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

226 CHAPIN ET AL.
Table 58
In Vivo Genetic Toxicity Studies of Bisphenol A
Species and sex Dose (route) Cells Endpoint Results Reference
Male rat 85 mg/kg bw/day Germ Dominant lethality Negative Bond et al. (1980) a,b
for 5 days (i.p.) (abstract only)
Male rat 200 mg/kg bw (i.p.) DNA Adduct formation Positive Atkinson and
and 200 mg/kg bw Roy (1995b)
for 4, 8, 12, or 16 days (oral)
Male and female 500–2000 mg/kg bw (oral) Bone marrow Micronuclei Negative Gudi and Krsmanovic
mouse (1999) a ; Shell Oil
Co. (1999) b
Male mouse 1 mmol/kg bw [228 mg/kg Peripheral Micronuclei Negative Masuda et al. (2005)
bw] (oral) blood
reticulocyte
20–22-day-old 0.02–0.100 mg/kg bw/day Oocyte Congression failure Positive at all doses; Hunt et al. (2003)
female mouse (oral) for 6–8 days or 0.02 mg/ statistically
kg bw for 3, 5, or 7 days significant
with 7-day
exposure
Pregnant mouse 0.4 mg/day s.c. pellet Oocyte Evaluation of pachytene Incomplete synapsis, Susiarjo et al. (2007)
GD 11.5–18.5 [B20 mg/kg bw/day] fetal oocyte and end-to-end
of ploidy in oocytes association
and 2-cell of sister
embryos from chromatids,
adults that mhyperploidy
were exposed
in utero
Female mouse 0.2 or 20 mg/kg bw acutely Oocyte Aneuploidy Negative Pacchierotti et al.
or daily for 7 days or (2007)
0.4 mg/L in drinking water
for 7 weeks
Male (102/ 0.002–0.2 mg/kg bw for Spermatocyte Meiotic delay Negative Pacchierotti et al.
ElxC3H/El) 6 days (oral) and aneuploidy (2007)
F 1 mouse
Drosophila 10,000 ppm (oral) Offspring Sex-linked recessive Negative Foureman et al.
melanogaster lethal test (1994) a,b
Turbot 50 ppb in aquarium Erythrocyte Micronuclei Positive Bolognesi et al.
water for 2 weeks (2006)
a Reviewed by Haighton et al. (2002).
b Reviewed by European-Union (2003).
days. The study authors concluded that bisphenol A was
a potential meiotic aneugen.
In a follow-up study (Susiarjo et al., 2007), pregnant
C57Bl/6 mice on GD 11.5 were implanted with s.c. pellets
designed to release bisphenol A 0 or 0.4 mg/day. [The
authors assume a 20 g bw, giving an estimated dose
level of 20 lg/kg bw/day.] Oocytes from GD 18.5 female
fetuses showed an increase in pachytene synaptic
abnormalities including incomplete synapsis and endto-end
associations of sister chromatids. There was also
paradoxically an increase in recombinant foci in pachytene
oocytes of bisphenol A-exposed females. Some
female offspring of bisphenol A-treated dams were
fostered to untreated dams. Eggs or 2-cell embryos from
these female offspring at 4–5 weeks of age showed an
increase in hyperploidy. Pachytene oocyte abnormalities
similar to those identified in fetuses exposed to bisphenol
A were seen in oocytes obtained from ERb
knock-out mice, suggesting to the authors that bisphenol
A may exert adverse effects on meiosis by blocking ERb.
In response to the study of Hunt et al. (2003),
Pacchierotti et al. (2007) investigated the aneugenic
effects of bisphenol A in mouse somatic and germ cells.
C57Bl/6 female mice were superovulated using pregnant
mare serum and hCG after which they were gavaged
with bisphenol A 0.2 or 20 mg/kg bw. Metaphase II
oocytes were collected after 17 hr and evaluated using Cbanding.
Additional female mice were gavaged with
bisphenol A 0.04 mg/kg bw/day for 7 days or were
given bisphenol A in drinking water at a concentration of
0.4 mg/L for 7 weeks. These mice were superovulated at
the end of the 7-day or 7-week treatment period and
housed overnight with untreated males. Females without
vaginal plugs were killed for evaluation of oocytes by Cbanding.
Females with vaginal plugs were treated with
colchicine to prevent the first embryonic cleavage, and
zygotes were collected the next morning for evaluation
by C-banding. There were no bisphenol A effects on
induction of aneuploidy. There was a statistically
significant increase in premature centromere separation
in the group treated for 7 weeks, but there was no effect
of bisphenol A treatment on the proportion of zygotes
with structural or numeric chromosome changes. Male
mice were treated with bromodeoxyuridine 8 days before
being treated with bisphenol A 0.2 mg/kg bw/day for 6
days. Evaluation of sperm after 21–25 days did not show
a significant mitotic delay in spermatocytes. Additional
male mice were given bisphenol A orally at doses of 0,
Birth Defects Research (Part B) 83:157–395, 2008