Reproductive Toxicology 71 (2017) 142145

Contents lists available at ScienceDirect

Reproductive Toxicology
journal homepage: www.elsevier.com/locate/reprotox

Review

Inuence of oil-related environmental pollutants on female

reproduction
Alexander V. Sirotkin a,b, , Abdul Halim Harrath c
a
Constantine The Philosopher University in Nitra, Nitra, Slovakia
b
Animal Production Research Centre Nitra, Luzianky, Slovakia
c
College of Science, King Saud University, Saudi Arabia

a r t i c l e i n f o a b s t r a c t

Article history: The petroleum low-weight aromatic hydrocarbons benzene, toluene, ethylbenzene, m/p-xylene, and
Received 9 January 2017 o-xylene, also known as BTEX, are among the most common hazardous sources of environmental con-
Received in revised form 24 April 2017 tamination. This paper reviews the available data concerning the effects of BTEX on different aspects of
Accepted 22 May 2017
female reproduction, including the fecundity, ovaries, central nervous system (CNS), oocytes, embryos,
Available online 31 May 2017
oviducts, cytogenetics of somatic and generative cells, intracellular signaling systems, and hypothalamic,
pituitary and peripheral reproductive hormones. Analysis of the available literature demonstrates that
Keywords:
BTEX can exert negative effects on various female reproductive sites, including the CNS-pituitary-ovarian
Oil pollutants
Ovary
axis, their signaling molecules and receptors, ovarian follicles, corpora lutea, oocytes, embryos, oviducts,
Hormones ovarian cycles, fertility, and the viability of offspring. These effects could be due to the ability of BTEX
Cytogenetics to destroy chromosomes, to affect cell metabolism, including the accumulation of free radicals, and to
Embryos affect the release of hormonal regulators of reproductive processes and intracellular protein kinases.
Fecundity 2017 Elsevier Inc. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
1.1. Effects of BTEX on the ovarian morphology and fecundity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
1.2. Effects of BTEX on the CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
1.3. Effects of BTEX on hypothalamic, pituitary, and peripheral reproductive hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
1.4. Effects of BTEX on oocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
1.5. Effects of BTEX on embryos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
1.6. Effects of BTEX on oviducts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
1.7. Effects of BTEX on cytogenetics of somatic and generative cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
1.8. Effects of BTEX on intracellular signaling systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
2. Conclusions and possible direction of future studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

products (e.g., crude oil, petroleum, petrochemical products, aro-

1. Introduction
matic hydrocarbons, etc.) are among the most common hazardous
sources of environmental contamination. The petroleum low-
Oil production and processing and the subsequent produc-
weight aromatic hydrocarbons benzene, toluene, ethylbenzene,
tion and consumption of petroleum products represent the basis
m/p-xylene, and o-xylene, also known as BTEX, are especially dan-
of a modern economy. Unfortunately, leaks and spills of oil
gerous because of their (1) multiple sources of contamination in the
environment (e.g., oil production, oil refrigeration, oil transporta-
Corresponding author at: Constantine the Pilosopher University, Nabrezie
tion, the production of petroleum, solvents, coal-derived products,
Mladeze 91, 949 74, Nitra, Slovakia.
trafc, tobacco smoking, voluntary inhalation as drugs of abuse,
E-mail addresses: asirotkin@ukf.sk (A.V. Sirotkin), halim.harrath@gmail.com etc.), (2) relatively high solubility in water and air and there-
(A.H. Harrath). fore easy migration and distribution in the environment and easy

http://dx.doi.org/10.1016/j.reprotox.2017.05.007
0890-6238/ 2017 Elsevier Inc. All rights reserved.
 A.V. Sirotkin, A.H. Harrath / Reproductive Toxicology 71 (2017) 142145
transport into the cells, (3) low physico-chemical and biological
degradation in ecosystems, and (4) multiple toxic inuences on
living organisms [1].
BTEX can express toxic [2,1,36], mutagenic [7,8], car-
cinogenic [2,8], embryotoxic and teratogenic [912], growth
retarding [13,9,4,14,11], metabolic [4,14], and neuromodulatory
[1518,8,19] effects.
The most dangerous effects of BTEX could be their inuence on
the most important biological process reproduction, especially
female reproduction and its regulators [20]. Female organisms
accumulate 3.76.8 times more xylene than males, and ovaries
are the primary accumulation site of these hydrocarbons [44]. The
developing fetus is particularly sensitive to BTEX action [12].
1.1. Effects of BTEX on the ovarian morphology and fecundity
Female workers contact with benzene is associated with ovar-
ian hypo- and hyperplasia, ovarian and uterine retardation [2],
reduction in the duration of the luteal phase of the menstrual
cycle [21,22], and the retardation of fetal growth during pregnancy
[11,12]. Increase benzene concentration in human ovarian follicular
uid was associated with reduced oocyte and embryo produc-
tion, although pregnancy rate was not linked with ovarian benzene
level [23]. Exposure of mice to benzene increased the incidence of
ovarian granulosa cell tumors and ovarian benign mixed tumors
[24]. Exposure of cows to benzene increases the incidence of odd
calves [10]. Toluene exposure in rats suppresses the development
of growing but not primordial ovarian follicles [25]. The inhalation
of toluene increases the incidence of maternal and fetal morbidity
and embryonic malformations in women [26,5], cows [10], and rats
[14], although other studies have not detected any adverse effects
on implantation or the number and viability of rat fetuses. Inhala-
tion of ethylbenzene does not affect rat ovarian structure, function,
and fertility [3]. The accessible databases do not contain publi-
cations concerning the reproductive effects of xylenes, although
decreased embryonic growth [13] and increased prenatal mortality
[9] in rats exposed to xylene have been reported.
Although extra- and intracellular mechanisms of BTEX action
could help to explain and prevent their negative effects on repro-
duction, they have been very poorly studied. There is some evidence
that BTEX can affect reproduction and fertility via several, most
likely interrelated, mechanisms and target sites: via toxic and
genomic effects on the CNS, hypothalamic, pituitary and peripheral
hormones, reproductive organs, oocytes, and embryos.
1.2. Effects of BTEX on the CNS
The inhibitory effects of benzene [8], toluene [15,1719,27],
and ethylbenzene [16,19] on neuromediator receptors in the
CNS are well known. In addition, toluene was able to exert
its neurotoxic effect via an increase in brain free radicals [17].
Neuromediators play a key role in the control of sexual behav-
ior and of neuromediator-dependent neurohormones, including
gonadotropin-releasing hormones, oxytocin, etc., which in turn are
the main regulators of the downstream pituitary-ovarian axis [28].
1.3. Effects of BTEX on hypothalamic, pituitary, and peripheral
reproductive hormones
Women with occupational exposures to various BTEX (benzene,
ethylbenzene, toluene, and xylenes) have reduced preovulatory
blood gonadotropin (follicle-stimulating hormone, FSH, luteinizing
hormone, LH) and prostaglandin level [22,29]. High benzene level
in woman ovarian follicular uid was associated with increased
FSH and decreased estradiol level in blood plasma [23]. The inhala-
tion of toluene by rats reduces the hypothalamic level of GnRH
143
and plasma levels of gonadotropins, changes the FSH:LH rate,
and increases the plasma level of anti-gonadotropin prolactin.
These changes are associated with reduced blood progesterone
and estradiol levels but not with their response to gonadotropin
administration [30]. Inhalation of para-xylene decreases plasma
progesterone and estradiol levels but not the release of these hor-
mones by ovaries in rats [13]. These observations suggest that BTEX
can reduce the output of ovarian steroid hormones via the inhibi-
tion of upstream hypothalamic gonadotropin-releasing hormone
(GnRH)/pituitary gonadotropin production or the response of the
ovary to gonadotropin.
1.4. Effects of BTEX on oocytes
Xenopus oocytes are used as a common model for studying the
effects of BTEX on membrane receptors. These oocytes demon-
strate inhibitory effects of benzene, m-xylene, and ethylbenzene
on membrane N-methyl-d-aspartate (NMDA) receptors [16]; of
benzene on gamma-aminobutyric acid (GABA) receptors [15]; of
toluene on nicotinic acetylcholine receptors [18,27] and ethanol-
sensitive potassium channels [31]; and of xylenes on nicotinic
acetylcholine receptors [32]. Therefore, BTEX might also suppress
reproduction via the inhibition of oocyte signaling systems.
1.5. Effects of BTEX on embryos
BTEX can disrupt reproduction due to their embryotoxic and
teratogenic actions. The suppressive effects of benzene, m-xylene,
ethylbenzene, and xylenes on bovine [10] and human [9,11,33]
embryogenesis and of toluene [34] and xylene [9] on rat embry-
onic growth have been reported. In addition, toluene is able to
inhibit steroidogenic enzymes and testosterone synthesis in fetal
rats [35], suggesting the potential inhibitory inuence of this aro-
matic hydrocarbon on gonadal steroidogenesis and related sexual
maturation. There are some evidence for critical windows of vul-
nerability during prenatal and early postnatal development, during
which BTEX exposures can cause potentially permanent damage to
the growing embryo and fetus [12] .
1.6. Effects of BTEX on oviducts
Fertility and embryo viability could be inuenced by BTEX via
an inuence of oviduct and uterine functions. Riveles et al. [36]
reported that benzene exposure inhibits ciliary beat frequency,
oocyte pickup rates, and infundibular smooth muscle contraction
rates. The inhalation of para-xylene does not inuence rat uterine
and ovarian venous outow [13].
1.7. Effects of BTEX on cytogenetics of somatic and generative
cells
Cytogenetic analysis demonstrated the mutagenic effects of
toluene and its analogues on hamster ovarian cells [7]. Benzene
increased the incidence of aneuploidy in mature mouse oocytes
[37]. The destructive effects of BTEX on chromosomes in somatic
ovarian, brain, and other cells and in oocytes could be due to the
ability of BTEX to increase the level of mutagenic and pro-apoptotic
free radicals in these cells. The inhalation of toluene increased the
activities of glutathione peroxidase and catalase and the intensity
of lipid peroxidation in rat ovaries and brain cortices [17].
1.8. Effects of BTEX on intracellular signaling systems
The ability of BTEX to inhibit growth and induce cell death
suggests that these hydrocarbons can suppress cell prolifera-
tion and promote cell apoptosis. Nevertheless, there is only
144 A.V. Sirotkin, A.H. Harrath / Reproductive Toxicology 71 (2017) 142145
Fig. 1. The known targets of oil-related contaminants in reproductive sytem (simplied). Explanations are in the text.
one paper demonstrating the inhibitory effect of BTEX on
markers/promoters of ovarian cell cycle. In the experiments of
Lin et al. [6], the xylene analogue (L1 = ,-diamino-p-xylene,
L2 = 4,4-methylenedianiline) arrested the cycle of cultured human
cancer cells (COC1) at G2 or M phase, most likely via dose-
dependent inuences on the accumulation and phosphorylation
of proliferation-related protein kinases Checkpoint kinase 1/2
(CHK1/2), extracellular signalregulated kinases 1/2 (ERK1/2), and
p38 subunit of mitogen-activated protein kinase (p38 MAPK). The
primary aim of this study was to identify new anti-cancer mito-
static effects, and it was suggested that CHK1/2, ERK1/2, and p38
MAPK can be intracellular mediators of some BTEX effects on ovar-
ian cell proliferation. Furthermore, because these MAP kinases can
be important regulators of oocyte maturation and ovarian hormone
release [28], these kinases might be mediators of BTEX in various
ovarian processes. It is not to be excluded, that BTEX can adverse
affect reproductive system and fecundity via generation of reactive
oxygene species, the known inductors of apoptosis in various cell
types [38].
2. Conclusions and possible direction of future studies
The analysis of the available literature demonstrates that BTEX
can exert negative effects on various female reproductive sites
(Fig. 1), including the CNS-pituitary-ovarian axis, their signaling
molecules and receptors, ovarian follicles, corpora lutea, oocytes,
embryos, oviducts, ovarian cycle, fertility, and the viability of off-
spring. These effects could be due to the ability of BTEX to destroy
chromosomes, to affect cell metabolism, including the accumula-
tion of free radicals, and to affect release of hormonal regulators of
reproductive processes and intracellular protein kinases.
Functional interrelationships between these effects are possible.
For example, BTEX action on the CNS can affect multiple CNS-
regulated sites (hypothalamus-pituitary-ovaries-oviduct-oocytes-
gravidity). It is also possible for toxic BTEX to destroy reproductive
processes at once at multiple regulatory levels.
Although understanding the effects of BTEX on reproduction
is very important from both theoretical and practical (e.g., med-
ical, ecological, etc.) viewpoints, the current available knowledge
is poorly understood and supercial. Not all BTEX hydrocarbons
are studied in relation to the main reproductive processes. Rather,
most available data concern the biological actions of benzene and
toluene, and nearly all of the studies were performed on only
three species: rats, humans, and Xenopus. Studies on farm ani-
mals are very rare, whilst the related publications on wild animals
are absent. A better understanding of the physiological, genetic,
endocrine, and intracellular mechanisms of BTEX action could
advance the characterization and prediction of the biological effects
of BTEX. Finally, little is known about how to prevent or neutralize
the negative effects of BTEX on reproduction at the physiological
level. It is known that some effects of stress on ovarian function
could be prevented or neutralized with stem cell therapy [39],
plants containing antioxidants and other adaptogenes [40,41], hor-
mones, growth factors, pharmacological and genomic regulators of
intracellular signaling molecules, and some complimentary DNA
(cDNA), small interfering RNA (siRNA), and microRNA (miRNA) con-
structs [42,43]. Nevertheless, characterizing the effects of BTEX on
various ovarian functions and the extra- and intracellular mecha-
nisms of their action on the molecules could be implemented in the
prevention and neutralization of the negative effects of BTEX and
for treatment of BTEX-induced reproductive disorders that remain
to be studied.
Acknowledgements
This work was supported by Slovak Research and Development
Agency under the contracts No. APVV-0854-11 and No. APVV-15-
0296. The authors extend their appreciation to the Deanship of
Scientic Research at King Saud University for funding the work
through the research group project No RGP-164.
 A.V. Sirotkin, A.H. Harrath / Reproductive Toxicology 71 (2017) 142145
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