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

336 CHAPIN ET AL.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate for the evaluation process but of
limited utility due to the route of administration.
Funabashi et al. (2004b), supported by Yokohama City
University and the Japanese Ministry of Education,
Culture, Sports, Science, and Technology, examined the
effects of bisphenol A exposure on expression of
progesterone receptor mRNA in brain of adult ovariectomized
rats. p-Nonylphenol and 4-tert-octyl phenol
were also examined, but will not be discussed. [No
information was provided on feed, housing, or bedding
materials.] Wistar rats were ovariectomized at 7 weeks of
age, and experiments were conducted 10 days following
ovariectomy. In the first experiment, 6 rats/group were
s.c. injected with sesame oil vehicle or 10 mg bisphenol A
(B40 mg/kg bw) [purity not reported]. Rats were killed
24 hr following injection, and frontal, parietal, and
temporal cortex were removed. In a second experiment,
frontal, temporal, and occipital cortex were collected
from rats at 0, 6, 12, or 24 hr following injection with
10 mg bisphenol A; 5–6 rats were killed and examined at
each time point. In both experiments, progesterone
receptor mRNA expression was determined by Northern
blot in each area of the cortex. Data were analyzed by
ANOVA followed by Fisher protected least significant
difference post-hoc test. At 24 hr following bisphenol A
exposure, expression of progesterone receptor mRNA
was increased in the frontal cortex and decreased in the
temporal cortex. In the time-course experiments, expression
of progesterone receptor mRNA was increased in
the frontal cortex and decreased in the temporal cortex
from 6–24 hr following exposure. Bisphenol A had no
effect on expression of progesterone receptor mRNA in
the parietal or occipital cortex. The study authors
concluded that bisphenol A can alter the neocortical
function through the progesterone receptor in adult rats,
but the physiological significance of the effect is not
known.
Strengths/Weaknesses: This study links relatively
high single-dose (10 mg) s.c. bisphenol A administration
to the induction of progesterone receptor mRNA, an
estrogenic response. Weaknesses is the absence of a
positive control to demonstrate maximal response in
estrogen-mediated increases in progesterone mRNA and
the failure to examine any physiological or functional
endpoints. It was also not determined if increases in
mRNA were associated with increases in progesterone
receptor protein. There was only one dose level administered
at a single time point. The s.c. route of dose
administration is a weakness.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate for inclusion but of limited utility.
Della Seta et al. (2005), supported by a grant from
MURST, Italy, examined the effects of bisphenol A
exposure on maternal behavior in rats. [No information
was provided in the manuscript on the type of chow,
bedding, and caging used. The Expert Panel has been
informed that Harlan Teklad 2018 chow, Lignocel
bedding, and polysulfone cages were used (F. Farabolli
et al., personal communication, March 1, 2007).] Female
Sprague–Dawley rats were trained to ingest peanut oil
from a micropipette. At 14 weeks of age, female rats were
mated for 48 hr. On the day following mating, females
were randomly assigned to groups administered peanut
oil (n 5 23) or 0.040 mg/kg bw/day bisphenol A [purity
not indicated in the manuscript; Z95% according to the
authors (F. Farabollini et al., personal communication,
March 1, 2007)] (n 5 17) through a micropipette. Dosing
was continued through the gestation and lactation
periods. Two days following delivery, litters were culled
to 4 male and 4female pups and were cross-fostered
within treatment groups. Pups were weighed on Days 2,
7, and 21 following birth. Maternal behavior was tested
at 3 and 4 days and at 8 and 9 days following delivery. In
30-min test sessions, frequency, duration, and latency of
behaviors such as retrieving pups, licking pups,
postures, and nest building were evaluated with pups
of the same sex. Behavior with pups of the opposite sex
was evaluated on the second day of the test period, and
the order of testing with male and female pups was
reversed during each testing period (Days 3–4 and 8–9).
Data were analyzed by general linear model, Duncan
multiple range test, and/or Mann–Whitney U test. The
numbers of females giving birth were 9 of 17 in the
bisphenol A group and 18 of 23 in the control group.
Nine dams in the control group and 7 in the bisphenol A
group were evaluated for maternal behavior. The only
significant effect reported for bisphenol A was reduced
duration of licking-grooming pups, which occurred with
both sexes of pups during both observation periods
[B25–50 % decrease as estimated from a graph]. Effects
reported to be marginally significant were decreased
frequencies of licking-grooming of pups (Po0.09),
anogenital licking of pups (Po0.08), and arched back
posture (Po0.07). The study authors concluded that
maternal behavior in rats is influenced by prolonged
exposure to low bisphenol A doses during pregnancy
and lactation.
This behavioral study suggested that a low, oral dose
of bisphenol A (0.040 mg/kg bw/day) affects pregnancy
and maternal behavior.
Strengths/Weaknesses: Weaknesses include the use of
a single dose level and an unusually low pregnancy rate
in the controls (18/23) as well as the authors emphasis on
marginally significant bisphenol A effects.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate and of high utility for the
evaluation process.
4.2.1.2 Mouse: Park et al. (2004), support not
indicated, examined the effects of bisphenol A exposure
on the reproductive and hematological systems of male
and female mice. [Results for females are discussed
here, and results for males are discussed in
Section 4.2.2.2.] Adult ICR mice were fed mouse
formulation feed (Cheil Feed). [No information was
provided about caging or bedding materials.] Fifteen
mice/sex/group were i.p. injected with bisphenol A
[purity unknown] in an ethanol/corn oil vehicle at 0.05,
0.5, or 5.0 mg/kg bw on 5 occasions (every 3 days over a
14-day period). One control group received no treatment
and a second control group was i.p. injected with corn oil.
Females were examined 7 days following administration.
Reproductive organs were weighed and fixed in Bouin
solution, and histopathological examination was conducted.
Hematological and clinical chemistry endpoints
were also assessed. Data were analyzed by least significant
difference test.
Exposure to bisphenol A had no effect on body
weight. Significant decreases were observed for right
ovary weight in the mid- and high-dose group
Birth Defects Research (Part B) 83:157–395, 2008