CYP1A1 3801T>C polymorphism

implicated in altered xenobiotic

metabolism is not associated
with variations in sperm production
and function as measured by total
motile sperm and fertilization rates
with intracytoplasmic sperm
injection
Jason M. Franasiak, M.D.,a Rebecca Barnett, M.D.,a Thomas A. Molinaro, M.D., M.S.C.E.,b David Gabriele, B.S.,b
Tori D. Gartmond, B.S.,b Nathan R. Treff, Ph.D.,a,b and Richard T. Scott, M.D., H.C.L.D.a,b
a
Division of Reproductive Endocrinology, Department of Obstetrics, Gynecology and Reproductive Science, Robert Wood
Johnson Medical School, Rutgers University, New Brunswick; and b Reproductive Medicine Associates of New Jersey,
Morristown, New Jersey

Objective: To evaluate the cytochrome P450 3801T>C polymorphism's frequency in relation to semen production, as determined
by semen analysis parameters, and sperm function, as determined by fertilization rates with intracytoplasmic sperm injection
(ICSI).
Design: Casecontrol study.
Setting: Academic-afliated private practice.
Patient(s): This study included patients undergoing IVF from 2004 to 2014 grouped into categories based on semen analysis param-
eters performed at a single andrology laboratory. Cases were patients with total motile sperm (TMS) counts of %20
106. Frequency-
matched controls were selected with TMS of >20
106.
Intervention(s): The 3801T>C polymorphism was identied using DNA from serum samples with real-time quantitative polymerase
chain reaction.
Main Outcome Measure(s): CYP1A1 3801T>C polymorphism frequency in TMS groups and distribution in fertilization rate outcomes
with ICSI.
Result(s): A total of 460 cases were identied with %20
106 TMS, and 489 age-matched controls with >20
106 TMS were selected
across the study time frame. For those with <5
106 vs. >20
106 TMS there was no difference when comparing heterozygous (odds
ratio [OR] 0.96; 95% condence interval [CI] 0.661.40) or homozygous mutant (OR 1.33; 95% CI 0.523.20) with the wild-type patients.
Additionally, no difference was seen when analyzing subgroups <5
106, 520
106, and >20
106 TMS in a similar fashion.
Receiver operating characteristic (ROC) curve analysis did not nd a signicant TMS count based on presence of the polymorphism
(area under the ROC curve 0.51). There were 460 patients who underwent IVF/ICSI, and fertilization rates did not differ with
presence of the polymorphism (area under the ROC curve 0.50).

Received December 23, 2015; revised March 18, 2016; accepted April 4, 2016; published online April 23, 2016.
J.M.F. has nothing to disclose. R.B. has nothing to disclose. T.A.M. has nothing to disclose. D.G. has nothing to disclose. T.D.G. has nothing to disclose. N.R.T.
has nothing to disclose. R.T.S. has nothing to disclose.
Reprint requests: Jason M. Franasiak, M.D., Division of Reproductive Endocrinology, Department of Obstetrics, Gynecology and Reproductive Science, Rob-
ert Wood Johnson Medical School, Rutgers University, 140 Allen Road, Basking Ridge, New Brunswick, New Jersey 07920 (E-mail: jfranasiak@rmanj.
com).

Fertility and Sterility Vol. 106, No. 2, August 2016 0015-0282/$36.00

Copyright 2016 American Society for Reproductive Medicine, Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.fertnstert.2016.04.003

VOL. 106 NO. 2 / AUGUST 2016 481

ORIGINAL ARTICLE: GENETICS
Conclusion(s): Allele frequency of the 3801T>C polymorphism does not correlate with semen production as determined by TMS
counts or sperm function as determined by fertilization rates with ICSI. The use of neither semen analysis parameters nor fertilization
rates with ICSI helps identify CYP1A1 polymorphism carriers. (Fertil Steril 2016;106:4816. 2016 by American Society for Repro-
ductive Medicine.)
Key Words: Fertilization, male infertility, P450 3801T>C polymorphism, total motile sperm
Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/franasiakj-cyp1a1-
polymorphism-sperm-parameters/
I
nfertility is a multifactorial disorder that affects approxi-
mately 15% of couples (1). Male factor infertility represents
a signicant portion of the causes of general infertility, and
it is thought that 15%30% of male factor infertility issues are
genetic abnormalities (2, 3). Additionally, environmental
factors, such as the accumulation of xenobiotics/foreign
chemicals, represent a major cause of the decline in human
semen quality over the past decades (4). Polymorphisms or
mutation in the genes that encode for the enzymatic
metabolism of these xenobiotics can link the environmental
causes and genetic causes of male infertility.
The cytochrome P450 (CYP450) mono-oxygenase gene
superfamily of enzymes is important in phase 1 oxidation
reduction reactions that catalyze toxic metabolites, which
can then be processed by phase 2 enzymes (4, 5). The CYP1
family has two genes: CYP1A1 and CYP1A2, which encode
P450 CYP1A1 and CYP1A2 enzymes. The aromatic
epoxidation and N-hydroxylation reactions catalyzed by
these enzymes during phase 1 oxidation result in the
activation of procarcinogens, in the case of CYP1A1
polycylic aromatic hydrocarbons, which then have
genotoxic and mutagenic properties before they are further
metabolized by phase 2 enzymes (5, 6). These compounds
can be found in seminal plasma, are increased in individuals
exhibiting teratozoospermia, and have also been associated
with increased risk of nonreproductive tract cancers (4, 7,
8). Further, CYP1A1 knockout mice have been shown to
have greatly increased toxicity, carcinogenicity, and
teratogenesis when exposed to environmental toxins,
although no data exist on the fertility status of male
knockout mice (9). In recent years several studies have
investigated the link between CYP1A1 polymorphisms and
idiopathic male infertility (4, 1018). In particular,
idiopathic male infertility has been linked to the
CYP1A1T>C polymorphism, which can alter gene
expression and RNA stability and results in a highly
inducible state of activity (19). These efforts have been made
in part to better characterize male infertility beyond simply
the semen analysis (SA). However, the results of these case
control studies have been conicting and inconclusive, even
in light of two recent systematic reviews and meta-analyses
of the literature (17, 18). Furthermore, little is known about
the correlation of the CYP1A1 polymorphisms and other
means of gauging male factor infertility, with limited data
at the evaluation stage utilizing SA parameters (11), and no
information in the treatment stage with fertilization rate
outcomes. This is a large decit in the knowledge required
to understand the pathophysiology of these polymorphisms
more completely.
482
To better understand how the CYP1A1T>C polymor-
phism may impact male infertility, this study characterizes
polymorphism frequencies in populations based on SA pa-
rameters. Furthermore, to determine whether there are defects
in function, fertilization rates were analyzed in the presence
or absence of the polymorphism in infertile couples undergo-
ing IVF and intracytoplasmic sperm injection (ICSI).
MATERIALS AND METHODS
The goal of this study was to further elucidate the impact of
the CYP1A1T>C polymorphism on parameters most widely
used to evaluate male factor infertility and factors most
widely viewed as the major outcome measure in male infer-
tility. A casecontrol study design was used to describe the
CYP1A1T>C polymorphism's prevalence in patients group-
ed by SA parameters. Additionally, the impact of
CYP1A1T>C polymorphism on fertilization rates was inves-
tigated in a secondary analysis. To best control for con-
founding variables, we specically looked at fertilization
rates in couples undergoing IVF with ICSI. All data collec-
tion and analysis was institutional review board approved.
Subjects provided written consent for use of these samples
in research.
Patient Population
Patients were identied from a DNA bank of specimens
collected under institutional review board approval at a single
academic center. The DNA bank was established and speci-
mens collected longitudinally in an effort to answer questions
related to reproductive competence and outcomes. Patients
within the DNA bank were identied using the electronic
medical record at a single, academic institution and querying
over a 10-year period of time from 2004 to 2014. To enrich the
number of patients with male factor infertility, a casecontrol
study design was used. The patient groups were established
using the SA parameters, in particular total motile sperm
(TMS), from the cycle most proximal to their infertility treat-
ment cycle. Subjects with %20
106 TMS were identied as
cases. This group was further broken down into subgroups
with <5
106 TMS and those with TMS between 5 and
20
106. The frequency-matched control group comprised
selected age-matched patients identied over that time frame
who had >20
106 TMS. In an effort to ensure generaliz-
ability to the general infertility population, only the rst
treatment cycle was evaluated for each patient included,
and thus each patient is included only once in the analysis.
A secondary analysis was then performed examining the
VOL. 106 NO. 2 / AUGUST 2016

impact of CYP1A1T>C polymorphism on fertilization rates
within this population.
Genotyping
Genomic DNA was extracted from peripheral blood samples
using a DNA isolation kit. The polymorphism was identied
with a TaqMan Custom SNP genotyping Assay (rs4646903)
with real-time quantitative polymerase chain reaction (PCR)
(Life Technologies). The primers used for the amplication
in PCR were forward 50 -GCACTGGTACCATTTTGTTTCACT-
30 and reverse 50 -GCTGAGGTGGGAGAATCGT-30 . Reporter
1 sequence was CACCTCCTGGGCTCA (VIC), and reporter 2
sequence was ACCTCCCGGGCTCA (FAM). Real-time quanti-
tative PCR was performed according to the manufacturer's
recommendations. Results were characterized as TT (homozy-
gous wild type), TC (heterozygous), and CC (homozygous
mutant).
Semen Parameters
The SA identied was the most proximal analysis per-
formed relative to the treatment cycle. The ejaculate was
obtained by masturbation after a minimum of 48 hours of
abstinence. Semen analysis was performed according to
the protocol recommended by the World Health Organiza-
tion, using a Mackler grid. The records of sperm concentra-
tions, sperm motility, and total motile sperm concentrations
were calculated in a single andrology laboratory using the
same strict quality assurance and quality control parame-
ters during the time period from which patients were
selected.
Fertilization Rates
The fertilization rates in patients undergoing IVF were
calculated by dividing the number of two pronuclei identi-
ed 1618 hours after fertilization by the number of meta-
phase II oocytes obtained at vaginal oocyte retrieval. To
limit confounding factors, only those couples who under-
went ICSI as part of their IVF treatment were included for
comparison of fertilization rates. In this case, couples were
undergoing ICSI secondary to preimplantation genetic
screening being part of their treatment paradigm, not
because of any component of male or female infertility diag-
nosis. Intracytoplasmic sperm injections is performed to
eliminate the possibility of sperm contamination at the
time of embryo biopsy in the case of conventional
insemination.
Study Design
The association between the CYP1A1 polymorphism and
semen parameters was analyzed as a casecontrol study.
Cases were those with low TMS, whereas controls were those
with TMS >20
106. The exposed groups were dened as
those individuals with one or both alleles positive for the
CYP1A1 polymorphism, whereas unexposed were those who
were wild type. The proportion of homozygous wild type, het-
erozygous, and homozygous mutants for the polymorphism
VOL. 106 NO. 2 / AUGUST 2016
Fertility and Sterility
was analyzed among the TMS groups of <5
106, 520

106, and >20
106 to determine whether the polymorphism
was more prevalent in patients with lower TMS. Additionally,
a receiver operating characteristic (ROC) curve analysis was
performed with TMS count as a continuous variable to deter-
mine a correlation with presence of the polymorphism. In the
secondary analysis, a ROC curve analysis was performed with
fertilization rate with ICSI as a continuous variable, to deter-
mine a correlation with presence of the polymorphism.
Statistical Analysis
The cases and controls were analyzed for allele frequency
(wild type, heterozygous, and homozygous mutant), and
odds ratios (ORs) with condence intervals (CIs) were calcu-
lated. This analysis was performed for <5
106 TMS and
>20
106 TMS, as well as among the subgroups of <5

106, 520
106, and > 20
106 TMS. Analysis of variance
was used to analyze age differences, and a c2 test was used to
analyze ethnicity differences across TMS populations.
Receiver operating characteristic curve analysis was per-
formed in standard fashion using Analyse-it3 (Analyse-it
Software). An a error of <0.05 was considered statistically
signicant.
RESULTS
Demographics
The study population comprised 949 patients undergoing
their rst IVF cycle at a large fertility practice. There were
460 cases identied who had %20
106 TMS. Of those,
230 had <5
106 TMS and 230 had 520
106 TMS. An
additional 489 had >20
106 TMS and were age-matched
controls selected across the study time frame. The mean age
for the sample population was 35.2 years (range, 19.9
54.8 years) and did not differ among TMS groups (P .59).
Population genotyping revealed a homozygous wild type
CYP1A1 gene in 681 patients (72%), heterozygous for the
polymorphism in 234 (25%) and homozygous mutant for
the polymorphism in 34 (3.6%).
According to self-reported ethnicity, the patients were
53.8% Caucasian (n 511), 9.6% Asian (n 93), 8.0% Afri-
can American (n 73), and 0.1% American Indian (n 1). In
this population 28.6% (n 271) self-reported their ethnicity
as other. There was no difference in ethnicity and TMS cate-
gories (P .60).
TABLE 1
Frequency of polymorphism seen among patients categorized
according to total motile sperm counts on SA.
CYP1A1 polymorphism
Total motile Homozygous Homozygous
sperm count (3106) wild type Heterozygous mutant
<5 162 (17.1) 58 (6.1) 10 (1.1)
5 to <20 174 (18.3) 48 (5.1) 8 (0.8)
R20 345 (36.4) 128 (13.5) 16 (1.7)
Note: Values are total counts (percentage).
Franasiak. CYP1A1 polymorphism and sperm parameters. Fertil Steril 2016.
483
ORIGINAL ARTICLE: GENETICS

CI 0.523.20; P .49) with the wild-type patients. There was

TABLE 2
also no difference seen when analyzing subgroups <5

Summary of ORs for comparison groups among TMS categories and
106, 520
106, and >20
106 TMS in a similar fashion.
genotype ndings for the CYP1A1 polymorphism. The ORs are summarized in Table 2. Of note, the subgroup
analysis performed analyzing only those individuals with
Comparison OR (95% CI) P value
TMS <20
106 did not show a difference when comparing
Wild type to heterozygous allele frequencies. Finally, ROC curve analysis did not nd a
<5
106 TMS vs. >20
106 0.96 (0.661.40) .85
<5
106 TMS vs. 520
106 1.36 (0.822.06) .24
signicant break point for TMS count when dividing patients
520
106 TMS vs. >20
106 0.74 (0.501.10) .12 into absence or presence (either heterozygous or homozygous)
Wild type to homozygous mutant for the 3801T>C polymorphism (area under the ROC curve
<5
106 TMS vs. >20
106 1.33 (0.523.20) .49 [AUC] 0.51). The ROC curve is shown in Figure 1. Perfor-
<5
106 TMS vs. 520
106 1.34 (0.464.02) .54
520
106 TMS vs. >20
106 0.99 (0.362.51) .98 mance of the ROC curve did not improve when restricting
Note: No differences were seen in polymorphism frequency among the total motile sperm TMS to <20
106. Given the possible difference between to-
categories. tal motile sperm and total progressively motile sperm, a sec-
Franasiak. CYP1A1 polymorphism and sperm parameters. Fertil Steril 2016. ond ROC curve analysis using total progressively motile
sperm was used. The performance of the curve did not change
(AUC 0.51).
SNP Association with Semen Analysis Parameters
In the rst comparison, the cases and controls were analyzed
for allele frequency among the TMS groups using ORs. This SNP Association with Fertilization Rate
was done for %20
106 TMS and >20
106 TMS, as well Of the patients in this population, a subset of 460 underwent
as among the subgroups of <5
106, 520
106, and >20 IVF/ICSI, and fertilization rates were calculated. Of those, 330

106 TMS. The frequencies of alleles by TMS are shown in were homozygous wild type, 113 were heterozygous, and 17
Table 1. For those <5
106 and >20
106 TMS, there was were homozygous mutant. A ROC curve analysis was per-
no difference when comparing heterozygous (OR 0.96; 95% formed and did not nd a signicant break point for fertiliza-
CI 0.661.40; P .85) or homozygous mutant (OR 1.33; 95% tion rate with ICSI dividing patients into absence or presence

FIGURE 1

Receiver operating characteristic curve analysis using TMS count as a continuous variable in comparison with presence (heterozygous or
homozygous mutant) for the CYP1A1 polymorphism. Area under the curve is 0.51. FPF false positive fraction; TPF true positive fraction.
Franasiak. CYP1A1 polymorphism and sperm parameters. Fertil Steril 2016.

484 VOL. 106 NO. 2 / AUGUST 2016


(either heterozygous or homozygous) for the 3801T>C poly-
morphism (AUC 0.50). The ROC curve is shown in Figure 2.
A post hoc power calculation was performed, and it was
determined that the study was able to detect a 14% difference
in fertilization rate between the homozygous wild type and
homozygous mutant populations.
DISCUSSION
The impact of the CYP1A1 polymorphism on infertility has
been incompletely studied, and results in the literature are
conicting. Few studies have analyzed its impact on impor-
tant parameters of semen production, such as total motile
sperm, and no studies to our knowledge have analyzed its
impact on sperm function and clinical outcomes related to
male factor infertility, namely fertilization. In this large
casecontrol study, the data demonstrate a lack of correlation
between TMS counts or fertilization rates with ICSI and the
3801T>C polymorphism.
Male factor infertility remains both a pervasive and chal-
lenging disorder in reproductive medicine. Although it is
commonly identied as a cause for infertility, the specic eti-
ology and pathophysiology is poorly understood. Novel tech-
nologies that analyze the impact of genetics on disease
process have been heralded as a promising path forward in
the understanding of male factor infertility (3). This has
FIGURE 2
Receiver operating characteristic curve analysis using fertilization rate as a continuous variable in comparison with presence (heterozygous or
homozygous mutant) for the CYP1A1 polymorphism. Area under the curve is 0.50. FPF false positive fraction; TPF true positive fraction.
Franasiak. CYP1A1 polymorphism and sperm parameters. Fertil Steril 2016.
VOL. 106 NO. 2 / AUGUST 2016
Fertility and Sterility
yielded results that have clear associations with male factor
infertility, both from mutations on the sex chromosomes,
such as azoospermia factor (AZFa, AZFb, AZFc) deletions
that result in azoospermia and oligozoospermia (20, 21),
and mutations on autosomes, such as mutations in the
CFTR gene on chromosome 7, which results in congenital
bilateral absence of the vas deferens (2).
There are a number of other autosomal mutations that
have been less clearly linked to male factor infertility. Inter-
esting areas of research are genes associated with downstream
effects of estrogen. Both ESR1 and ESR2 have been shown to
be involved in altered spermatogenesis (22, 23), although this
evidence has not been uniformly replicated (24). The CYP1A1
and CYP1B1 genes are associated with endogenous estrogen
metabolism and thus may be involved in modulating
spermatogenesis, as well as their role in mediating
metabolism of harmful xenobiotics (25, 26). It is important
to note that genome-wide association studies that attempt
to determine genetic links to male infertility are challenging
to reliably interpret, given the issue with de novo mutations
and the variability of the SA that is often an outcome indica-
tor used for studies in the eld.
The data presented here reveal no association with the
major workup, in the form of SA, and outcomes, in the
form of fertilization for couples undergoing infertility treat-
ment with IVF/ICSI. These ndings are an important addition
485
ORIGINAL ARTICLE: GENETICS
to the body of evidence surrounding the correlation between
CYP1A1 polymorphisms and male factor infertility. To date,
there have not been data presented that detail sperm function
as demonstrated by fertilization rates among different
genotypes.
There are some limitations to this study that must be
noted. In terms of the polymorphism's effect on fertilization,
only those undergoing ICSI were analyzed. This was done in
an effort to limit bias introduced because it is common prac-
tice for those with poorer sperm quality to have ICSI recom-
mended for treatment. Thus, it seemed most prudent to
reduce bias by using only those who were undergoing ICSI
rather than a mixture of ICSI and conventional insemination.
It is possible that effects may have been different if outcomes
based on IUI or conventional IVF insemination were used,
given that these conditions rely on sperm motility. Second,
the prevalence of the polymorphism in our patient population
was lower than in some other published studies; however, no
difference was found in that dataset either (13). Further, the
prevalence of homozygous mutant for the polymorphism
was low, and with higher prevalence a genetic association
may be found. Although the number of male patients under-
going infertility treatment included in this analysis is large
when compared with the currently published literature, the
possibility remains that the study of a population in which
the prevalence of the polymorphism is higher may yield dif-
ferential ndings. Additionally, given the wide variety of
semen parameter results included, uniform information about
patient testis size, endocrine parameters, occupational status,
smoking status, and body mass inex were not uniformly
available. Although there is not a reason to think the
CYP1A1 polymorphism would cluster in one particular group
given these parameters, it is possible this confounds the anal-
ysis. Finally, when analyzing fertilization rate, oocyte quality
is a factor. The fertilization rate was high in all groups, and no
difference was found. Further, there is no indication that poor
oocyte quality would be overrepresented in one polymor-
phism group over another, although this cannot be deni-
tively ruled out.
In summary, neither TMS counts nor fertilization rates
with ICSI were found to be associated with the frequency of
the CYP1A1 3801T>C polymorphism. More data are needed
analyzing its effect in different patient populations to deter-
mine the signicance of its impact, if any. At present, it
does not seem to have predictive value when it comes to the
major clinical parameters associated with male infertility.
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