Reproductive Toxicology 31 (2011) 359–362
Contents lists available at ScienceDirect
Reproductive Toxicology
journa l homepage: www.e lsev ier .com
Perinat ts f
overvie
Smita Sa
National Cente Repro
J M Street, Pare
a r t i c l
Article history:
Received 29 M
Received in re
22 September
Accepted 8 Oc
Available onlin
Key words:
Perinatal expo
Endocrine disr
Bisphenol A
Fertility
h fun
rom p
n to h
ental
fert
rmen
ttemp
re and
The increasing incidence of reproductive disorders observed
over the past few decades has raised concern about the role of sub-
stances known as endocrine disrupters (EDs) that are capable of
modulating or disrupting the function of the endocrine system. One
such estrog
A (BPA), a m
bonateplas
It easily leac
containers
sealants int
tles after re
[1,2].
Investiga
placental tis
indicate tha
BPA measu
extensively
in breast m
neonatal de
a higher ris
efficiency a
warrants st
periods of d
∗ Correspon
E-mail add
1. Critical factors for evaluating the effects of BPA exposure
Recent studies demonstrate that the non-monotonic dose
response of BPA leads to a variety of adverse effects, including its
0890-6238/$ –
doi:10.1016/j.enic ED, known for its ubiquitous exposure is Bisphenol
onomer that is used in the manufacturing of polycar-
tics, epoxy resins andamultitudeof consumerproducts.
hes from the inner lining of tin cans and microwavable
into food during heating. It also leaches from dental
o saliva and into beverages from polycarbonate bot-
peated usage or contact with any acidic/alkaline liquids
tion into the levels of BPA in maternal and fetal plasma,
sue, amniotic fluid and umbilical cord blood in humans,
t BPA can easily transverse the placental barrier [3–6].
rements in various human tissues and fluids have been
reviewed by Vandenberg et al. [7]. The presence of BPA
ilk suggests its potential to influence crucial periods of
velopment [8]. Developing fetuses and neonates have
k of BPA exposure due to a decreased metabolizing
nd limited serum binding proteins [3,9]. This evidence
udying the effects of BPA exposure during vulnerable
evelopment.
ding author. Tel.: +91 22 24192022/24192139; fax: +91 22 24139412.
resses: vanageg@nirrh.res.in, saliansmita@yahoo.com (G. Vanage).
effect on reproduction at low doses [10,11]. These studies have
generated an entirely new paradigm in toxicity evaluation. Proper
selection of animal strains and the use of an appropriate positive
control are critical pre-requisites for drawing significant inferences
from low-dose BPA studies [12]. Additionally, sensitivity to BPA
is not the same at all stages of life, and there are certain critical
windows of development that are more sensitive to BPA exposure
[13].
One such sensitive and vulnerable “window” wherein organ
differentiation and development occurs is the perinatal period.
The perinatal stage encompasses the crucial periods of gestation
and lactation where the development and programming of the
hypothalamus–pituitary–testicular (HPT) axis mainly occurs. To
study perinatal exposure of rodents to BPA, an oral route of admin-
istration is used, which is considered a more relevant route of
exposure for evaluating BPA effects. The aim of this article is to
present an overview of the reproductive toxicity caused by BPA
exposure during the perinatal period.
2. Effects of perinatal BPA exposure on female offspring
Female rat offspring obtained from mothers perinatally exposed
to BPA have been associated with a wide range of reproductive dis-
orders during development, including an early onset of puberty,
see front matter © 2010 Elsevier Inc. All rights reserved.
reprotox.2010.10.008al exposure of rats to Bisphenol A affec
w
lian, Tanvi Doshi, Geeta Vanage ∗
r for Preclinical Reproductive and Genetic Toxicology, National Institute for Research in
l, Mumbai 400 012, Maharashtra, India
e i n f o
arch 2010
vised form
2010
tober 2010
e 20 October 2010
sure
upters
a b s t r a c t
Endocrine disruptors (ED) induce bot
A (BPA) is a known ED that leaches f
Maternal BPA exposure has been show
rats exposed perinatally to environm
cantly impaired spermatogenesis and
germ line which manifested as impai
F3 generations. This overview is an a
with regards to perinatal BPA exposu/ locate / reprotox
ertility of male offspring—An
ductive Health (ICMR),
ctional and behavioral reproductive abnormalities. Bisphenol
olycarbonate plastics, as such human exposure is common.
ave negative effects on the fertility of male offspring. Pregnant
ly relevant doses of BPA gave birth to offspring with signifi-
ility. Perinatal exposure had deleterious effects on the male
ts in the fertility of F1 male offspring and subsequent F2 and
t to summarize the currently available data in the literature
male fertility.
© 2010 Elsevier Inc. All rights reserved.

360 S. Salian et al. / Reproductive Toxicology 31 (2011) 359–362
Fig. 1. Diagram oduct
gestation day
disruption i
mone (LH)
leads to du
phogenesis
[14,15]. Ad
low-dose pe
ual activity
3. Perinata
The role
extensively
published l
sure to low
information
Perinatal ex
pogenesis i
perinatally
dose-depen
long-term e
theeffectof
Both in vitr
disrupting g
[23]. Thus,
tributing fa
and diabete
4. Perinata
Significa
tract (Fig. 1
5. Influenc
(a) Onmale
terone l
epididy
[24]. Stu
its effec
changes
ing beh
d neo
t BP
igeno
taine
ects o
A’s e
gely
the
T axi
e sys
riod c
et a
BPA a
plasm
par
um t
mula
osed
the h
A on
sper
rphomatic representation of significant developmental changes occurring in the repr
and postnatal day respectively and W represents day of weaning.
n estrus cyclicity and decreased plasma luteinizing hor-
levels in adulthood [14]. Perinatal exposure to BPA also
ctal hyperplasia and persistent alterations in the mor-
of the mammary glands and uterus in female offspring
ditionally, a number of studies have documented that
rinatal exposure to BPA affects brain development, sex-
and behavior [16,17].
l exposure and linkages to obesity and diabetes
of BPA in body weight regulation of rodents has been
reviewed by Rubin and Soto [18]. There is extensive
iterature demonstrating the effects of perinatal expo-
doses of BPA on female offspring; however, minimal
exists with regards to BPA’s effect on male offspring.
posure to BPA via drinking water leads to increased adi-
n female rats at weaning [19,20]. Male and female rats
exposed to BPA also exhibit higher body weights in a
dent manner when compared to controls [14]. These
ffects on body weight have been largely attributed to
BPAon thyroidhormone levels in theseanimals [21,22].
an
tha
ep
ob
eff
BP
lar
(b) On
HP
tiv
pe
abe
to
in
com
ser
sti
exp
in
BP
(c) On
moo and in vivo studies in rodents have linked BPA to
lucose homeostasis by influencing pancreatic function
BPA exposure in the perinatal window could be a con-
ctor in predisposing rats to the development of obesity
s.
l window and male reproductive development
nt developmental changes in the male reproductive
) occur during the perinatal window.
e of perinatal BPA exposure
organs anddevelopment: Effects of BPA on serum testos-
evels and reproductive organs such as the prostate and
mis have been reviewed to some extent by Richter et al.
dies on perinatal BPA exposure have also documented
t on target organs like the brain. These studies found
in morphogenesis and disturbances in sexual and mat-
avior as well as memory [25–27,16,17,28]. Gestational
ing end
changes
axis we
of slou
observa
affect th
offsprin
utero (G
sperm p
umente
to BPA
morpho
findings
in BPA-
substan
BPA cou
these o
(d) On ferti
generat
evidencive tract of male rats during perinatal period. GD and PND represent
natal exposure to BPA have provided further evidence
A exposure can lead to epigenetic alterations in the
me of the prostrate and uterus [29,30]. Male offspring
d after perinatal exposure to BPA showed no obvious
n somatic growth or anogenital distance [31]; however
ffect on other male reproductive organs, like the testis,
remains unknown.
HPT axis of male offspring: Optimal functioning of the
s is required for normal regulation of the male reproduc-
tem.Minorhormonalperturbationsduring theperinatal
an leave a long and lasting impact on fertility. Watan-
l. [32] reported that perinatal exposure (GD 6 to PND 20)
t 4 mg/kg body weight (bw) led to a significant increase
a testosterone concentrations in adulthood by 88%,
ed to controls. In our study, we observed increases in
estosterone and LH levels coupled with reduced follicle-
ting hormone (FSH) levels in adult F1 males perinatally
to BPA (1.2 and 2.4g/kg bw) [33]. These disruptions
ormonal profile are indicative of the adverse effects of
the HPT axis in the developing fetus.
matogenesis of male offspring: Changes in testicular
logy can act as an important indicator for evaluat-
-points related to reproductive function. In our study,
in endocrine regulation and impairment of the HPT
re evident at the testicular level with the presence
ghing (Fig. 2) in the seminiferous tubules [33]. Our
tions suggest that BPA may also have the potential to
e process of spermatogenesis. Earlier reports of male
g exposed to low doses of BPA (20g/kg bw/day) in
D 11–GD 17) resulted in reduced efficiency in daily
roduction. Subsequently a number of studies have doc-
d that prenatal and neonatal exposure of male rats
causes significant impairments in sperm motility and
logy [33–36]. This evidence further substantiates our
of a significantly decreased sperm count and motility
exposed male offspring during adulthood [33]. These
tial perturbations in the spermatogenesis suggest that
ld induce a long and lasting impact on the fertility of
ffspring during adulthood.
lity of male offspring: Previous reports on two and three
ional toxicity studies of BPA have provided negative
e with regards to its effect on fertility [37,38]. While