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

BISPHENOL A
Table 77 Table 78
Effects on Prostate Development in Mice After Prenatal
Exposure to 0.010 mg/kg bw/day Bisphenol A a
Endpoint b
Prostate region
Dorsolateral
Dorsolateral Ventral and ventral
No. of prostate ducts m 41% 2 m 40%
Prostate duct volume m 99% m 78% m 91%
Proliferating cell m 44% 2 No data
nuclear antigen staining
a Timms et al. (2005).
b Percent changes calculated by CERHR differed slightly from
values presented by authors; it was not clear which part of the
prostate the authors’ values represented.
m,k Statistically significant increase, decrease; 2 no statistically
significant effect.
between a male and female fetus was examined. Prostate
morphology was determined by a 3D computer reconstruction
technique. Immunohistochemistry techniques
were used to measure levels of proliferating cell nuclear
antigen and mouse keratin 5. Statistical analyses included
ANOVA, followed by Fisher least-squares mean
test when statistical significance was obtained. In a
separate study, prostate morphology was examined in 4
pregnant mice/group that were dosed with vehicle or
200 mg/kg bw/day diethylstilbestrol according to the
procedures described above.
Bisphenol A increased numbers of ducts, volume, and
proliferation in one or more prostate regions, as outlined
in Table 77. The pattern of proliferating cell nuclear
antigen staining was similar to that observed with mouse
keratin 5, a basal epithelial cell maker. The study authors
also reported a 56% increase in the volume of the
coagulating glands. [Data were not shown by study
authors.] An abnormal narrowing was observed in the
portion of the urethra near the neck of the bladder. [The
volume of the cranial urethra was reduced by 35%
compared to controls. Malformation of prostatic sulci
was reported, but no information was provided on
incidence or severity.] Similar effects on the prostate
were reported in mice exposed to ethinyl estradiol and
the low dose of diethylstilbestrol. Narrowing of the
cranial urethra was observed in mice exposed to ethinyl
estradiol. In contrast, exposure to the high diethylstilbestrol
dose resulted in inhibited morphogenesis of the
prostate. The study authors concluded that the differentiating
urogenital system of male mice is very sensitive
to a low dose of bisphenol A.
Strengths/Weaknesses: Strengths are the oral route of
administration, the low dose level of bisphenol A, the use
of diethylstilbestrol and ethinyl estradiol as positive
controls, and the sophisticated measures applied to the
prostate. Weaknesses are the use of a single dose level
and small sample size, although the Panel judged it to be
adequate for the methodology.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate and of high utility for the
evaluation.
Palanza et al. (2002), supported by NIEHS, NIH,
MURST, the University of Parma, and the National
Birth Defects Research (Part B) 83:157–395, 2008
285
Maternal Behavior Effects in Mice Exposed to Bisphenol
A During Gestation or Adulthood a
Bisphenol A exposure during gestation/adulthood
Bisphenol Vehicle/ Bisphenol
Percent time b A/vehicle bisphenol A A/bisphenol A
Nursing k 15% k 14% 2
Nest building m 73% m 146% 2
Resting alone m 67% m 29% m 46%
Grooming m 25% m 18% 2
Active 2 m 18% 2
In nest k 12% k 10% 2
Out of nest m 17% m 12% 2
a Palanza et al. (2002).
b Data were presented graphically. Values were provided by the
study author (personal communication, P. Palanza, February 26,
2007).
m,k Statistically significant increase/decrease compared to
vehicle-vehicle group, 2 no statistically significant effect.
Council for Research, examined the effects of bisphenol
A treatment on maternal behavior following exposure of
mice during prenatal development and/or adulthood.
The CD-1 mice used in this study were maintained as an
outbred colony. Mice were housed in polypropylene
cages with corn cob bedding. During pregnancy and
lactation, mice were fed Purina 5008 (soy-based) chow.
After weaning, mice were fed Purina 5001 (soy-based)
chow. Water was provided in glass bottles. On GD 14–18
(GD 0 5 day of vaginal plug), 14 mice were fed the
tocopherol-stripped corn oil vehicle and 9 mice were fed
0.010 mg/kg bw/day bisphenol A [purity not reported]
using an electronic micropipette. Dams were housed 3/
cage after mating and individually housed on GD 17.
Body weights of dams were measured during gestation.
The day of birth was considered PND 1, and offspring
were weaned on PND 20. At 2–2.5 months of age, F 1
female offspring from vehicle- and bisphenol A-treated
dams were mated and exposed to vehicle or 0.010 mg/kg
bw/day bisphenol A on GD 14–18. There were 4 groups
of F1 females that were exposed during gestation–
adulthood to vehicle–vehicle (n 5 20), vehicle–bisphenol
A(n 5 15), bisphenol A–vehicle (n 5 15), and bisphenol
A–bisphenol A (n 5 15). Maternal behavior was observed
in F1 dams every 4 min during a 120-min period on PND
2–15. On PND 1, F 2 pups were weighed, sexed, and
counted. Litters were then culled to 10 pups, with equal
numbers of male and female pups when possible. Pups
were weighed during the lactation period and cliff-drop
aversion and righting reflex were evaluated in all pups of
a subset of 8 litters/group on PND 3, 5, 7, and 9. For
statistical analyses, all pup data were adjusted for litter.
Data were analyzed by ANOVA, Holms t-test, and/or
Fisher protected least-squared difference test.
Bisphenol A treatment did not affect gestational body
weight gain in F 0 or F 1 dams. Statistically significant
effects for F1 maternal behavior collapsed across 14
observation days are presented in Table 78. Exposure to
bisphenol A either in gestation or in adulthood resulted
in decreases in the percentage of time the dams spent
nursing and in the nest and increases in the percentage of
time the dams spent nest building, resting alone,