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

Utility (Adequacy) for CERHR Evaluation Process:
This study is inadequate for the evaluation process based
on the limitations noted above.
Matsumoto et al. (2004), support not indicated,
examined the effect of maternal bisphenol A exposure
on growth of offspring in mice. Mice were fed standard
rodent chow (CE-2, Japan Clea). [No information was
provided on caging and bedding materials.] Mice of the
ddY strain were exposed to bisphenol A (Z97% purity)
through feed at 0 or 1% from GD 14–PND 7. The study
authors stated that the bisphenol A dose was equivalent
to 1000 mg/kg bw/day. [The number of dams treated
was not indicated. Day of vaginal plug and day of birth
were not defined]. Mice delivered pups on PND 21.
During the postnatal period, body weight was monitored
in 31 pups from the control group and 61–89 pups from
the bisphenol A group. Serum prolactin levels were
measured by RIA in 3 dams/group 4 days following
delivery. Pups were killed on PND 7, and stomach
weight was measured. Data were analyzed by Student ttest.
[It was not clear if the litter or offspring was
considered the statistical unit.]
No differences were reported for live pups at birth.
During the postnatal period, body weights of pups in the
bisphenol A group were significantly lower [by B40%]
than control group pups. No deaths were reported for
pups in the control group, but 30% of pups in the
bisphenol A group died before PND 7. On PND 1, milk
could be seen in stomachs of pups from the control
group, but not the bisphenol A group. [The number of
pups evaluated for milk in stomach was not reported.]
On PND 7, stomach weight was significantly lower [by
40%] in pups from the bisphenol A than control group.
Serum prolactin level was significantly reduced [by 46%]
in dams from the bisphenol A group. The authors
concluded that administration of a high bisphenol A
dose to mice resulted in suppressed postnatal growth of
offspring that probably resulted from an insufficient
supply of milk, which might have been due to decreased
prolactin secretion. [Because of the implications of this
study for lactation competence, this study will be
discussed again in Section 4.2.]
Strengths/Weaknesses: Weaknesses of the study are
the difficulty in calculating bisphenol A intake, the likely
high exposure level, the lack of information on dam
number and husbandry, and the high level of pup body
weight decrement and mortality.
Utility (Adequacy) for CERHR Evaluation Process:
This study is inadequate for the evaluation process due
to the reasons stated above.
Suzuki et al. (2003), supported by the Japanese
Ministry of Health, Labor, and Welfare and the Ministry
of Education, Culture, Sports, Science, and Technology
conducted a study to determine the effect of prenatal
bisphenol A exposure on dopamine-receptor mediated
actions in mice. Female ddY mice were fed chow
containing bisphenol A at 0.002, 0.5, or 2 mg/g feed
from mating through weaning of offspring. [No information
was provided on the number of dams
treated, purity of bisphenol A, or the type of chow,
bedding, or caging materials. Assuming a female
mouse eats B0.2 kg feed/kg bw/day (USEPA, 1988),
bisphenol A intake would have been 0.4, 100, or 400 mg/
kg bw/day.] Male offspring were subjected to a series of
tests [age at testing not stated]. In a conditioned place-
Birth Defects Research (Part B) 83:157–395, 2008
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preference test, groups of 6–10 mice were injected with
0.5 mg/kg bw methamphetamine and placed in either
the dark or light area of the test apparatus for 3 days. On
the other 3 days, males were injected with saline and
placed in the other compartment of the testing apparatus.
On Day 7, the divider in the apparatus was raised and
the time spent in each compartment was measured.
Activity was measured in groups of 9–10 mice for 3 hr
following injection with saline or 2 mg/kg bw methamphetamine.
Dopamine-induced binding of 35 S-guanosine-5
0 [g-thio]-triphosphate in the limbic system was
measured (n 5 3 samples/group). Protein levels of
dopamine and vesicle monoamine transporters in brain
were determined by Western blot (n 5 6 samples), and
mRNA levels of dopamine receptor in brain were
determined by RT-PCR. Data were analyzed by ANOVA
with Bonferroni/Dunnett test. [It was not clear if the
litter or offspring was considered the statistical unit.]
In conditioned-preference testing, exposure to all 3
bisphenol A doses resulted in a significant and doserelated
increase in preference for compartments associated
with methamphetamine exposure. [Control mice
showed no compartment preferences while the times
spent in the methamphetamine-associated compartment
were B150, 200, and 275 sec by animals in each
respective dose group.] Preference for the methamphetamine
compartment was eliminated by injecting the
animals with SCH23390, A dopamine D 1 receptor
antagonist. In mice exposed to the high-dose of bisphenol
A, activity was significantly increased [by B80% at
peak] compared to the control group following methamphetamine
challenge, and sensitization to methamphetamine-induced
activity was also enhanced. Dopamineinduced
binding of 35 S-guanosine-5 0 [g-thio]-triphosphate
in the limbic system was potentiated [increased by
B15%; not clear if statistically significant] and Gprotein
activation was increased [by B75%] in mice
exposed to the high bisphenol A dose. The effects on Gprotein
activation were eliminated following injection
with SCH23390 or sulpiride, a dopamine D2 receptor
antagonist. No changes were observed for expression of
dopamine and vesicle monoamine transporter proteins.
Expression of dopamine D 1 receptor mRNA was upregulated
significantly to 130% of control levels in the highdose
bisphenol A group. [For all endpoints except for
conditioned preference, only the data from the highdose
bisphenol A group was shown. It was not clear if
that was the only dose tested for those endpoints or if
the high-dose data were shown because it was the only
dose that resulted in a statistically significant effect.]
The study authors concluded that ‘‘prenatal and neonatal
exposure to bisphenol A can potentiate central dopamine
D1 receptor-dependent neurotransmission, resulting in
supersensitivity of methamphetamine-induced pharmacological
actions related to psychological dependence on
psychostimulants.’’
Strengths/Weaknesses: Strengths include a wide range
of doses administered orally. Weaknesses include absence
of adequate experimental details, inappropriate
statistical procedures that did not account for litter or
repeated measurement, inadequate presentation of body
weight data, and use of high-doses.
Utility (Adequacy) for CERHR Evaluation Process:
This study is inadequate for the evaluation process due
to the reasons stated above.