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Toxicology Mechanisms and Methods

Volume 26, 2016 - Issue 3
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Review article

Exposure to bisphenol A (BPA) in Wistar

rats reduces sperm quality with disruption
of ERK signal pathway
Juan Li, Rui Mao, Qin Zhou, Ling Ding, Jin Tao, Mao-Mei Ran, show all
Pages 180-188 | Received 26 Oct 2015, Accepted 04 Jan 2016, Published online: 10 Feb
2016

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http://dx.doi.org/10.3109/15376516.2016.1139024
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Abstract

Bisphenol A (BPA) is an estrogenic environmental toxin widely used in the production of

plastics and ubiquitous human exposure to this chemical has been proposed to be a potential
risk to human health. Exposure to BPA can negatively impact sperm quality. However, the
mechanism remains largely unknown. The objectives of this study were to assess the role of
BPA on sperm quality and explore the possible mechanisms. The Wistar male rats (aged 28
days) were administered BPA by oral gavage for 28 days at dose of 50, 100 and
200mg/kg/day; meanwhile, the negative control with corn oil (0mg/kg/day BPA) and
positive control with E2 at the dose of 100g/kg/day. The sperm density, sperm activity and
sperm survival rate were analyzed byCASA system, and the sperm abnormality rate was
analyzed by improved Papanicolaou stained. The protein expression levels of Src/p-Src,
ERK1/2, p-ERK1/2 and CREB/p-CREB were detected by Western bolt. The results showed
that the body weight gain, testes weight, testis coefficient, sperm density, sperm activity,
sperm survival rate and protein expression levels of p-ERK1, p-ERK2 and p-CREB
decreased, but the sperm abnormality rate increased with increasing BPA concentrations.
There were positive correlations between sperm density, sperm activity and sperm survival
rate with protein expression levels of p-ERK1, p-ERK2 and p-CREB, and negative
correlations between sperm abnormality rate with the protein expression levels of p-ERK1, p-
ERK2 and p-CREB. Results from the structural equation model demonstrated that BPA
retained a significant negative effect to p-ERK, whereas p-ERK retained a significant positive
effect to sperm quality and acted as the mediate variable. This study provides a novel insight
regarding the potential role of p-ERK1 and p-ERK2 protein kinase on reproductive toxicity
of BPA. The adverse effects of BPA on adult male sperm quality may be through the
induction of the disruption of ERK signal pathway. However, additional research is needed to
confirm our findings and to further test the suggested potential mechanisms.

Keywords:Bisphenol A, ERK signal pathway, sperm quality

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Search this

Even though BPA is a weak oestrogen, there is a

mechanism by which low levels of BPA could have a
powerful health effect
July 14, 2009 at 3:11 pm | Posted in Briefing | 2 Comments

Update, October 2011: Read more about how EDCs can have effects at low doses in our 2-
part series. Part 1: Are EDCs too swamped by natural hormones to have an effect? and Part
2: About why being less attracted to receptors than natural hormones does not mean EDCs
have less effect.
A new study [EHP 117:10531058 (2009); Bouskine et al.] has shed some light on how
bisphenol-A (BPA) can substantially interfere with hormone signalling within the body,
even though it is a relatively weak xenoestrogen.

As regular readers of H&E will know, BPA is an increasingly controversial chemical additive
commonly used in plastics such as food packaging and medical devices.

Concerns centre on its ability to mimic the hormone oestrogen, but sceptics of the potential
for BPA to harm health argue that it is too weak a hormone to have an effect on cell function.

Here, we sketch out a mechanism by which BPA could have a much stronger effect than the
sceptics argue, via an indirect pathway rather than a direct effect on the part of the cell
nucleus which responds to oestrogen.

Note: We have tried to make this article as accessible as possible; if you are familiar with the
cellular processes described, please be patient with our slightly long-winded explanation. Full
references are at the bottom of this post.

KEY
ED = Endocrine Disruptor
ER = Oestrogen Receptor
E2 = Oestrogen

Is there a mechanism by which BPA, even though a weak xenoestrogen, can

disrupt hormone signalling at environmentally-relevant concentrations?

Summary: The xenoestrogen BPA can stimulate cell proliferation and endocrine disruption
at extremely low levels by acting on a G Protein Coupled Receptor. BPA does not therefore
need to be present at the high levels needed for it to affect the nuclear Oestrogen Receptor
(ER) in order to have a substantial effect.

by Dr John Newby, Medical Information Scientist, Cancer Prevention and Education Society

One of the main arguments against the idea that endocrine disruptors (EDs) such as BPA can
have adverse health effects at low levels, is the oestrogenicity of such EDs at
environmentally relevant levels is too weak to have an effect.

The argument is based on how EDs like BPA interact with the Oestrogen Receptor (ER-alpha
or beta), found in the cell nucleus.

When ER is bound to oestrogen (E2), ER-E2 acts as a transcription factor, which regulates
gene expression: the E2-ER complex binds to the DNA and regulates gene activity.

This may increase cell proliferation, especially during developmental periods, fetal, puberty,
menses etc. This is a genomic effect.

Editors note: The fact that BPA may increase proliferation is important to later understand
why diethylstilbestrol (a highly problematic drug given to women between 1940 and 1980 to
prevent miscarriage, and structurally similar to BPA) has a suppressive effect. We will return
to this topic in a later post.
To get ER-mediated responses (genomic) with BPA or other EDs, very high concentrations
are usually needed because they have a weaker affinity for the receptor. Sceptics often jump
on this fact to say that BPA is not around at levels high enough to act directly on the ER and
cause disruption.

The significance of the Bouskine study is that it shows a way in which BPA can act indirectly
of the classic ER and exert effects at low doses, through a non-genomic rather than genomic
pathway.

This is because of the way signalling works within cells: cells have receptors on their
membranes, a bit like an antenna, which receive low level signals from, for example,
hormones, drugs and xenochemicals.

The membrane receptors then transmit this signal elsewhere within the cell. One such
membrane protein is a G protein. The signal is passed on from the G protein via what is
known as a 2nd messenger.

The role of the 2nd messenger is to amplify the signal to make it much more effective. Thus
an initial low-level signal will turn into a much stronger signal at the target.

The G protein in this study is called a G-protein coupled oestrogen receptor and can be
activated by both oestrogen and BPA at picomolar (parts per trillion) or nanomolar (parts per
billion) levels, which in turn activates transcription factors via 2nd messengers (which is non-
genomic).

In this case the BPA mediates (via G protein and 2nd messengers) a chemical activation of
two transcription factors, one called CREB and one called Rb. Rb is a cell cycle regulator,
which helps govern cell division. Interference with this process, especially during critical
windows of development, could have a range of permanent health effects [see H&E issue 13,
PDF].

Thus we have a process in which low levels of BPA can cause endocrine disruption and
possible adverse effects despite its low oestrogenicity, because only pico (10^12 M) or
nanomolar (10^9 M) levels, are needed to elicit a response via the G protein coupled receptor
mechanism.

These are the sorts of concentrations found in peoples blood, and far lower than the BPA
levels needed for a genomic ER response, which are around micromolar (10-6 M) levelsand
1,000 to 1,000,000 times higher.

Can other weak xenoestrogens have a similar effect?

Other EDs have been shown to act indirectly too. In one of my studies [Newby and Howard,
2005], I describe a mechanism whereby weakly oestrogenic PCBs can interfere with the
action of an enzyme (SULTE 1E1) which breaks down and aids excretion of oestrogen and
therefore regulates the amount of oestrogen that is bioavailable in the body [Kester et al.,
2000; Kester et al., 2002].

In this case, if PCBs bind to the enzyme then more oestrogen is bioavailable to oestrogen
sensitive tissues such as the testes/ mammary glands, and could cross the placenta resulting in
increased oestrogen in the fetal bloodstream. This provides a mechanism where PCBs,
although very weak oestrogens, could act to disrupt the endocrine system indirectly.

References

Bouskine A, Nebout M, Brcker-Davis F, Benahmed M, Fenichel P. (2009) Low Doses of

Bisphenol A Promote Human Seminoma Cell Proliferation by Activating PKA and PKG via a
Membrane G-ProteinCoupled Estrogen Receptor. Environmental Health Perspectives
Volume 117(7): 1053-1058. [Link]

Newby J A and Howard C V (2006) Environmental influences in cancer aetiology. JNEM

(15) 56-114. [Link]

Kester HA, Bulduk S, Tibboel D, et al., (2000) Potent inhibition of Oestrogen

Sulphotransferase by Hydroxylated PCB metabolites: A novel pathway explaining the
oestrogenic activity of PCBs. Endocrinology. 141: 1897-1900.

Kester HA, Bulduk S, van-Toor H, et al., (2002) Potent Inhibition of Estrogen

Sulfotransferase by Hydroxylated Metabolites of Polyhalogenated Aromatic Hydrocarbons
Reveals Alternative Mechanism for Estrogenic Activity of Endocrine Disrupters. J Clin
Endocrinol Metabol. 87: 1142-1150.

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2 Comments
RSS feed for comments on this post. TrackBack URI

1. [] Pete Myers, founder and CEO of Environmental Health Sciences and author of
Our Stolen Future, helpfully pointed out the following items which follow the same
line of thought we expressed in proposing a mechanism for how BPA can act as a
powerful endocrine disruptor. []
 Pingback by Follow-up: More on how weak oestrogen BPA can act as a powerful endocrine
disruptor Health & Environment July 17, 2009 #

Reply

2. [] Even though BPA is a weak oestrogen, there is a mechanism by which low levels
of BPA could have a po. It is often argued that BPA is too weak a hormone to have
an effect on cell function. Here, we sketch out a mechanism by which BPA could
potentially have a strong effect via an indirect pathway rather than a direct effect on
the part of the cell nucleus which responds to oestrogen. (July 2009) []

Pingback by A Health & Environment retrospective: concerns that talking about causes of cancer can
cause cancer; the difficulties of defining endocrine disruptor; shedding light on the obesogen
hypothesis; and more. | Health & Environment August 14, 2013 #

Reply

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About Bisphenol A
Human Health & Safety

Environmental Safety

Scientific Publications

Press Room
Human Health & Safety >> Health Effects Research Health Effec
Research
Endocrine Activity Studies on Bisphenol A General Toxi
Background on Endocrine Disruption Carcinogenic
Endocrine Disruption and Bisphenol A
Estrogenic Activity of Bisphenol A Reproductive
Low-Dose Endocrine Effects Developme
Toxicity

Endocrine Ac
Background on Endocrine Disruption
Low-Dose En
Our Stolen Future, a book published in 1996, popularized the Effects
theory that natural and man-made substances that exhibit
hormone-like properties in the laboratory can affect wildlife Metabolism
populations, thus speculating that humans may be at risk of
"hormone disruption." While this theory has been widely Health Effect
discussed in the open scientific literature, it caught the public's Research Ref
attention resulting in a U.S. Congressional mandate to test man-
made chemicals for any hormonal properties.

Since that time there have been hundreds of published studies Join the Bisp
testing the hypothesis, including assays that show a positive mailing list.
response. These assays are often misused to label certain email addre
substances "endocrine disrupters," although a more accurate
term, "hormonally active agents," was recently coined by the
U.S. National Academy of Sciences.

To date, the mechanisms through which hormonally active

agents act in a living organism have not been documented,
although a number of theories have been proposed. The research
community in cooperation with government agencies and
industry are working to clarify and characterize any risks posed
by hormonally active agents in the environment.

Endocrine Disruption and Bisphenol A

There is no known risk from environmentally relevant exposures

of bisphenol A to humans, wildlife or the environment.

Bisphenol A exhibits extremely weak hormonal activity in test

tube assays, such as those utilizing yeast or human breast cancer
cells. Effects have also been observed in compromised
laboratory animals at high doses of bisphenol A. However,
reproduction and development are not affected by relatively high
levels of bisphenol A in multi-generational studies, which are
designed to detect disruptions in normal hormone activity (doses
are compared to the extremely low levels of possible consumer
exposure).

Estrogenic Activity of Bisphenol A

The estrogenic activity of bisphenol A (BPA) has been

identified over the past several decades. The earliest reference
noted for the estrogenic action of BPA was a report of a
bioassay for a positive estrus response, as measured by
cornification in vaginal smears, that occurred in ovariectomized
rats dosed (route unspecified) twice daily with 100 mg BPA
dissolved or suspended in sesame oil on three successive days
(Dodds and Lawson, 1936). In this study, the effective estimated
daily dose was 800 mg/kg/day (100 mg/250 grams body
weight/twice daily).

A more comprehensive study was reported in 1970 (Bitman and

Cecil, 1970) in which DDT and 52 structurally related
compounds, including BPA, were injected subcutaneously into
immature rats. Estrogenic activity was measured 18 hours
following dosing by measuring uterine glycogen content. The
minimally effective dose of BPA to produce an increase in
uterine glycogen content was 0.25 mg/rat, or about 5 mg/kg/day.

A series of similar studies were undertaken in rats by the

National Institute for Occupational Safety and Health (NIOSH)
(Bond et al., 1980); also personal communication from NIOSH
to Morrissey, et al. mentioned in Morrissey, et al., (1987). In
these studies ovariectomized rats were administered BPA:
intraperitoneally (50-130 mg/kg), orally (1250 mg/kg, dermally
(8000 mg/kg), or via inhalation (156 mg/m3 for 6 hours), and,
following various times, estrogenic activity was confirmed by
measuring changes in percentage uterine water.

An example of a more recent reference demonstrating estrogenic

activity of BPA is an in vitro study where levels of BPA were
found to induce progesterone receptors in cultured human
mammary cancer cells (MCF-7) at a potency of 5000 times less
than estradiol. BPA also increased the rate of proliferation of
MCF-7 cells, and competed with estradiol for estrogen receptor
binding sites (Krishnan, et al., 1993).

These studies have shown that BPA possesses estrogenic

activity in special experimental systems. However, it is not at all
 clear how these results can be related to specific toxicologic
endpoints that are relevant to human health. For example,
estrogenic activity was mainly identified in ovariectomozed rats
or in even less relevant in vitro models. In addition, estrogenic
activity was seen in animals administered large doses of BPA or
animals exposed via only experimental routes of exposure, such
as intraperitoneally or subcutaneously.

Low-Dose Endocrine Effects

For a discussion of bisphenol A and low-dose endocrine effects

research, click here.

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