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

272 CHAPIN ET AL.
Table 74
Effects in Female Rats Exposed to Bisphenol A During the Neonatal Period a
Dose, mg/kg bw/day [CERHR estimate]
Endpoint 26 105 427 BMD10 BMDL10 BMD1SD BMDL1SD
Body weight gain
PND 9 2 2 k16% 286 200 233 156
PND 97 2 2 m10% 432 261 430 253
Day of vaginal opening 2 k2.9 days k4.1 days 345 267 159 116
No. with normal estrous cycles b 2 (8/8) 2 (2/8) k (0/6) 81 28
No. with cleft clitoris c
Relative organ weight
2 (0/8) m (0/8) m (6/6) 299 failed
Ovary 2 2 k59% 85 59 140 93
Uterus, wet 2 2 k60% 66 55 128 96
Uterus, blotted 2 2 k21% 273 128 318 168
Uterine fluid weight 2 k42% k97% 42 34 139 104
No. with polycystic ovaries c
No data m (4/8) m (5/5) 81 24
No. with corpora lutea b
No data 2 (8/8) k (0/5) 238 90
No. of corpora lutea No data 2 k (none) 65 38 137 83
Corpora lutea area No data k 30% k (none) 42 37 84 66
a Kato et al. (2003).
b Control rate 8/8.
c Control rate 0/8.
m,k Statistically significant increase or decrease compared to controls; 2 no statistically significant effect.
group had deep clefts in the clitoris. Additional effects
observed in rats of the high-dose group included
disrupted estrous cycles (e.g., irregular cycles or persistent
estrous) and decreased relative (to body weight)
ovary and wet or blotted uterus weights. Absolute
weights of wet uterus and ovary were also reduced in
the high-dose group. No corpora lutea were observed in
rats of the high-dose group. Qualitatively similar effects
were observed in the group treated with 17b-estradiol.
The study authors concluded that exposure of rats to
bisphenol A during the neonatal period resulted in
changes in female reproductive organs.
Strengths/Weaknesses: The strengths are the carefully
performed and documented experiments. The major
limitation is that the s.c. route of administration and
the doses of bisphenol A were relatively high. The
changes in the female reproductive organs seen are well
documented, but given the extremely high-dose of agent
used, broadly unsurprising.
Utility (Adequacy) for CERHR Evaluation Process:
The results of this study reflect a careful documentation
of the experiments performed. The study is adequate for
the evaluation process but has limited utility due to
concerns about the route of administration.
Toyama and Yuasa (2004), supported in part by the
Japanese Ministry of Environment and Ministry of
Education, Science, Sports and Culture, examined the
effects of neonatal bisphenol A [purity not reported]
exposure on spermatogenesis during puberty and adulthood
in rats and mice. [No information was provided
about chow or bedding and caging materials. The
mouse data are reported in Section 3.2.8.] Wistar rats
were s.c. injected on a mg/pup basis with bisphenol A in
a DMSO and olive oil vehicle on PND 1, 3, 5, 7, 9, and 11
(PND 0 5 day of birth). Bisphenol A doses were 1.0, 10.0,
100.0, and 600.0 mg/pup. Additional animals were
treated with 17b-estradiol and estradiol benzoate. Animals
were killed weekly at 2–10 weeks of age, and other
pups were killed at 24 and 31 days of age. There were 5
animals/dose/time point in bisphenol A groups and
apparently 5 vehicle control rats/time period. Testes
were examined by light and electron microscopy. Males
from each experimental group (a total of 11 rats) were
mated with 2 females [number tested in each dose
group not reported]. A total of 11 rat dams were allowed
to complete pregnancy. [It does not appear that
statistical analyses were conducted.]
All rats given 0.600 mg/pup bisphenol A died before 20
days of age and were excluded from analysis. In
mature spermatids of 8-week-old rats in the vehicle
control group, the incidences of deformed acrosomes,
deformed nuclei, and abnormal ectoplasmic specialization
were o0.3%. In 8-week-old rats treated with
Z0.010 mg/pup bisphenol A, the incidence of deformed
acrosomes was 450–60%, the incidence of deformed
nuclei was 440%, and the incidence of abnormal
ectoplasmic specialization was 460–70%. [Data were
not shown for individual dose levels.] Similar effects
were observed in the groups treated with 17b-estradiol
and estradiol benzoate. No effects were reported at other
ages. [Data were not shown by study authors.] The
blood–testis barrier remained intact based on histologic
observations. All tested males from the bisphenol A
group were fertile, and sex ratio, litter sizes, and pup
weights were reported to be normal. [No results were
shown for individual dose levels. Fertility data presented
in Table 4 and 5 of the study, were not clearly
identified by dose level.] The study authors concluded
that bisphenol A acts as an estrogen and induces
transient changes in the male reproductive system of
rodents that resolve in adulthood.
Strengths/Weaknesses: The strengths include the use
of multiple doses of bisphenol A and the use of both
rats and mice, allowing interspecies comparisons.
Weaknesses include selective and unclear data presentation,
absence of statistical analyses, subcutaneous injection
on a per pup basis, and failure to examine sperm
morphology in the fertile 15-week-old animals to
Birth Defects Research (Part B) 83:157–395, 2008