.
Sasso A, Latella G (2018) Role of heme iron in the
association between red meat consumption and colorectal cancer. Nutr Cancer 70:
1173-1183.
21.
Yilmaz B, Li H (2018) Gut microbiota and iron: the
crucial actors in health and disease. Pharmaceuticals 11: 98.
22.
Buret AG, Motta JP, Allain T, Ferraz J, Lawrence J (2019)
Pathobiont release from dysbiotic gut microbiota biofilms in intestinal
inflammatory diseases: A role for iron? J Biomed Sci 26: 1.
23.
Ashmore JH, Rogers CJ, Kelleher SL, Lesko SM, Hartman TJ
(2016) Dietary iron and colorectal cancer risk: A review of human population
studies. Crit Rev Food Sci Nutr 56: 1012-1020.
24.
Luo H, Zhang NQ, Huang J, Zhang X, Feng XL, et al. (2019)
Dietary intakes of different forms and sources of iron and colorectal cancer
risk: A case-control study in China. Br J Nutr 121: 735-747.
25.
Hooda J, Shah A, Zhang L (2014) Heme, an essential
nutrient from dietary proteins, critically impacts diverse physiological and
pathological processes. Nutrients 6: 1080-1102.
26.
Wallace DF (2016) The regulation of iron absorption and
homeostasis. Clin Biochem Rev 37: 51-62.
27.
Manz DH, Blanchette NL, Paul BT, Torti FM, Torti SV
(2016) Iron and cancer: Recent insights. Ann N Y Acad Sci 1368: 149-161.
28.
Coffey R, Ganz T (2017) Iron homeostasis-an
anthropocentric perspective. J Biol Chem 292: 12727-12734.
29.
Neves J, Haider T, Gassmann M, Muckenthaler MU (2019)
Iron homeostasis in the lungs - A balance between health and disease.
Pharmaceuticals 12: 5.
30.
Wen CP, Lee JH, Tai YP, Wen C, Wu SB, et al. (2014) High
serum iron is associated with increased cancer risk. Cancer Res 74: 6589-6597.
31.
O’Mahony F, Thomas W, Harvey BJ (2009) Novel female
sex-dependent actions of estrogen in the intestine. J Physiol 587: 5039-5044.
32.
Keum NN, Giovannucci EL (2017) Epidemiology of colorectal
cancer. In: Loda M, et al. (eds.), Pathology and Epidemiology of Cancer ©
Springer International Publishing Switzerland, Chapter 21, pp: 391-407.
33.
Cho NL, Javid SH, Carothers AM, Redston M, Bertagnolli MM
(2007) Estrogen receptors α and β are inhibitory modifiers of Apc-dependent
tumorigenesis in the proximal colon of Min/+ mice. Cancer Res 67: 2366-2372.
34.
Caiazza F, Ryan EJ, Doherty G, Winter DC, Sheahan K
(2015) Estrogen receptors and their implications in colorectal carcinogenesis.
Front Oncol 5: 19.
35.
Niv Y (2015) Estrogen receptor β expression and
colorectal cancer: A systematic review and meta-analysis. Eur J Gastroenterol
Hepatol 27: 1438-1442.
36.
Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, Hubbell
FA, Ascensao J, et al. (2004) Estrogen plus progestin and colorectal cancer in
postmenopausal women. N Engl J Med 350: 991-1004.
37.
Foster PA (2013) Estrogen and colorectal cancer:
Mechanisms and controversies. Int J Colorectal Dis 28: 737-749.
38.
Foley EF, Jazaeri AA, Shupnik MA, Jazaeri O, Rice LW
(2000) Selective loss of estrogen receptor β in malignant human colon. Cancer
Res 60: 245-248.
39.
Sato R, Suzuki T, Katayose Y, Miura K, Shiiba K, et al.
(2012) Aromatase in colon carcinoma. Anticancer Res 32: 3069-3076.
40.
Comision Honoraria de Lucha Contra el Cancer (1993)
Knowledge, believes, attitudes and practices related to cancer: population
survey. Technical co-operation PNUD/BID. Comision Honoraria de Lucha Contra el
Cancer, Montevideo, Uruguay (in Spanish).
41.
International Agency for Research on Cancer (1991)
Coffee, tea, mate, methylxanthines and methylglyoxal: IARC Monogr Eval Carcinog
Risks Hum 51: 273-287.
42.
Kamangar F, Schantz MM, Abnet CC, Fagundes RB, Dawsey SM
(2008) High levels of carcinogenic polycyclic aromatic hydrocarbons in mate
drinks. Cancer Epidemiol Biomarkers Prev 17: 1262-1268.
43.
Thea AE, Ferreira D, Brumovsky LA, Schmalko ME (2016)
Polycyclic aromatic hydrocarbons (PAHs) in yerba mate (Ilex paraguariensis St. Hil) traditional infusions (mate and
terere). Food Control 60: 215-220.
44.
De Mejia EG, Song YS, Heck CI, Ramirez-Mares MV (2010)
Yerba mate tea (Ilex paraguariensis):
Phenolics, antioxidant capacity and in vitro inhibition of colon cancer cell
proliferation. J Funct Foods 2: 23-34.
45.
Zapaterini JR, Bidinotto LT, Rodrigues MAM, Barbisan LF
(2010) Chemopreventive effects of mate against mouse mammary and colon
carcinogenesis. Hum Exp Toxicol 29: 175-185.
46.
Puangpraphant S, Berhow MA, Gonzalez de Mejia E (2011)
Mate (Ilex paraguariensis St.
Hilaire) saponins induce caspase-3-dependent apoptosis in human colon cancer
cells in vitro. Food Chem 125: 1171-1178.
47.
Gnoatto SCB, Dassonville-Klimpt A, Da Nascimento S,
Galéra P, Boumediene K, et al. (2008) Evaluation of ursolic acid isolated from Ilex paraguariensis and derivatives on
aromatase inhibition. Eur J Med Chem 43: 1865-1877.
48.
Kashyap D, Tuli HS, Sharma AK (2016) Ursolic acid (UA): A
metabolite with promising therapeutic potential. Life Sci 146: 201-213.
49.
Limami Y, Pinon A, Leger DY, Mousseau Y, Cook-Moreau J,
et al. (2011) HT-29 colorectal cancer cells undergoing apoptosis over express
COX-2 to delay ursolic acid-induced cell death. Biochimie 93: 749-757.
50.
Way TD, Lee HH, Kao MC, Lin JK (2004) Black tea
polyphenol theaflavins inhibit aromatase activity and attenuate tamoxifen
resistance in HER2/neu-transfected human breast cancer cells through tyrosine
kinase suppression. Eur J Cancer 40: 2165-2174.
51.
Kim HI, Quan FS, Kim JE, Lee NR, Kim HJ, et al. (2014)
Inhibition of estrogen signaling through depletion of estrogen receptor alpha
by ursolic acid and betulinic acid from Prunella
vulgaris var. lilacina. Biochem
Biophys Res Commun 451: 282-287.
52.
Colpo AC, Rosa H, Lima ME, Pazzini CE, de Camargo VB, et
al. (2016) Yerba mate (Ilex
paraguariensis St. Hill.)-based beverages: How successive extraction
influences the extract composition and its capacity to chelate iron and
scavenge free radicals? Food Chem 209: 185-195.
53.
Huang WY, Lee PC, Hsu JC, Lin YR, Chen HJ, et al. (2014)
Effects of water quality on dissolution of yerba mate extract powders. Sci
World J 768742.
54.
Salkic A, Zeljkovic SC (2015) Preliminary investigation
of bioactivity of green tea (Camellia
sinensis), rooibos (Asphalatus
linearis) and yerba mate (Ilex
paraguariensis). J Herbs Spices Med Plants 21: 259-266.
55.
Rempe CS (2016) Metabolomics approaches to decipher the
antibacterial mechanisms of yerba mate (Ilex
paraguariensis) against Staphylococcus
aureus and Salmonella enterica serovar
typhimurium. PhD diss., University of
Tennessee. Available at: http://trace.tennessee.edu/utk_graddiss/3957
56.
Ronco AL, De Stefani E, Lasalvia-Galante E, Mendoza B, Vázquez
A, et al. (2017) Hot infusions and risk of colorectal cancer in Uruguay: A
case-control study. Eur J Clin Nutr 71: 1429-1436.
57.
Murphy N, Moreno V, Hughes DJ, Vodicka L, Vodicka P, et
al. (2019) Lifestyle and dietary environmental factors in colorectal cancer
susceptibility. Mol Aspects Med pii: S0098-2997(19)30033-0.
58.
Vieira AR, Abar L, Chan DSM, Vingeliene E, Polemitti E,
et al. (2017) Foods and beverages and colorectal cancer risk: A systematic
review and meta-analysis of cohort studies, an update of the evidence of the
WCRF-AICR Continuous Update Project. Ann Oncol 28: 1788-1802.
59.
Martin OCB, Olier M, Ellero-Simatos S, Naud N, Dupuy J,
et al. (2019) Heme-iron reshapes colonic luminal environment: Impact on mucosal
homeostasis and microbiome through aldehyde formation. Microbiome 7: 72.
60.
Hou Y, Zhang S, Wang L, Li J, Qu G, et al. (2012)
Estrogen regulates iron homeostasis through governing hepatic hepcidin
expression via an estrogen response element. Gene 511: 398-403.
61.
Ikeda Y, Tajima S, Izawa-Ishizawa Y, Kihira Y, Ishizawa
K, et al. (2012) Estrogen regulates hepcidin expression via
GPR30-BMP6-dependent signaling in hepatocytes. PloS One 7: e40465.
62.
Haziman AA, Ravinderan S, Thangavelu T, Thomas W (2019) A
novel role for estrogen-induced signaling in the colorectal cancer gender bias.
Ir J Med Sci 188: 389-395.
63.
Ashmore JH, Lesko SM, Miller PE, Cross AJ, Muscat JE, et
al. (2013) Association of dietary and supplemental iron and colorectal cancer
in a population-based study. Eur J Cancer Prev 22: 506-511
64.
Ronco AL, Calderon JM, Espinosa E (2017) Dietary iron,
‘mate’ intake and breast cancer risk: A case-control study in Uruguay. J Breast
Cancer Res Adv 1.
65.
Ronco AL, Espinosa E, Calderon JM (2018) A case-control
study on heme/non-heme iron and breast cancer risk. Ann Clin Nutr 3: 1011.
66.
Ronco AL, Lasalvia-Galante E, Calderon JM, Espinosa E
(2019) Dietary iron source and lung cancer risk: A case-control study in
Uruguayan men. Multidiscip Cancer Invest 3: 20-36.
67.
Ronco AL, De Stefani E, Boffetta P, Deneo-Pellegrini H,
Acosta G, et al. (2006) Food patterns and risk of breast cancer: A factor
analysis study in Uruguay. Int J Cancer 119: 1672-1678.
68.
Mazzei ME, Puchulu MR, Rochaix MA (1995) Table of food
chemical composition. Cenexa y Feiden Publishers, 2nd Edn., Buenos
Aires (in Spanish).
69.
Kabat GC, Miller AB, Jain M, Rohan TE (2007) A cohort
study of dietary iron and heme iron intake and risk of colorectal cancer in
women. Br J Cancer 97: 118-122.
70.
Zhang W, Iso H, Ohira T, Date OC, Tanabe N, et al. (2012)
Associations of dietary iron intake with mortality from cardiovascular disease:
The JACC study. J Epidemiol 22: 484-493.
71.
Cross AJ, Harnly JM, Ferrucci LM, Risch A, Mayne ST, et
al. (2012) Developing a heme iron database for meats according to meat type,
cooking method and doneness level. Food Nutr Sci 3: 905-913.
72.
Breslow NE, Day NE (1980) Statistical methods in cancer
research: The analysis of case-control studies. IARC Sci Publ 1: 5-338.
73.
Levi F, Pasche C, Lucchini F, La Vecchia C (2000)
Selected micronutrients and colorectal cancer. A case-control study from the
canton of Vaud, Switzerland. Eur J Cancer 36: 2115-2119.
74.
Senesse P, Meance S, Cottet V, Faivre J, Boutron-Ruault
MC (2004) High dietary iron and copper and risk of colorectal cancer: A
case-control study in Burgundy, France. Nutr Cancer 49: 66-71.
75.
Van Lee L, Heyworth J, McNaughton S, Iacopetta B,
Clayforth C, et al. (2011) Selected dietary micronutrients and the risk of
right- and left-sided colorectal cancers: A case-control study in Western
Australia. Ann Epidemiol 21: 170-177.
76.
Key TJ, Appleby PN, Masset G, Brunner EJ, Cade JE, et al.
(2012) Vitamins, minerals, essential fatty acids and colorectal cancer risk in
the United Kingdom dietary cohort consortium. Int J Cancer 131: E320-325.
77.
Cross AJ, Pollock JR, Bingham SA (2003) Heme, not protein
or inorganic iron, is responsible for endogenous intestinal N-nitrosation
arising from red meat. Cancer Res 63: 2358-2360.
78.
Northstone K (2012) Dietary patterns: The importance of
sex differences. Br J Nutr 108: 393-394.
79.
Bechaux J, De la Pomélie D, Théron L, Santé-Lhoutellier
V, Gatellier P (2018) Iron-catalysed chemistry in the gastrointestinal tract:
Mechanisms, kinetics and consequences. A review. Food Chem 268: 27-39.
80.
Kabat GC, Rohan TE (2007) Does excess iron play a role in
breast carcinogenesis? An unresolved hypothesis. Cancer Causes Control 18:
1047-1053.
81.
Miller EM (2014) Iron status and reproduction in US
women: National Health and Nutrition Examination Survey, 1999-2006. PLoS One 9:
e112216.
82.
Roe T (2015) The role of iron and heme in breast cancer.
Doctoral thesis, School of Cancer Sciences, Univ. of Birmingham. Available at: https://etheses.bham.ac.uk/id/eprint/6233/1/Roe15MD.pdf
83.
Dashwood R, Yamane S, Larsen R (1996) Study of the forces
stabilizing complexes between chlorophylls and heterocyclic amine mutagens.
Environ Mol Mutag 27: 211-218.
84.
Blaszczyk U, Duda-Chodak A (2013) Magnesium: Its role in
nutrition and carcinogenesis. Rocz Panstw Zakl Hig 64: 165-171.
85.
Wang Y, Zhu M, Mei J, Luo S, Leng T, et al. (2019)
Comparison of furans formation and volatile aldehydes profiles of four
different vegetable oils during thermal oxidation. J Food Sci 84: 1966-1978.
86.
Guillen MD, Uriarte PS (2012) Aldehydes contained in
edible oils of a very different nature after prolonged heating at frying
temperature: Presence of toxic oxygenated α, β unsaturated aldehydes. Food Chem
131: 915-926.
87.
Hansen SL, Ashwell MS, Moeser AJ, Fry RS, Knutson MD, et
al. (2010) High dietary iron reduces transporters involved in iron and
manganese metabolism and increases intestinal permeability in calves. J Dairy
Sci 93: 656-665.
88.
Cindric M, Cipak A, Zapletal E, Jaganjac M, Milkovic L,
et al. (2013) Stobadine attenuates impairment of an intestinal barrier model
caused by 4-hydroxynonenal. Toxicol Vitr 27: 426-432.
89.
Lee SE, Park YS (2013) Role of lipid peroxidation-derived
α, β-unsaturated aldehydes in vascular dysfunction. Oxid Med Cell Longev
629028.
90.
Glei M, Klenow S, Sauer J, Wegewitz U, Richter K, et al.
(2006) Hemoglobin and hemin induce DNA damage in human colon tumor cells HT29
clone 19A and in primary human colonocytes. Mutat Res 594: 162-171.
91.
Knoll N, Ruhe C, Veeriah S, Sauer J, Glei M, et al.
(2005) Genotoxicity of 4-hydroxy-2-nonenal in human colon tumor cells is
associated with cellular levels of glutathione and the modulation of
glutathione S-transferase A4 expression by butyrate. Toxicol Sci 86: 27-35.
92.
Fang S, Zhuo Z, Yu X, Wang H, Feng J (2018) Oral
administration of liquid iron preparation containing excess iron induces
intestine and liver injury, impairs intestinal barrier function and alters the
gut microbiota in rats. J Trace Elem Med Biol 47: 12-20.
93.
Kortman GAM, Dutilh BE, Maathuis AJH, Engelke UF,
Boekhorst J, et al. (2016) Microbial metabolism shifts towards an adverse
profile with supplementary iron in the TIM-2 in vitro model of the human colon.
Front Microbiol 6: 1481.
94.
Pierre F, Tache S, Petit CR, Van der Meer R, Corpet DE
(2003) Meat and cancer: Hemoglobin and hemin in a low-calcium diet promote
colorectal carcinogenesis at the aberrant crypt stage in rats. Carcinogenesis
24: 1683-1690.
95.
Pierre FHF, Martin OCB, Santarelli RL, Taché S, Naud N,
et al. (2013) Calcium and α-tocopherol suppress cured-meat promotion of
chemically induced colon carcinogenesis in rats and reduce associated
biomarkers in human volunteers. Am J Clin Nutr 98: 1255-1262.
96.
Pierre F, Tache S, Guéraud F, Rerole AL, Jourdan MLL, et
al. (2007) Apc mutation induces resistance of colonic cells to
lipoperoxide-triggered apoptosis induced by fecal water from heme-fed rats.
Carcinogenesis 28: 321-327.
97.
Martin OCB, Lin C, Naud N, Tache S, Raymond-Letron I, et
al. (2015) Antibiotic suppression of intestinal microbiota reduces heme-induced
lipoperoxidation associated with colon carcinogenesis in rats. Nutr Cancer 67:
119-125.
98.
Pierre FH, Santarelli RL, Allam O, Tache S, Naud N, et
al. (2010) Freeze-dried ham promotes azoxymethane-induced mucin-depleted foci
and aberrant crypt foci in rat colon. Nutr Cancer 62: 567-573.
99.
Fraumeni JF Jr, Lloyd JW, Smith EM, Wagoner JK (1969)
Cancer mortality among nuns: Role of marital status in etiology of neoplastic
disease in women. J Natl Cancer Inst 42: 455-468.
100.Zervoudakis A, Strickler
HD, Park Y, Xue X, Hollenbeck A, et al. (2011) Reproductive history and risk of
colorectal cancer in post-menopausal women. J Natl Cancer Inst 103: 826-834.
101.English MA, Kane KF,
Cruickshank N, Langman MJ, Stewart PM, et al. (1999) Loss of estrogen
inactivation in colonic cancer. J Clin Endocrinol Metab 84: 2080-2085.
102.Fiorelli G, Picariello
L, Martineti V, Tonelli F, Brandi ML (1999) Estrogen synthesis in human colon
cancer epithelial cells. J Steroid Biochem Mol Biol 71: 223-230.
103.Gantt SL, Denisov IG,
Grinkova YV, Sligar SG (2009) The critical iron-oxygen intermediate in human
aromatase. Biochem Biophys Res Commun 387: 169-173.
104.Gunter MJ, Hoover DR, Yu
H, Wassertheil-Smoller S, Rohan TE, et al. (2008) Insulin, insulin-like growth
factor-I, endogenous estradiol and risk of colorectal cancer in post-menopausal
women. Cancer Res 68: 329-337.
105.Fan W, Gao X, Ding C, Lv
Y, Shen T, et al. (2019) Estrogen receptors participate in carcinogenesis
signaling pathways by directly regulating NOD-like receptors. Biochem Biophys
Res Comm 511: 468-475.
106.Williams C, Dileo A, Niv
Y, Gustaffson JA (2016) Estrogen receptor beta as target for colorectal cancer
prevention. Cancer Lett 372: 48-56.
107.Saleiro D, Murillo G,
Benya RV, Bissonnette M, Hart J, et al. (2012) Estrogen receptor-b protects
against colitis-associated neoplasia in mice. Int J Cancer 131: 2553-2561.
108.Looijer-van Langen M,
Hotte N, Dieleman LA, Albert E, Mulder C, et al. (2011) Estrogen receptor-b
signaling modulates epithelial barrier function. Am J Physiol Gastrointest
Liver Physiol 300: G621-626.
109.Nüssler NC, Reinbacher
K, Shanny N, Schirmeier A, Glannemann M, et al. (2008) Sex-specific differences
in the expression levels of estrogen receptor subtypes in colorectal cancer.
Gender Med 5: 209-217.
110.Van Maanen JMS, Moonen
EJC, Maas LM, Kleinjans JCS, van Schooten FJ (1994) Formation of aromatic DNA
adducts in white blood cells in relation to urinary excretion of
1-hydroxypyrene during consumption of grilled meat. Carcinogenesis 15:
2263-2268.
111.Van de Wiele T,
Vanhaecke L, Boeckaert C, Peru K, Headley J, et al. (2005) Human colon
microbiota transforms polycyclic aromatic hydrocarbons to estrogenic
metabolites. Environ Health Perspect 113: 6-10.
112.Flores R, Shi J, Fuhrman
B, Xu X, Veenstra TD, et al. (2012) Fecal microbial determinants of fecal and
systemic estrogens and estrogen metabolites: A cross sectional study. J Transl
Med 10: 253.
113.Kwa M, Plottel CS,
Blaser MJ, Adams S (2016) The intestinal microbiome and estrogen
receptor-positive female breast cancer. J Natl Cancer Inst 108: djw029.
114.Plottel CS, Blaser MJ
(2011) Microbiome and malignancy. Cell Host Microb 10: 324-335.
115.Chen KL, Madak-Erdogan Z
(2016) Estrogen and microbiota cross-talk: Should we pay attention? Trends
Endocr Metab 27: 752-755.
116.Baker JM, Al-Nakkash L,
Herbst-Kralovetz MM (2017) Estrogen-gut microbiome axis: Physiological and
clinical implications. Maturitas 103: 45-53.
117.Blasco-Baque V, Serino
M, Vergnes JN, Riant E, Loubieres P, et al. (2013) High-fat diet induces
periodontitis in mice through lipopolysaccharides (LPS) receptor signaling:
Protective action of estrogens. PLoS One 7: e48220.
118.Kim YS, Unno T, Kim BY,
Park MS (2019) Sex Differences in gut microbiota. World J Mens Health 37: e15.
119.Vemuri R, Sylvia KE,
Klein SL, Forster SC, Plebanski M, et al. (2019) The microgenderome revealed:
Sex differences in bidirectional interactions between the microbiota, hormones,
immunity and disease susceptibility. Semin Immunopathol 41: 265-275.
120.Duda-Chodak A, Tarko T,
Satora P, Sroka P (2015) Interaction of dietary compounds, especially
polyphenols, with the intestinal microbiota: A review. Eur J Nutr 54: 325-341.
121.Li G, Ma D, Zhang Y,
Zheng W, Wang P (2012) Coffee consumption and risk of colorectal cancer: A
meta-analysis of observational studies. Publ Health Nutr 16: 346-357.
122.Schmit SL, Rennert HS,
Rennert G, Gruber SB (2016) Coffee consumption and the risk of colorectal
cancer. Cancer Epidemiol Biomarkers Prev 25: 634-639.
123.Kiyama R (2019)
Estrogenic activity of coffee constituents. Nutrients 11: 1401.
124.Tseng M, Sandler RS, Greenberg
ER, Mandel JS, Haile RW, et al. (1997) Dietary iron and recurrence of
colorectal adenomas. Cancer Epidemiol Biomarkers Prev 6: 1029-1032.
QUICK LINKS
- SUBMIT MANUSCRIPT
- RECOMMEND THE JOURNAL
-
SUBSCRIBE FOR ALERTS
RELATED JOURNALS
- Journal of Pathology and Toxicology Research
- International Journal of Diabetes (ISSN: 2644-3031)
- Advance Research on Alzheimers and Parkinsons Disease
- Journal of Rheumatology Research (ISSN:2641-6999)
- Journal of Infectious Diseases and Research (ISSN: 2688-6537)
- Journal of Ageing and Restorative Medicine (ISSN:2637-7403)
- Chemotherapy Research Journal (ISSN:2642-0236)