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16 Recent Patents on Food, Nutrition & Agriculture, 2014, 6, 16-22

Hypothetical Link Between Infertility and Genetically Modified Food

Mingxia Gao*, Bin Li, Wenzhen Yuan, Lihui Zhao and Xuehong Zhang

Reproductive Medicine Hospital, General Surgery Department, Oncological Surgery Department, of the First Affiliated
Hospital, Lanzhou University, Lanzhou, 730000, China

Received: July 05, 2014; Revised: August 11, 2014; Accepted: October 20, 2014

Abstract: It is speculated that genetically modified food (GMF)/genetically modified organism (GMO) is responsible for
infertility development. The risk linked with a wide use of GMFs/GMOs offers the basic elements for social criticism.
However, to date, it has not been justified whether the bad effects are directly resulted from products of genetic modifica-
tions or trans-genesis process. Extensive experience with the risk assessment of whole foods has been applied recently on
the safety and nutritional testing of GMFs/GMOs. Investigations have tested the safety of GMFs including sub-acute,
chronic, reproductive, multi-generation and carcinogenicity studies. We extrapolated the potential risks associated with
GMFs/GMOs on reproduction, and analyzed the multi-aspect linked between infertility and GMFs/GMOs. It could be
conjectured that GMFs/GMOs could be potential hazard on reproduction, linking to the development of infertility through
influencing the endocrine metabolism, endometriosis. However, little evidence shows the impaction on embryo or repro-
ductive related tumor due to the limited literatures, and needs further research. The article presents some related patents on
GMFs/GMOs, and some methods for tracking GMOs.
Keywords: Endometriosis, gamete and embryo, genetically modified food, neoplasms, trans-genesis process.

INTRODUCTION
Genetically modified food (GMF) refers to the food
whose genetic material has been modified by genetic engi-
neering techniques. GMF includes genetically modified
(GM) plants, animals and their products. The origins of ge-
netically modified organism (GMO) date back to 1973, the
pioneers used genetic engineering and marked plants are
subjected to the process of trans-genesis involved tobacco
and petunia. The modified FlavrSavr tomato plant came on
the scene in 1994, and forecasted the commercialization of
GM products. GMF includes a series of plants, and some
narrow range of animals and microbes. In parallel with these
advancements in agricultural biotechnology, a large number
of GMFs entered a worldwide trade and consumption. The
most common GM plants include soybean, maize, rice and
rape, furthermore, plants like cotton, tomatoes, potatoes,
tobacco and special animals such as cow, cattle and pigs are
dealt by the transgenic techniques. The purpose of genetic
modifications is to improve the agronomic properties such as
drought resistance, herbicide tolerance and salt tolerance, or
to enhance the nutritional properties or health benefits [1-7].
Despite the growing use and popularity of GMOs, it remains
controversial between benefits and risks associated with
GMF products, especially the potential threats to health gets
growing concern in recent years. By reason of commercial
and benefit conflict, scientists and organizations have not yet
fully exposed the potential environmental and health
*Address correspondence to this author at the Reproductive Medicine Hos-
pital of the First Affiliated Hospital, Lanzhou University, Lanzhou, 730000,
P. R. China; Tel: 86-0931-8357358; Fax: 86-0931-8357356;
E-mail: gaomx05@163.com
risks of GMOs, or have not yet done further researches about
these risks. The classical risk paradigm has been reported
includes food allergy, metabolic disturbance, tumor genesis,
genetic contamination, chronic toxic effects and develop-
ment of resistance to antibiotics [8-12]. Some evidence re-
vealed that GMF could also be linked to infertility associated
diseases, such as endometriosis, sex hormonal disorder, en-
docrine-metabolic anomaly and reproductive correlated can-
cers [13-15], each of them could be the cause of infertility.
Therefore, particular attention should be devoted to the short
and long-lasting undesirable reproductive effects.
Infertility seems to be a great worldwide problem. Clini-
cally a couple is considered to be infertile after at least one
year without contraception and without pregnancy. Epidemi-
ologic data shows that the incidence of infertility is between
8% and 22%, nearly one in five women attempting concep-
tion experienced infertility, and the prevalence is on the rise
[16-20]. The causes of infertility cover ovulatory disorders,
tubal dysfunctions, endometriosis, male reproductive dys-
function and other unexplained infertility. Ovulatory disor-
der, identified as a main reason of female infertility, take
21% to 32% among of all infertile couples, tubal dysfunc-
tions vary from 14% to 26% and 5% to 6% for endometriosis
[21-23]. Male infertility is rising year by year and reaches
half of all infertile couples [24]. The percentage of unex-
plained infertility is 8% to 30% [25]. While one-third of in-
fertile couples have both male and female contributory
causes [21, 22]. One-third to half of the couples required
treatment with IVF or ICSI [20]. Even though infertility is a
multi-related disease, plenty of medical and non-medical
conditions can attribute to it. The present study concentrates
mainly on factors associated with physical disorders, no mat-

1876-1429/14 $100.00+.00 2014 Bentham Science Publishers

Hypothetical Link Between Infertility and Genetically Modified Food
ter primary or secondary, they are all caused by the infection,
environmental toxins, cancer and autoimmune disorders
[26], but seldom on the foods, especially the GMF. With the
emergence of GMFs, the health problems accompanied are
of particular concern, it seems that GMFs may reduce the
fertility, no matter animals or humans, these potential risks
are worthy of consideration. A significant problem linked
with the effects of GMO to consumers reproduction is po-
tentially related with abnormal steroid hormones and their
receptors, toxic products or products which increase risk
of endocrine-metabolic processes.
ENDOCRINE-METABOLIC DISORDERS
The transfer of targeted genes from the cells of one or-
ganism to the cell nucleus of another organism brings new
expressed and synthesized proteins, which are short in their
parental cells. The amino acid sequence forming structure
of a given protein increases the risk of endocrine-metabolic
disorders due to exposure to GMFs. In 2002, results which
demonstrated that milk from genetically modified cows
increases the levels of Insulin-like Growth Factor-1 (IGF-1)
in consumers were published [27]. We already know that
IGF-1 factor is correlated with development of tumors in
some organs, such as lungs, breast, colon, etc. This factor is
also relevant to some endocrine-metabolic diseases, such as
polycystic ovary syndrome (PCOS). In order to find out the
health impact of trans-genic products, a group of rats fed
with various doses of NK603 modified maize was studied,
and control group was set. After two years of experiment,
the results show disturbances in the function or tumorous
development in some organs, and a higher mortality of
animals in the experimental groups, and show gender dif-
ferences, the female rats manifested an increasing sensitiv-
ity to the NK603 modified maize [15]. It was reported that
after the consumption of GM maize, the mice showed slight
but dose- related significant variations in growth for both
genders, resulting in 3.3% decrease in weight in males and
3.7% increase in females. Moreover, signs of hepatorenal
toxicity, marked also by sensitivities discrepancy in males
and females, were also noted, while triglycerides increased
by 24-40% in females [28]. Another comparative research
of blood and organ system data from trials with rats fed
three main commercialized GM maize (NK 603, MON 810
and MON863) was performed, finding that the three GMOs
new side effects linked with GM maize consumption,
which were often sex- and dose-dependent. Although it is
different between the three GMOs, effects were primarily
associated with the dietary detoxifying organs, such as the
kidney and liver toxicity. Besides, other effects were also
observed in heart, adrenal glands, spleen and hematopoietic
system. We could conclude that these data highlighted
signs of hepatorenal toxicity, possibly due to the pesticides
specific to each GM corn (glyphosate and AMPA in NK
603, modified Cry1Ab in MON 810 and modified Cry3Bb1
in MON 863). In addition, unintended direct or indirect
metabolic consequences of the genetic modification could
not be excluded [29]. It was demonstrated that the isofla-
vonoids have modulating effect on estrogen receptors, as
well as chemo-preventive and anti-inflammatory effects.
Moreover, in female rats, the androgen/estrogen balance in
serum was subjected by GM maize and Roundup (R) herbi-
Recent Patents on Food, Nutrition & Agriculture, 2014, Vol. 6, No. 1 17
cide treatments, and for male animals at the highest R-
treatment dose, levels of estrogens were more than doubles
[15, 30]. Roundup, which can be tested rising in tap water,
the most widely used herbicide in the world, is parallel
with the flourishing Roundup-tolerant GM plants. Indeed,
Roundups active principle is glyphosate (G). G is a non-
selective broad-used herbicide that inhibits 5- enolpyruvyl-
shikimate-3 -phosphate synthase (EPSPS), which is a key
enzyme in the aromatic amino acid biosynthesis pathway of
microorganisms and plants. The purpose of manipulating
bacterial EPSPS gene is to reduce its affinity for G, while
as we know, the transfer of E is one of the most effective
approaches for the production of glyphosate-tolerant plants
[31]. Therefore, transgenic plants have a higher concentra-
tion of EPSPS so that they can tolerate a higher concentra-
tion of G. Glyphosate-based herbicides has been shown to
disrupt aromatase which synthesizes estrogens [32], they
also interfere with estrogen and androgen receptors of or-
ganisms [33]. In addition, R appears to be a sex endocrine
disruptor in vivo, also in males [34]. Sex steroids are also
modified in treated rats. These hormone-dependent phe-
nomena are confirmed by enhanced pituitary dysfunction in
treated females. An estrogen modified feedback mechanism
may act at this level [35, 36]. These results can be ex-
plained by the nonlinear endocrine-disrupting effects of
GMFs, also by the overexpression of the transgene in the
GMO and its metabolic consequences.
ENDOMETRIOSIS
Endometriosis is an estrogen-dependence inflammatory
disease and often lies at the root of otherwise unex-
plained infertility. Implants of this disease can be identi-
fied by laparoscopy in approximately 21% of women with
infertility [37]. The clinical manifestations of endometri-
osis are relatively well-described, but the pathogenesis re-
mains uncertain. The most widely accepted mechanism to
explain the initiating event involved with the establishment
of endometriosis is that of retrograde menstruation [38].
However, most menstruating women undergo some degree
of retrograde menstruation, and certainly not all of these
women develop endometriosis [39]. The abnormal endo-
metrium is revealed by alterations in gene expression Fig.
(1). A direct comparison of gene expression between pro-
liferative-phase uterine endometrium of infertile women
who are diagnosed endometriosis and fertile women with-
out endometriosis has been performed, indicating that the
pattern of gene expression in proliferative-phase endo-
metrium is different when comparing tissue from patients
with endometriosis versus fertile controls [40]. In spite of
the underlying cause of infertility in women with endome-
triosis has not been clearly established, a growing number
of evidences point to the implication of environmental
toxicants. In the past ten years, an increase in the reports of
endometriosis has been published and may be related with
the introduction of GMDs in our daily foods. Even though
assessments of GMFs risk have not directly related too
much hazard with human health, xenobiotics-associated
GMF, such as pesticides residues and xenoproteins, could
be harmful in the long-run. The low-dose hypothesis,
gathering and bio transforming of xenobiotic associated
GMD and the multiplied toxicity of pesticides formulation
18 Recent Patents on Food, Nutrition & Agriculture, 2014, Vol. 6, No. 1
Fig. (1). Epigenetic modulation of endometriosis.
SF1: Steroidogenic factor 1; ER-: Estrogen receptor; PGE2: Prostaglandine E2; PR: Progesterone receptor; HSD172: Estradiol 17-beta-
dehydrogenase 2. ( Aris A, et al. 2010).
adjuvants support this hypothesis. Their potential roles in
the pathophysiology of endometriosis include genic toxi-
cants, immune toxicants, pro-oxidants, endocrine disrup-
tors, epigenetic modulators and so on Fig. (2).
REPRODUCTIVE RELATED NEOPLASMS
The risk of increased morbidity to tumors resulting from
the consumption of GM food seems to be equally alarming.
Although a review on health impact of GM plant diets has
concluded that there is no major change on animal health [9],
significant disturbances have been found in mammals [41].
As mentioned, the milk of GM cows increases levels of IGF-
1 factor in consumers, showing a positive correlation with
occurrence of tumors in lungs, breast and colon, which is
associated with the abnormal estrogen receptor. Since G is
designed to inhibit the enzyme EPSPS involved itself in es-
sential aromatic amino acids metabolism in plants [42, 43], it
is possible that G (in R) could fit in a binding site in a mole-
cule with an aromatic cycle, such as those in steroid recep-
tors or steroid metabolizing enzymes [44]. It is also possible
that, as suggested for other xenobiotics, these herbicides can
bind to more than one site on steroid receptors [45], in this
way; it increases hormone-dependent diseases such as breast
or prostate cancer [14]. In order to define the health effects
of chronic alimentation with transgenic products, a group of
rats was studied, fed with various doses of NK603 modified
maize, grown in or in absence of exposure to Roundup her-
bicide, using food free of GMO but containing water with
the addition of varying amounts of Roundup, or using food
Gao et al.
free of GMO as control. The results of the two-year experi-
ment, compared with the control group, the mice fed by
roundup shows a likelihood with some unphysical-related
disease, such as disturbances in the function of liver and kid-
neys, a higher mortality of animals, and manifestation of
palpable tumors [15]. Also, the agglutinin found in GM pota-
toes was toxic for the growth and development of mammals
and negatively affected the alimentary tract in rodents. The
diet, the unfavourable effects were identified as the distur-
bance of cell division, especially in the gastric mucosa [3,
46, 47], this may be a potential carcinogenic factor, moreo-
ver, experiments are being conducted to evaluate links be-
tween cultivable plants rendered resistant to pesticides with
the frequency of lymphoma developed in humans and ani-
mals consuming products resulting from the transformation
of such plants [48, 27]. There have been several claims that
transgenic DNA could become incorporated into human or
bacterial cells and increase the likelihood of cancer [49-51].
However, the study about reproductive related neoplasms is
limited; the hypothetical link between GMFs and potential
reproductive tumor is primarily depending on the overex-
pression of some cytokines and the abnormal expression of
estrogen receptor.
EFFECT ON GAMETE AND EMBRYO
Although some studies did not reveal any impact of GM-
maize on mammalia progeny development [52-54], Reports
about reproduction of mammals affected by G-based herbi-
cides are already published that this kind of GM herbicides
Hypothetical Link Between Infertility and Genetically Modified Food
Fig. (2). Hypothetical mechanisms of xenobiotics action in the pathophysiology of endometriosis. BPA: bisphenol A; Mt: methoxychlor;
RU: roundup; DES: diethylstilbestrol; Vn: vinclozolin; Cry: Cry1Ab; P: pesticides; TCDD: 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin; Ph: phtha-
lates; Op: organophosphates; Pr: pyrethrins; Bp: bipyridines; Oc: organochlorine. (Aris A, et al. 2010).
does affect their sperm production or pregnancy problems
and outcomes [55, 56]. Cellular mutagenic and toxic effects
are now explained that when occurring at very low doses in
cells, G-based herbicides will affect reproduction such as
embryonic, fetal and placental ones [55, 57]. Some agricul-
tural workers using glyphosate have been showed pregnancy
problems [55], but the mechanism is questioned. It shows
that glyphosate is toxic to human placental JEG3 cells, and
these bad effects are increasing by the accumulation of con-
centration and time. The glyphosate-based herbicide disrupts
aromatase activity and mRNA levels and interacts with the
active site of aromatase, it concludes that endocrine and
toxic effects of glyphosate-based herbicide can be observed
in mammals [32]. These xenobiotic may produce inhibition
to the active site or allosteric effects on above- mentioned
enzyme [56]. Scientists researched the ultramicro and immu-
nocytochemical distinction of pre-implantation embryos of
mice fed respectively by GM and non-GM soybean in order
to confirm whether the diet could affect the morphological
and functional development of the embryonic ribonucleopro-
tein structural elements involved in premRNA pathways
[58]. Morphological observations showed that the general
aspect of embryo nuclear components were similar in both
GM and non-GM groups. However, immunohistochemical
detection in situ hybridization results revealed a temporary
decrease of pre-mRNA transcription and splicing in 2-cell
embryos and resumption in 4-8-cell embryos from mice fed
by GM soybean. Besides, pre-mRNA maturation seemed to
be less effective in either 2- cell or 4-8-cell embryos from
mice fed by GM than those fed by non-GM. A model system
used sea urchin embryonic first divisions following fertiliza-
Recent Patents on Food, Nutrition & Agriculture, 2014, Vol. 6, No. 1 19
tion was established, which is appropriate for the study of
universal cell cycle regulation without interference with tran-
scription. It shows that 0.8% Roundup induces a kinetic de-
lay in the first cell cleavage of sea urchin embryos. The de-
lay is dependent on the concentration of Roundup. The effect
of Roundup delays the activation of CDK1/cyclin Bs com-
bination, by synergic effect of glyphosate and formulation
products [59]. Considering the universality among species of
the CDK1/cyclin B regulator, this result questioned the
safety of Glyphosate- based herbicides on human embryo, as
well as Glyphosate- tolerant GM plants, which may increase
chromosomal aberration frequency, in rats bone marrow
cells observed at later sampling times after administration of
Stomp suggests that the induction of aberrations may be due
to biosynthesis of genotoxic metabolites, mitotic spindle
disruption [60]. Then the toxicity of four Glyphosate-based
herbicides was evaluated respectively on three different hu-
man cell types-human umbilical, embryonic, and placental
cells. The resident of Glyphosate-based herbicides could
cause cell damage and even death, especially in food and
feed derived from R formulation-treated crops [55]. There-
fore, it can be deduced that GMFs/GMOs may affect the
normal splitting of gamete and embryo, but still need further
research.
CURRENT & FUTURE DEVELOPMENTS
The paper provides a review on the potential risks associ-
ated with GMFs/GMOs on reproduction, multi-aspects are
analyzed. It could be conjectured that GMFs/GMOs could
exist potential hazard on reproduction, link to the develop-
20 Recent Patents on Food, Nutrition & Agriculture, 2014, Vol. 6, No. 1
ment of infertility, mainly by influencing the endocrine me-
tabolism, endometriosis. Little evidence shows the impaction
on embryo or reproductive related tumor due to the limited
literatures, and needs further research. In spite of the notable
increase of the using of citations about GMFs/GMOs, those
concerning specifically to studies focused on demonstrating
the reproduction safety of GM foods, which remain limited.
Future studies should be undertaken according to European
Food Safety Authority recommendations which have under-
lined the necessity of an improved methodology when statis-
tics are involved [61], and the distinction shows relevance
between statistical significance and biology [62]. Therefore,
it should be possible to model the sensitivity of the rat in
long-term feeding study for the detection of hypothetically
increased amount of compounds such as anti-nutrients, toxi-
cants, or secondary metabolites. It also reminds that legisla-
tion for GMFs/GMOs is required. We noticed that the
French and German authorities have already launched a pro-
cedure called safeguard clause to ban cultivation of GE
maize, but they did not use food safety arguments to evaluate
it, in the EU action called safeguard clause permits some
State providing valid excuses to consider that a GM crop
plant will led a risk to human/animal health or to the envi-
ronment, to marginally restrict or prohibit the use and/or sale
of that product on its land [63]. Instead, these governments
tried to show health-related dangers for the development of
GM plants; debates which also failed to provide scientifi-
cally valid data [64]. Therefore, more studies are needed, and
long-term exposure to GMFs/GMOs need carry out in ani-
mals and cells experiment.
RECENT PATENTS OF GMFs/GMOs
Here we introduce some of the most recent patents based
on GMOs. Kossmann, et al. invented a method of using tu-
bers having genetically modified potato plant cells in patent
US8586722 [65], this method is able to reduce undesirable
products of Maillard reactions comprising producing french
fries or crisps from a tuber comprising genetically modified
potato plant cells having a reduced expression of a nucleic
acid molecule, and wherein undesirable able products of
Maillard reactions are reduced in said french fries or crisps
as compared to french fries or crisps produced from a wild-
type tuber. This invention appears to reduce the risk of ge-
netically modified potato, however, more evidence have
shown its disadvantage. There are some classical patents
with regard to common GMOs [66-71], Arbelbide, et al.
invented the maize hybrid X95C381 in patent US8716552
[66], a new maize variety designated with X95C381 and
seed, plants and plant parts thereof, produced by crossing
Pioneer Hi-Bred International, Inc. proprietary inbred maize
varieties, which produced a maize plant that comprises cross-
ing hybrid maize variety X95C381 with another maize plant.
Benson, et al. invented maize variety hybrid X13A498 in
patent US 8716579 [67], a novel maize variety containing in
its genetic material one or more traits are introgressed into
X13A498 through backcross conversion and/or transforma-
tion, and to the maize seed, plant and plant part produced
thereby. This invention relates to the maize variety
X13A498, the seed, the plant produced from the seed, and
variants, mutants, and minor modifications of maize variety
X13A498. These inventions also relate to the herbicide Gly-
Gao et al.
phosate. US patent NO. 4940835 to Shah, et al. [68], which
describes genes encoding EPSPS enzymes and discloses the
nucleotide sequence of a PSPS form capable of conferring
glyphosate tolerance in US patent No. 5627061 to Barry, et
al. [69]. It also describes genes encoding EPSPS enzymes.
Glyphosate tolerance is also imparted to plants that express a
gene that encodes a glyphosate oxido-reductase enzyme as
described more fully in US patents Nos. 5776760 [70] and
5463175 [71] which are incorporated herein by reference for
this purpose. In addition glyphosate tolerance can be im-
parted to plants by the over expression of genes encoding
glyphosate N-acetyltransferase. Furthermore, Naleway, et al.
invented some methods of altering glycosylation of proteins
in response to nojirimycin glucuronide in a plant cell ex-
pressing glucuronidase in patent US8716558 [72]. The
methods describe the specific activation of the pro-drugs at
or near transformant host cells expressing a gene for an en-
zyme that activates the pro-drugs. Pro-drugs according to a
preferred embodiment of the invention are conjugates of a
bioactive compound and a chemical group that is capable of
being cleaved from the bioactive compound by action of an
enzyme. Methods according to this invention include intro-
ducing into targeted cells a gene encoding an enzyme and
administering a pro-drug, wherein the enzyme releases the
pro-drug from conjugation. In a preferred embodiment of the
invention, the gene encoding the enzyme is a marker gene.
Methods according to a preferred embodiment of the inven-
tion include altering protein production in a plant cell such as
altering glycosylation of a protein produced by the plant cell.
Its also mentionable that some methods for tracking GMOs
are invented since we know that GMOs are potentially harm-
ful to humans if eaten. Angell, et al. invented a method of
tracking GMOs in patent US7868768 [73], which is intended
for consumption by livestock only, is laced with Radio Fre-
quency Identification (RFID) tags at or near a time of har-
vest. If the RFID tags appear in a product that is intended for
human consumption, then the product is pulled from distri-
bution. Lan, et al. disclosed a method about the detection of
genetically modified maize BT11 in patent US8367341 [74].
The principle of the method is that the DNA template of the
sample is amplified at a temperature range from 63 to
65degree Celsius for 45 to 60 mins by using 4 specific prim-
ers and a DNA polymerase with strand displacement activ-
ity. The identification thereof is to make a judgment on
whether BT11 component is contained in the sample by di-
rectly observing the turbidity in the reaction tube or the color
change after the addition of SYBR Green with naked eyes or
by agarose gel electrophoresis. The detection method of the
invention has the advantages of high specificity, quickness,
simplicity and convenience and the like, which provides a
convenient method for the detection of genetically modified
maize BT11 with an extensive application prospect.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
This work was supported by Reproductive Medicine
Center of First Hospital of Lanzhou University.
Hypothetical Link Between Infertility and Genetically Modified Food
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