Monograph on the Potential Human Reproductive and ... - OEHHA

Endpoint
Relative organ weight
Testis
Epididymis
Ventral prostate
Epididymal sperm motility b
Epididymal sperm count
BISPHENOL A 345
Table 90
Reproductive Effects in Male Rats Orally Dosed With Bisphenol A a
Dose, mg/kg bw/day
0.0002 0.002 0.020 BMD10 BMDL10 BMD1SD BMD1SD
k 5%
k 13%
m 13%
k 23%
2
k 6%
k 17%
m 34%
k 37%
k 18%
k 7%
k 26%
m 29%
k 41%
k 27%
0.056
0.011
0.014
a Chitra et al. (2003a).
b Values estimated from a graph by CERHR; data estimated from graphs were not modeled.
m,k Statistically significant increase, decrease; 2 no statistically significant effect.
these values were equivalent to 0.011, 0.116, 1.094, and
11.846 mg/kg bw/day. [No information was provided
about bisphenol A purity, or feed, caging, or bedding
materials.] Body weight and food and water consumption
were measured during the study. Urine was
collected for 24 hr following completion of dosing, and
then animals were killed. Blood was collected. Organs,
including those of the male reproductive system, were
weighed. Parts of organs were preserved in formalin and
examined histologically. Testes and epididymides were
preserved in liquid nitrogen to obtain sperm counts and
for measurement of levels of testicular enzymes. Data
were analyzed by ANOVA.
Bisphenol A treatment had no significant effect on
body weight or food or water intake. There were no
effects on absolute or relative weights of the testis,
epididymis, prostate, seminal vesicle, liver, kidney, heart,
lung, spleen, or brain. Daily sperm production and
number of sperm heads were unaffected by bisphenol A
treatment. No significant effects were observed for
activities of testicular g-glutamyl transpeptidase, sorbitol
dehydrogenase, acid phosphatase, or b glucuronidase.
No histopathological alterations were reported for the
testis, epididymis, seminal vesicle, prostate, spleen, or
brain. Bisphenol A levels in urine are reported in Section
2. The study authors concluded that sperm density and
the male reproductive system do not appear to be
affected in F344 rats exposed to bisphenol A.
Strengths/Weaknesses: Strengths include a wide range
of doses, use of an appropriate route of exposure, and the
use of Fischer 344 rats. Weaknesses include marginal
sample size and the absence of information about certain
study design features.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate and of high utility in the
evaluation process.
Chitra et al. (2003a), supported by the Lady Tata
Memorial Trust, Indian Council of Medical Research, and
the Population Council, examined the effects of bisphenol
A on the reproductive system of male rats. Animals were
given ‘‘standard commercial laboratory chow.’’ [Bedding
and caging materials were not reported.] Six 45-day-old
male Wistar rats/group were orally dosed [gavage
assumed] with bisphenol A (97% purity) in olive oil at
0, 0.0002, 0.002, and 0.020 mg/kg bw/day for 45 days.
Rats were killed 24 hr following the last treatment. Testes,
epididymides, seminal vesicles, and ventral prostate were
weighed. Epididymal sperm counts and motility were
assessed. Antioxidant enzyme activities were measured
Birth Defects Research (Part B) 83:157–395, 2008
0.021
0.0082
0.0083
0.014
0.0069
0.015
0.0087
0.0050
0.0089
in sperm. Statistical analyses included ANOVA followed
by Student t-test. Significant effects on organ weights and
sperm endpoints are summarized in Table 90. Bisphenol
A treatment did not affect body weight. Absolute and
relative (to body weight) weights of testis and epididymis
and were reduced, and absolute and relative ventral
prostate weights were increased at all dose levels. Effects
on relative organ weights are summarized in Table 90.
Sperm motility was decreased at all dose levels, and
sperm counts were reduced at the mid and high-dose.
There were dose-related decreases in activity of superoxide
dismutase, catalase, glutathione reductase, and
glutathione peroxidase in sperm at all dose levels.
Hydrogen peroxide generation and lipid peroxidation in
sperm increased dose-dependently at all dose levels. The
study authors concluded that adverse effects of bisphenol
A on the male reproductive system may be due to
oxidative stress.
Although these studies have a limited number of
animals per group, they appear to be relatively well
conducted, and there are apparently consistent dosedependent
changes in testis and epididymis weights and
sperm parameters. The epididymal (portion not mentioned)
sperm numbers measured in this study are
consistent with the daily sperm production measured
by Sakaue et al. (2001). A potential significant concern in
this study is the use of olive oil as the vehicle. The
stability/reactivity of bisphenol A was not determined
and it is possible that bisphenol A interacted with olive
oil, resulting in the observed findings. This study
provides suggestive data that bisphenol A induces
oxidative stress in epididymal sperm and alters testis
and epididymis weights at low doses.
Strengths/Weaknesses: Strengths include the use of
oral and low multiple doses and appropriate measures.
A weakness includes the marginal sample size.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate for inclusion but of limited utility
based on small group size.
Chitra et al. (2003b), supported by the Population
Council, New York, examined the effects of bisphenol A
and vitamin C exposure on epididymis and sperm
counts in rats. Wistar rats (45-days old) were fed
standard commercial laboratory chow and housed in
plastic cages. [No information was provided about
bedding.] Four rats/group were orally dosed with
bisphenol A (97% purity) at 0 (olive oil vehicle), 0.0002,
0.002, or 0.020 mg/kg bw/day for 60 days. Additional
rats received the same bisphenol A doses in conjunction