Environmental Toxicology and Pharmacology 69 (2019) 16–25

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Environmental Toxicology and Pharmacology

journal homepage: www.elsevier.com/locate/etap

Environmental inhibitors of the expression of cytochrome P450 17A1 in T

mammals
⁎,1
Zhiheng Penga, , Guoqiang Xuebb,2, Wenci Chenc,3, Shenglong Xiad,4
a
Department of Clinical Laboratory Center, The second Hospital of Lanzhou University, Lanzhou, Gansu 730000, China
b
Second Provincial People's Hospital of Gansu, Lanzou, Gansu 730000, China
c
Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Wenzhou, Zhejiang, 32500, China
d
The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 32500, China

A R T I C LE I N FO A B S T R A C T

Keywords: Cytochrome P450 17A1 (CYP17A1; EC: 1.14.14.19) is a critically important bifunctional enzyme with nicoti-
Steroidogenic enzymes namide adenine dinucleotide phosphate (NADPH) as its cofactor that catalyzes the formation of all endogenous
Androgen androgens. Its hydroxylase activity catalyzes the 17α-hydroxylation of pregnenolone (PREG)/progesterone (P4)
Reproduction to 17α-OH-pregnenolone/17α-OH-progesterone, and its 17,20-lyase activity converts 17α-OH-pregnenolone/
CYP17A1 expression
17α-OH-progesterone to dehydroepiandrosterone/androstenedione. Androgens are required for male re-
Environmental inhibitors
productive development, so androgen deficiency resulting from CYP17A1 inhibition may lead to reproductive
disorders. There has been some advances on the study of environmental chemicals inhibiting mammalian
CYP17A1 expression but no related review was available so we think it now necessary to review their char-
acteristics and inhibiting properties.

1. Introduction
In human species, cytochrome P450 17A1 (CYP17A1, also called
P450c17 and P450sccII; EC: 1.14.14.19) is encoded by a single gene,
Cyp17a1, which lies on chromosome 10q24.3.(2018). This gene spans
6.6 kb, and contains eight exons(Nakajin et al., 1981) and seven introns
(Huber et al., 2015). From that gene, a messenger RNA(mRNA) mole-
cule with the length of 2.1 kb is transcribed, in which there is a 1.6 kb
coding region. Eventually, the mRNA molecule would be translated into
a 57.4 kDa, a 509 residues-containing polypeptide named CYP17A1
(Chung et al., 1987).
CYP17A1 is anchored in the membrane of smooth endoplasmic re-
ticulum (ER) through an N-terminal α helix. The active site of CYP17A1
is isolated from the surrounding solvent, and its heme cofactor is buried
in the core of the enzyme (Miller, 1988). Its substrates enter or exit the
active site of the enzyme via a dynamic tunnel gate formed by amino
acids Trp220 and Phe224 (Cui et al., 2015). In the 1980s, it was de-
monstrated that CYP17A1 was a bifunctional enzyme in that the active
site possessed both 17α-hydroxylase and 17,20-lyase activities (Chung
et al., 1987; Guengerich, 2001). The amino acid Arg347 is indis-
pensable for 17,20-lyase activity but not for 17α-hydroxylase activity as
mutant R347 A just destroys 17,20-lyase activity (Zhang et al., 1995). In
addition, phosphorylation of serine and threonine residues increases
17,20-lyase activity by increasing electrostatic affinity for electron
donors (Pandey et al., 2003). Moreover, pH of 7.25 and temperature of
37℃ are optimal for its viability (Schoborg et al., 2015).
CYP17A1 expression is very extensive. It is expressed in the testis,
ovary, adrenal (Nakamura et al., 2015), placenta (Szabo et al., 2015),
skin (Slominski et al., 2013), brain (Shi et al., 2009), and also in various
tumors (Noce et al., 2001). In humans, adrenal cortex and the gonad
(testis for male and ovary for female) are regarded to be the main
CYP17A1-expressing tissues (Geller et al., 1997). In the testis, CYP17A1
has been proved to participate in the testosterone (T) biosynthesis (Ye
et al., 2011a).
Some environmental contaminants inhibit the expression of
CYP17A1 and disrupt the T biosynthesis or metabolism, which may
furthermore cause reproductive disorder. This review mainly aims to
provide insight into the characteristics and inhibiting properties of

⁎
Corresponding author.
E-mail addresses: zhihengpeng@126.com (Z. Peng), q4923547@163.com (G. Xueb), 409601277@qq.com (W. Chen), xsl1989@foxmail.com (S. Xia).
1
Tel.: +8613919086963.
2
Tel.: +8615025899101.
3
Tel.: +8615868532956.
4
Tel.: +8615868532956.

https://doi.org/10.1016/j.etap.2019.02.007
Received 3 October 2018; Received in revised form 9 February 2019; Accepted 14 February 2019
Available online 14 March 2019
1382-6689/ © 2019 Elsevier B.V. All rights reserved.
Z. Peng, et al. Environmental Toxicology and Pharmacology 69 (2019) 16–25

Fig. 1. Testosterone biosynthetic and metabolic pathways.

those environmental inhibitors of CYP17A1 expression in mammals.

2. Androgen biosynthesis and metabolism

In the testis, CYP17A1 is involved in T biosynthesis by Leydig cells.

As shown in Fig. 1, T biosynthesis is an enzyme-controlled steroido-
genic process. The primary substrate cholesterol is transported into the
inner membrane of mitochondria by scavenger receptor B1 (SCARB1)
and steroidogenic acute regulatory protein (STAR). Cholesterol is cat-
alyzed into pregnenolone (PREG) by cholesterol side chain cleavage
enzyme (CYP11A1). PREG then diffuses into the surrounding smooth

Fig. 3. The structure of gossypol.

Fig. 2. The structure of tributyltin (TBT). Fig. 4. The structure of 2,4-Dichlorophenoxyacetic acid (2,4-D).

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Z. Peng, et al. Environmental Toxicology and Pharmacology 69 (2019) 16–25

Fig. 5. The structure of N-hexane.

Fig. 9. The structure of atrazine (ATZ).

Fig. 10. The structure of polychlorinated biphenyls (PCBs).

Fig. 6. The structure of benomyl (BNL).

Fig. 11. The structure of bisphenol A (BPA).

Fig. 7. The structure of methoxychlor (MXC).

Fig. 8. The structure of 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane

(HPTE).

Fig. 12. The structure of prochloraz (PCZ).

endoplasmic reticulum to be catalyzed into T by three other steroido-
genic enzymes including 3β-hydroxysteroid dehydrogenase (HSD3B),
which goes from PREG to progesterone (P4), then to androstenedione
CYP17A1, and 17β-hydroxysteroid dehydrogenase 3 (HSD17B3) (Ye
and ultimately to T. The ⊿5 pathway is prevalent in the human testis,
et al., 2011a).
shifting from pregnenolone to 17α-hydroxypregnenolone, then to de-
However, during the conversion, there are two different pathways
hydroepiandrosterone, after that to androstenedione, and eventually to
in diverse species. The ⊿4 pathway is predominant in the rat testis,

18
Z. Peng, et al.
Fig. 13. The structure of 1,2-Dibromo-3-chloropropane (DBCP).
Fig. 14. The structure of dipentyl phthalate (DPP).
T (Ye et al., 2011a). For CYP17A1, it catalyzes a two-step reaction with
its two enzymatic activities. 17α-hydroxylase activity catalyzes PREG/
P4 into 17α-OH-pregnenolone/17α-OH-progesterone, which C17,20-
lyase activity catalyzes into dehydroepiandrosterone/androstenedione
(Fernandez-Cancio et al., 2017).
In testis, once formed, T is metabolized to dihydrotestosterone
(DHT) by 5α-reductase (SRD5A) 1, 2, or 3 isoform in Leydig cells or
peripheral tissues. Among the three 5α-reductase isoforms, SRD5A2
turns out to have the highest affinity for T. Both T and DHT are an-
drogens, however, DHT is 5 times more potent than T (Eik-Nes, 1975).
In the female gonad, namely ovary, androstenedione/T is catalyzed by
endoplasmic reticulum enzyme aromatase (CYP19A1) into estrogen
including estrone (E1)/estradiol (E2), respectively(Ghosh et al., 2009;
Milani et al., 2009).
During androgen biosynthesis and metabolism, HSD3B requires
cofactor nicotinamide adenine dinucleotide (NAD+), and CYP11A1,
CYP17A1, HSD17B3, SRD5A, and CYP19A1 needs cofactor nicotina-
mide adenine dinucleotide phosphate (NADPH) (Hanukoglu, 1992).
It is widely known that this steroidogenic process is regulated by the
hypothalamus-pituitary gonad axis (HPG): gonadotrophin-releasing
hormone secreted by the hypothalamus binds to its receptor in the pi-
tuitary and stimulates luteinizing hormone (LH) (encoded by Lhb) and
follicle stimulating hormone (FSH) (encoded by Fshb) secretion, which
play significant roles in promoting Leydig cell androgen production by
binding to their receptors LHR (encoded by Lhr) on Leydig cell and
FSHR (encoded by Fshr) on Sertoli cell. After binding to their receptors,
LH activates AC-cAMP-PKA pathway and FSH strengthen Sertoli cell's
function of supporting Leydig cells (Baker et al., 2003; Liu et al., 2015).
In addition, to achieve optimal steroidogenic function of CYP17A1
during androgen biosynthesis, steroidogenic factor-1 (SF-1), GATA-6,
and the sterol regulatory binding protein 1 (SREBP1) recruit to its
promoter and assemble a complex for transcription coordination (Sewer
and Jagarlapudi, 2009). Another transcription factor DAX (dosage-
sensitive sex reversal adrenal hypoplasia congenital critical region on
the X chromosome, gene 1) negatively regulates CYP17A1 expression
(Shibata et al., 2000). Additionally, two redox partners called P450
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Environmental Toxicology and Pharmacology 69 (2019) 16–25
reductase (Sakaki et al., 1991) and cytochrome b5 (Duggal et al., 2016)
are responsible for electron transfer with NADPH as their cofactor and
are indispensable for the functionality of CYP17A1, as CYP17A1 cannot
perform its catalytic function in their absence.
3. Consequences of inhibition on androgen production
Both T and DHT are androgens. During fetal period, the two an-
drogens are responsible for inducing differentiation of the male geni-
talia, and testis descent, as well as maintaining the development of male
reproductive tract (Huhtaniemi and Pelliniemi, 1992). At adulthood,
they are required for sperm formation in the seminiferous tubules
(Awoniyi et al., 1989), the maintenance of accessory sex organs (Fujii,
1977) and stimulating sexual behavior (Wilson, 2001).
In the testis, Leydig cells account for only 5% of all cell types, yet
they secret 95% of circulatory T by the steroidogenic process mentioned
above (Guo et al., 2017). Thus, chemicals interfering with the Leydig
cell T secretion, known as Environmental endocrine disruptors (EEDs),
can cause drastic T deficiency and ultimately reproductive disorders
including abnormal reproductive tract, diminished fertility and hypo-
gonadism (Hu et al., 2009). More than 200 chemicals meet the criteria
for classification as EEDs, including compounds such as plasticizers,
pesticides, natural plant metabolites, detergents, and metals (Goldman
et al., 2000). This review discusses about the characteristics and in-
hibiting properties of EEDs inhibiting CYP17A1.
4. Some EEDs inhibiting CYP17A1
Some environmental chemicals are frequently used in daily life,
which can directly disrupt the T biosynthesis or metabolism by tar-
geting CYP17A1, and may furthermore cause reproductive toxicity.
This review mainly aims to provide insight into the characteristics and
inhibiting properties of those environmental inhibitors of CYP17A1
expression in mammals, whether the CYP17A1-inhibiting is its main or
side effects. The properties of those EEDs are further summarized in
Table 1. Actually this is not an exhaustive list of environmental
CYP17A1 inhibitors in mammals but the chosen ones are much more
common used in our daily life.
4.1. Tributyltin (TBT, structure shown in Fig. 2)
Organotin compound TBT is extensively used as biocides in various
kinds of consumer and industrial products. It is highly toxic as it can
cause DNA damage and its adverse effects on human health has been
demonstrated (Benachour et al., 2007; Zuo et al., 2012). In addition,
TBT is a confirmed environmental contaminant, it is ubiquitously per-
sistent in the environment, it can be found in freshwater, estuarine and
marine ecosystems and causes ecotoxicological threats to aquatic or-
ganisms because of its industrial applications (Revathi et al., 2013; Zuo
et al., 2012). TBT accumulation in water and their bio-accumulation up
in the food chain have been reported world-widely (Graceli et al.,
2013). In some locations, the concentrations of TBT exceed the acute
and chronic toxicity threshold of sensitive fresh water or marine or-
ganisms (Jiang et al., 2001).
It was demonstrated that TBT imparted very serious disruption to
the testis (Kanimozhi et al., 2014). As for our focus, it was found that
oral administration of 50, 100, and 150 ppm/kg/day TBT to adult male
Syrian hamsters for 65 days significantly and dose-dependently down-
regulated testicular Cyp17a1 mRNA level. The protein level change
followed exactly the same trend. These results were supported by the
weakened immunofluorescence of CYP17A1 in Leydig cells (Kanimozhi
et al., 2017). Similar results were observed using male ICR mice (Kim
et al., 2008). The inhibition on CYP17A1 as well as other steroidogenic
enzymes partly contributed to the decreased T production by Leydig
cells and thereby leading to male infertility (Kanimozhi et al., 2018,
2014). These in vivo effects of TBT on CYP17A1 concur with the
Z. Peng, et al. Environmental Toxicology and Pharmacology 69 (2019) 16–25

Table 1
Environmental inhibitors of cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) expression.
Chemicals Application Source CYP17A1 mRNA/protein Enzyme kinetics Reference

TBT (infertility) biocide Syrian hamster ↓/↓ unknown Kanimozhi et al. (2017)
Gossypol food bovine theca cell ↓/unknown unknown Myat, T. S. et al
(2017)
2,4-D herbicide Sv/129 mice ↓/unknown unknown Harada et al. (2016)
(infertility)
N-hexane solvent Wistar rat ↓/↓ unknown Li et al. (2016)
BNL anti-fungal agent H295R cell ↓/↓ ↓ Robitaille et al. (2015)
MXC pesticide SD rat/human beings ↓/unknown ↓ Ye et al. (2014)
HPTE MXC's metabolite unknown ↓
ATZ herbicide ICR mice ↓/unknown unknown Jin et al. (2013)
PCBs food Human beings ↓/unknown unknown Karmaus, W. et al
(2011)
BPA food Human beings/rat unknown ↓ Ye, L et al. (2011)
PCZ pesticide SD rat -/unknown ↓ Blystone, C. R et al. (2007)
DBCP pesticide SD rat unknown ↓ Kelce, W. R et al.
(1990)
DPP plasticizer SD rat ↓/unknown ↓ Foster, P. M et al (1983)

TBT, tributyltin; 2,4-D, 2,4-Dichlorophenoxyacetic acid; BNL, benomyl; MXC, methoxychlor; HPTE, 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane; ATZ, atrazine;
PCBs, polychlorinated biphenyls; BPA, bisphenol A; PCZ, prochloraz; DBCP, 1,2-Dibromo-3-chloropropane; DPP, dipentyl phthalate.

previous in vitro results (Kanimozhi et al., 2017).
4.2. Gossypol (structure shown in Fig. 3)
Gossypol is a yellowish polyphenolic compound rich in cotton seeds,
and it was once proposed as a drug for male contraceptive use in China
in the 1970s. But after evaluating its side effects such as hypokalemia
and irreversible suppression of spermatogenesis, World Health
Organization declared gossypol would not be acceptable as a male
contraceptive (Yu and Chan, 1998). The exposure source of gossypol
could be from ingestion of cotton seed oils and materials. It is necessary
for food and animal agricultural industries to carefully manage cotton-
derivative product levels to avoid gossypol toxicity (Yu and Chan,
1998).
Gossypol was demonstrated to downregulate gene expression of
Cyp17a1 in bovine theca cells at concentrations of 0.2–5 μg/mL after
24 h in vitro culture. This was achieved by blocking LH effect. The
downregulation of Cyp17a1 gene expression led to decreased T pro-
duction (Myat and Tetsuka, 2017). But no reliable study has been
carried to testify whether the inhibition on CYP17A1 and T production
is related to gossypol's application as contraceptive and those side ef-
fects.
4.3. 2,4-Dichlorophenoxyacetic acid (2,4-D, structure shown in Fig. 4)
2,4-D is a well-known herbicide, which has been widely used to
control a wide variety of broadleaf plants in agriculture, forestry, and
lawn care (Sturtz et al., 2008). In addition, 2,4-D exposure induces
neurotoxicity (Mattsson et al., 1997), genotoxicity (Amer and Aly,
2001), and lesions in renal tubules (Ozaki et al., 2001). The most no-
table is its testicular toxicity. Significant asthenospermia, necrospermia
and teratospermia have been observed among male farm sprayers
handling2,4-D (Lerda and Rizzi, 1991).
2,4-D was thought to impose its toxicity by binding to proliferator-
activated receptor α (PPARα) and causing peroxisome proliferation
(Kawashima et al., 1984; Lee et al., 1995). PPARα is abundantly ex-
pressed in Leydig cells and is indispensable for maintaining constitutive
steroidogenic gene expression of Cyp17a1, as Cyp17a1 mRNA level was
decreased in the Pparα-null mice compared with the wild-type coun-
terparts (Gazouli et al., 2002; Harada et al., 2016). In addition, after
gavaging at a dose of 130 mg/kg/day for 14 days, 2,4-D significantly
decreased the Cyp17a1 level in the male Sv/129 wild-type mice, which
partly contributed to the decrease in testicular and serum T levels.
Contrarily, no such variation was observed in the Pparα-null mice with
the same treatment. The two opposite results indicated that the down-
regulation of Cyp17a1 level by 2,4-D was mediated by PPARα (Harada
et al., 2016). However, the expression levels of other steroidogenic
enzymes remains unchanged, and exhausted cellular cholesterol
sources is the main reason for reduced testicular T and male infertility
caused by 2,4-D (Harada et al., 2016). In addition, speculated increased
circulating LH as a feedback of reduced T did not appear, this may be
due to the short-term treatment (Harada et al., 2016).
4.4. N-hexane (structure shown in Fig. 5)
N-hexane has been widely applied in shoes, chemicals, foods and
electronics industries as a solvent. N-hexane is such a highly volatile
liquid that occupational exposure is almost inevitable. Statistically,
concentrations of n-hexane in workshops generally range from 188 to
7848 mg/m3, which are enough to cause reproductive toxicity (Liu
et al., 2012). So reports of reduced female fertility caused by n-hexane
occupational poisonings have been increasing in recent years (Sallmen
et al., 2008). Furthermore, as n-hexane's main active metabolite in vivo,
2,5-hexanedione (2,5-HD) is able to cross the placental barrier, in utero
n-hexane exposure exerts some negative effects on fetal development
(Cheng et al., 2012).
Actually N-hexane exposure has been demonstrated to induce dra-
matic endocrine changes in adult F1 females after maternal exposure
during gestation. This is achieved by leaving pregnant Wistar rats to
inhale 0, 100, 500, 2500, or 12,500 ppm n-hexane for 4 h daily during
their initial 20 gestational days, which equal to occupational exposure
at concentrations of 360, 1800, 9000, and 45,000 mg/m3 respectively.
The expression levels of steroidogenic genes in F1 female offsprings'
ovarian granulosa cells were assessed on PND 56. As for our concern on
CYP17A1, it was very interesting to note that Cyp17a1mRNA levels
were significantly higher in the 500 ppm group than in any other group
but considerably lower in the 2500 and 12,500 ppm group compared
with the control. The changes in the CYP17A1 protein levels followed
exactly the same level. These results suggested that 2,5-HD tended to
inhibit CYP17A1 expression at high exposure levels but the effects turn
out to be stimulative when the concentrations are low, which account
partly for the changes in P4 and E2 levels in the supernatant of the
granulosa cells and finally oestrus cycle irregularities (Li et al., 2015).
DNA methylation of promoter regions is an important pre-tran-
scriptional regulational mechanism which causes gene silencing, and
vice versa demethylation reactivates the silenced genes. Briefly
speaking, the methylation degree of the promoter regions is negatively
correlated with the gene expression levels (Cheng et al., 2003). What's

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Z. Peng, et al.
more, the promoter region undergoes de novo methylation during em-
bryonic development, which is susceptible to environmental chemical
substances. De novo methylation partially accounts for the reason why
embryonic development is sensitive to exogenous chemicals during
gestation. Sometimes the abnormal changes caused by toxicants in
methylation status seem likely to persist until offspring reach adulthood
and exert impacts on development and functions (Maccani et al., 2013;
Sanders et al., 2014). This principle actually applies in this case of N-
hexane exposure. Using both MeDIP-chip and MS-HRM, it was found
that when compared with the control group, the methylation degree of
a site 451–500 bp downstream of the transcription start sites in
Cyp17a1 promoter region was slightly decreased in the 100 and
500 ppm groups, slightly increased in the 2500 ppm groups, and sig-
nificantly increased in the 12,500 ppm group. The changes in the me-
thylation degree of that site ultimately lead to the changes in the mRNA
and protein levels as well as other subsequent reproductive and endo-
crine changes in the female offspring (Li et al., 2015).
4.5. Benomyl (BNL, structure shown in Fig. 6)
The aneuploidogen, anti-mitotic and anti-fungal agent BNL is a
benzimidazole derivative used throughout the world against a wide
range of agricultural fungal diseases (Gupta et al., 2004). BNL has been
taken advantage in the application of increasing food crop yields and
protecting ornamental plants from fungi (Lim and Miller, 1997).
Human exposure to BNL and its accumulation in vivo seems inevitable.
Indeed BNL is detectable in the urine of exposed individuals (Hoekstra
et al., 1996). BNL has been shown to be involved in disturbing some
biological processes including protein synthesis (Marinovich et al.,
1996), cell differentiation (McLean et al., 1998) and cytoskeleton as-
sembly (Urani et al., 1995). BNL is also a developmental toxicant, as it
results in anophthalmia in the developing fetus (Hewitt et al., 2005).
The antiandrogenic characteristic of BNL has been demonstrated.
30 μM BNL significantly reduced DHT-stimulated LNCaP cell pro-
liferation by as much as 55% after 72-hour incubation. And exposure to
30 μM BNL for 24 h significantly decreased Cyp17a1 gene expression in
H295R cells, to a extremely great extent of over 90%. CYP17A1 protein
level change followed similar trend under the same conditions. Besides,
catalytic activity of CYP17A1 was also significantly inhibited
(Robitaille et al., 2015). The inhibitory effects of BNL on steroidogenic
enzymes contributed just partly to its anti-androgenic characteristic,
because BNL can also reduce the transactivational capacity of the AR
(Robitaille et al., 2015). It has been proved that BNL caused decreased
testicular and epididymal weights and reduction in epididymal sperm
counts and fertility, and this may be caused by BNL's negative effects on
CYP17A1 expression/activity and T production (Hess et al., 1991).
In the environment, BNL is rapidly degraded to CBZ (Zbozinek,
1984). CBZ is much more efficient in inhibiting testicular microtubule
assembly (IC50 5 μM versus 75 μM) (Lim and Miller, 1997). But no
available report about the effects of CBZ on CYP17A1 was found.
4.6. Methoxychlor (MXC) and its metabolite (structure shown in Figs. 7
and 8)
MXC is a kind of organochlorine which is taken advantage as a
preferred substituent to the once famous and world-widely used yet
environment and health hostile pesticide dichlorodiphenyltri-
chloroethane (DDT). It was initially registered for use in 1948 (Stuchal
et al., 2006) and has gradually replaced DDT's role in agriculture and is
widely used to protect fruits, crops, vegetables, and home gardens from
insects (Gupta et al., 2006). MXC and its residues were found to be quite
persistent in soil, they were present in soil after 18-month treatment by
MXC-scavenging microbes (Golovleva et al., 1984). Expectedly, MXC
has been found to be an environmental pollutant as MXC levels in fish
were previously determined to be as high as 128 μg/kg (Kumar and
Byrtus, 1993). After entering human bodies, MXC is rapidly absorbed
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Environmental Toxicology and Pharmacology 69 (2019) 16–25
and metabolized by hepatic cytochrome P450 enzymes to form 1,1,1-
trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl) ethane and 2,2-
bis-(p-hydroxyphenyl)-1,1,1-trichloroethane, which are commonly
known asmono-OH MXC and bis-OH MXC (HPTE) respectively (Kapoor
et al., 1970). It is important to know that mono-OH MXC (Miller et al.,
2006) and HPTE (Gupta et al., 2007) are thought to be more toxic than
MXC.
It was found that MXC significantly downregulated the mRNA ex-
pression levels of Cyp17a1 in antral follicles from CD-1 mice at 10 and
100 μg/ml after 48-hour culture in vitro, or at 1, 10, 100 μg/ml after 96-
hour culture in vitro (Basavarajappa et al., 2011). MXC showed about
50% inhibition on rat CYP17A1 enzymatic activity, and the endogenous
NADPH system is indispensible for MXC to be a CYP17A1 inhibitor. But
it shows no inhibition on human CYP17A1 (Ye et al., 2014). Contrarily
HPTE was found to inhibit both human and rat CYP17A1 activity in
testis microsome with IC50 values of 1.13 ± 0.10 and 6.87 ± 0.13 μM,
respectively. These results indicated that MXC needed metabolic con-
version in liver into HPTE to become an active CYP17A1 inhibitor (Ye
et al., 2014). Through assessing enzyme kinetics, Lineweaver–Burk plot
analysis showed that both in human and rat testis, HPTE was an un-
competitive inhibitor of CYP17A1, meaning that HPTE exerts its in-
hibitory action via binding to the CYP17A1-progesterone complex (Ye
et al., 2014). HPTE concentration-dependently inhibited T production
by immature Leydig cells with IC50 values of 3.78 ± 0.003 μM. Be-
sides, the inhibition upon CYP17A1 is an important mechanism in this
process (Ye et al., 2014). As for the mechanism by which MXC and
HPTE induced these changes, it is thought to be through the binding to
both nuclear and membrane estrogen receptors. This theory is now
waiting for testify (Basavarajappa et al., 2011). As the results of redu-
cing T, MXC and HPTE adversely affects male reproductive tract de-
velopment in several animal models (Chapin et al., 1997; Gray et al.,
1989).
4.7. Atrazine (ATZ, structure shown in Fig. 9)
ATZ is a widely used triazine herbicide that effectively kills off
broadleaf weeds and grasses through inhibiting photosynthesis
(Markovic et al., 2010). ATZ has been the most commonly and heavily
used pesticide in the United States and other countries to increase food
crop yields for more than 50 years (Jin et al., 2010). The widespread
application of ATZ has caused contamination of the environment in
several countries, including China (Gfrerer et al., 2002; Na et al., 2006;
Ren et al., 2002).
ATZ has been demonstrated to be able to disrupt endocrine home-
ostasis. ATZ achieved this not through T or E2 receptor pathways, but
by down-regulating steroidogenic enzyme expression (Jin et al., 2013).
Among its targets, there is CYP17A1. Though there exist some con-
troversial over the effects of ATZ on some steroidogenic enzymes such
as CYP19A1, ATZ was shown to exert negative effects on CYP17A1 (Jin
et al., 2013; Sanderson et al., 2000). After daily gavaging for 3 weeks,
50, 100 and 200 mg/kg ATZ significantly downregulated the testicular
Cyp17a1 mRNA levels in adult male ICR mice, with decreases of
38%,48% and 30% respectively (Jin et al., 2013). These results were
consistent with another study employing male Wistar rats. Oral ad-
ministration with 50 and 200 mg/kg body weight/day ATZ from post-
natal day (PND) 23 to 50 significantly reduced the transcript levels of
CYP17A1 in testis by 53 and 81%, respectively (Pogrmic et al., 2009).
Together with the inhibition on other steroidogenic enzymes, ATZ fi-
nally caused a reduction of T production and the related male re-
productive abnormalities (Pogrmic et al., 2009).
ATZ is still in a continued widespread use nowadays. As reported,
there are approximately an annual 64–80 million-pound ATZ con-
sumption taken in the United States for agricultural and residential
purposes over the past few decades (Jin et al., 2014).
Z. Peng, et al.
4.8. Polychlorinated biphenyls (PCBs, structure shown in Fig. 10)
As early as 1920s, PCBs were introduced into the USA to be used
primarily in electrical appliances in the form of dielectric fluid for
transformers and capacitors. Besides, PCBs were also used in the
manufacturing ink, plastic and rubber products, and carbonless paper
(Longnecker et al., 1997). Nowadays, the major sources of PCBs in
humans come from meat, fish and the milk of humans and cows (La
Rocca and Mantovani, 2006). It was has been proved that prenatal
exposure to PCBs significantly decreased the gene expression of
Cyp17a1 in adult female offsprings (Karmaus et al. 2011). The inhibi-
tion on Cyp17a1 further causes reproductive disorders (Yu et al., 2000).
4.9. Bisphenol A (BPA, structure shown in Fig. 11)
BPA is used in the manufacturing polycarbonate plastics and epoxy
resins, which are used in many consumer products. There are many
sources of human exposures to BPA, such as packaged and canned food
products, indoor air, dust ingestion and so on (Loganathan and Kannan,
2011).
BPA has been proved to significantly inhibit human and rat testi-
cular CYP17A1 activity in a fixed-type mode. Compared to rat enzyme,
human CYP17A1 was much more sensitive to BPA’s inhibition, because
The IC50 of BPA to inhibit human CYP17A1 activity is
18.99 ± 3.75 μM, and the IC50 to inhibit rat enzyme is
64.67 ± 4.04 μM. The inhibition on CYP17A1 along with the negative
effects on 3β-HSD1 and 17β-HSD3 by BPA, contributed to the decreased
T production by Leydig cells (Ye et al., 2011b). And the decreased T
production induced by BPA further caused reproductive disorders such
as reduced seminal vesicle weights and daily sperm production
(Akingbemi et al., 2004; Herath et al., 2004).
4.10. Prochloraz (PCZ, structure shown in Fig. 12)
The conazole pesticide prochloraz (PCZ) is widely used for horti-
culture and agriculture. It fights against fungi by inhibiting fungal cell
membrane synthesis.
But PCZ is also an antiandrogen. There was a report published in
2007 in which pregnant SD rats were gavaged with 0, 7.8, 15.6, 31.3,
62.5, and 125 mg PCZ/kg/day from gestational day (GD) 14 to 18.
Though PCZ had no effect on fetal testicular Cyp17a1 mRNA levels at all
the doses tested, PCZ significantly inhibited CYP17A1 hydroxylase ac-
tivity with a Ki value of 865 nM. The inhibition on CYP17A1 hydro-
xylase activity contributed to the decrease in serum T levels and finally
caused male reproductive tract malformation in fetal male rats
(Blystone et al., 2007a, b). And another study demonstrated that PCZ
also concentration-dependently inhibited human CYP17A1 activity
(Ohlsson et al., 2009). The inhibition of PCZ on CYP17A1 may lead to
reproductive disorders (Kongsbak et al., 2014).
4.11. 1,2-Dibromo-3-chloropropane (DBCP, structure shown in Fig. 13)
DBCP is a pesticide, it has ever been used for over 20 years to fight
against plant worms. But as it was shown to be antiandrogenic and
cause infertility among male workers, DBCP was banned by the US
Environmental Protection Agency in 1977 (Kano and Natori, 1983; Rao
et al., 1983).
DBCP exerted toxicity on testis and the route of exposure seems to
be a critical factor for the testicular toxicity (Chayoth et al., 1988;
Heindel et al., 1989; Leone et al., 1988). Leydig cell is thought to be the
potential site for the primary toxic effects of DBCP in the SD rat testis.
Interestingly, for CYP17A1 DBCP showed a direct inhibitory effect on
its 17α-hydroxylase but not 17,20-lyase activity (Kelce et al., 1990).
The inhibition of DBCP on CYP17A1 may lead to reproductive disorders
(Semenza et al., 1997).
22
Environmental Toxicology and Pharmacology 69 (2019) 16–25
4.12. Dipentyl phthalate (DPP, structure shown in Fig. 14)
Phthalates are synthetic compounds, which are widely used as
plasticizers and solvents in a variety of polyvinyl chloride consumer
products. But phthalates are not chemically bound to polyvinyl chloride
so they easily leached out. As phthalates usually make up to 40% of the
volume of the plastics, the leached phthalates in the environment can
not be overstated (Binder et al., 1984). Worldwidely, one billion pounds
of phthalates are produced by manufacturers per year (Boxmeer et al.,
2007). DPP has been proved to inhibit CYP17A1. Single or multiple
doses of oral intubation at 7.2 mmol/kg body DPP to SD rats for up to 4
days produced significant decreases in testicular CYP17A1 content and
activity (Foster et al., 1983). And the inhibition on CYP17A1 by DPP
may lead to reproductive disorders (Euling et al., 2013).
5. CYP17A1 inhibition and castration-resistant prostate cancer
(CRPC)
Prostate cancer (PCa) ranks as the second most common cause of
male cancer-related deaths in the United States (Siegel et al., 2012).
91% cases of PCa patients are localized and mostly curable. But for
other patients, PCa exhibits properties of metastatic or localized but
unresponsive to first line therapies(Siegel et al., 2012; Thompson et al.,
2007). The primary treatment strategy for these advanced disease types
is Androgen Deprivation Therapy (ADT), which is accomplished via
bilateral orchiectomy (Loblaw et al., 2007). However, in some cases
primary PCa progresses to CRPC, for which bilateral orchiectomy is
uncurable (Eisenberger et al., 1998). This is based on the fact that some
androgens come from adrenal, in which androgen synthetic and me-
tabolic enzymes are also expressed (Labrie, 2004). And tumors from
CRPC patients exhibit 16.9-fold higher CYP17A1 expression when
compared with primary prostate tumors, which makes CYP17A1 a hot
target for treating CRPC (Scott et al., 2012). Some drugs have been
developed as the therapy for CRPC through inhibiting CYP17A1. These
drugs include abiraterone, TAK-700 (Orteronel) and so on. Inhibition
on CYP17A1 has been established as an important route for fighting
against CRPC, and new CYP17A1-inhibiting drugs are worth in-
vestigation (Porubek, 2013). However, as extensive reviews have been
published on this topic (Audenet et al., 2013; Gomez et al., 2015; Ripert
et al., 2013), and in order to focus on the role of environmental
CYP17A1 inhibition in reproductive disorders, this review does not
discuss those drugs anymore.
6. Summary and conclusions
Leydig cells in the interstitial compartment of the testis are the main
source of circulatory androgens. Androgens, especially T, are indis-
pensable for male genitalia differentiation, testis descent and stimu-
lating the development of male reproductive tract during the fetal
period. And at adulthood they are required for producing sperms,
maintaining accessory sex organs and sexual behavior. Thus disruption
of androgen biosynthesis by EEDs inhibiting CYP17A1 may cause male
reproductive disorders. However, our knowledge on the different EEDs
targeting CYP17A1 is still very limited, further studies are warranted to
assess the properties of environmental CYP17A1 inhibitors.
Conflict of interest
The authors declare no conflicts of interest.
Transparency document
The Transparency document associated with this article can be
found in the online version.
Z. Peng, et al.
Acknowledgement
We would like to thank Jing Wang for critical comments and advice
on this review.
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