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

286 CHAPIN ET AL.
grooming, and out of the nest. Increased activity was also
observed in the group exposed to bisphenol A in
adulthood. The only significant effect observed in mice
exposed to bisphenol A during gestation and adulthood
was increased time resting. When data were presented
for individual evaluation days, time resting was significantly
increased on PND 9, 10, 11, 12, and 14 in the
group exposed to bisphenol A during gestation. Time
spent resting was significantly increased on PND 9 and
14 in the group exposed to bisphenol A during gestation
and adulthood. No other significant effects were
observed on specific evaluation days. There were no
significant differences in the number of live F2 pups/
litter, sex ratio, or body weight at birth or in weight gain
during the lactation period. [Data were not shown]. No
significant effects were observed for cliff aversion or
righting reflexes. The study authors concluded that
reduced levels of nursing behavior were observed in
mice exposed to bisphenol A only as fetuses or only as
adults. [Because this study involves effects of adult
exposure on maternal behaviors, it is also discussed in
Section 4.2.]
Strengths/Weaknesses: Strengths are the oral route of
administration, the low dose level of bisphenol A, and
the exploration of effects on complex maternal behaviors.
It is unusual that pre- and postnatal exposure had effects
but not the combination of pre- and postnatal exposure,
and failure to explain this finding is a weakness. The use
of a diet high in soy isoflavones is an additional
weakness.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate and of high utility for the
evaluation process.
Nishizawa et al. (2003), supported by the Japanese
Ministry of Education, Culture, Sports, Science, and
Technology, examined the effects of prenatal bisphenol A
exposure on expression of retinoic acid receptor a and
retinoid X receptor a in mouse embryos. ICR mice were
fed standard feed (CM; Oriental Yeast). [No information
was provided about caging and bedding materials.]
Mice were orally dosed with bisphenol A [purity not
indicated] at 0 (olive oil vehicle) or 0.002 mg/kg bw/day
on 6.5–11.5, 6.5–13.5, 6.5–15.5, and 6.5–17.5 days postcoitum.
Day of vaginal plug was considered 0.5 days
post-coitum. [No information was provided about the
specific method of oral dosing.] Twelve dams/group
were killed at 12.5, 14.5, 16.5, and 18.5 days post-coitum,
24 hr after receiving the last dose. Expression of
mRNA for retinoic acid receptor a and retinoid X
receptor a was measured by RT-PCR in fetal cerebrum,
cerebellum, and gonads. Data were analyzed by ANO­
VA. [It was not clear if the litter or offspring was
considered the measurement unit.] Numerous changes
in mRNA expression were observed following in utero
exposure to bisphenol A, and they varied according to
sex, tissue, and dosing period. The study authors
concluded that these findings suggest a novel mechanism
of bisphenol A toxicity mediation by disruption of
the expression of retinoic acid receptor a and retinoid X
receptor a.
Strengths/Weaknesses: Strengths are the oral route of
delivery, the use of a low dose level of bisphenol A, and
the exposure at different time periods. The study has
value for understanding mechanisms of action although
these changes were not tied to any adverse findings that
might be related to these changes. Weaknesses include
the use of a single dose level and lack of clarity on
number of embryos per litter sampled. This is not
considered a critical weakness because it is known that
standard procedures for these methods require pooling
of embryos within litter.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate but of limited utility for the
evaluation because of the mechanistic nature of the
endpoints.
Nishizawa et al. (2005b), supported by the Japanese
Ministry of Education, Culture, Sports, Science, and
Technology and by the Japan Society for the Promotion of
Science, examined the effects of bisphenol A exposure on
expression of mRNA for arylhydrocarbon and retinoid
receptors in mouse embryos. ICR mice were fed standard
diet (CM; Oriental Yeast). [No information was provided
about caging or bedding materials.] Pregnant mice were
orally dosed with bisphenol A [purity not indicated] at 0
(olive oil vehicle), 0.00002, 0.002, 0.20, or 20 mg/kg bw/
day from 6.5 to 13.5 days post-coitum or 6.5 to 17.5 days
post-coitum. Day of vaginal plug detection was considered
0.5 days post-coitum. [No information was provided
about the specific method of oral dosing.] Twelve
pregnant mice/group were killed on 14 and 18.5 days
post-coitum, 24 hr after the last bisphenol A dose was
administered. RT-PCR analyses were conducted to
determine expression of mRNA for retinoic acid, retinoid
X, and arylhydrocarbon receptors in fetal cerebrum,
cerebellum, ovary, and testis. Data were analyzed by
ANOVA. [It was not clear if the litter or offspring was
considered the measurement unit.] Numerous changes
in mRNA expression were observed following bisphenol
A exposure and they varied according to dose, sex,
tissue, and exposure period. The study authors concluded
the this study shows a novel mechanism by
which bisphenol can induce endocrine disruption
through upregulation of arylhydrocarbon receptor (a
key factor in the metabolism of some xenobiotics
compounds) and retinoid receptors (key factors in
nuclear receptor signal transduction).
Strengths/Weaknesses: The wide dose range from
0.00002 to 20 mg/kg bw/day and the oral route are
strengths. The study has value for understanding
mechanisms of action although these changes were not
tied to any adverse findings that might be related to
these changes. Weaknesses include the lack of specification
of the method of oral dosing and lack of clarity on
sample origins and sizes for each assay. Again, this is not
considered a critical weakness because it is known that
standard procedures for these methods require pooling
of embryos within litter.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate but of limited utility for the
evaluation because of the mechanistic nature of the
endpoints.
Nishizawa et al. (2005a), supported by the Japan
Society for the Promotion of Science, examined the
effects of bisphenol A exposure on expression of aryl
hydrocarbon receptors, related factors, and metabolizing
enzymes in mouse embryos. ICR mice were fed standard
diet (CM; Oriental Yeast). [No information was provided
about caging and bedding materials.] Mice were orally
dosed with bisphenol A [purity not indicated] at 0 (olive
oil vehicle), 0.00002, 0.002, 0.2, or 20 mg/kg bw/day from
Birth Defects Research (Part B) 83:157–395, 2008