Table 4 Bisphenol A and reproductive system morphology and functions

Experimental

studies in vitro and ex vivo

Mouse

Sensitivity to FVB

32-day-old

In vitro administration

24–120 h

4.4, 44, and 440 μM

24–120 h

BPA inhibits follicle growth and decreases hormone production in mouse ovarian antral follicles. Pregnenolone protected follicles from BPA-induced inhibition of steroidogenesis.

Peretz 2011

[32]

Mouse

Kunming

N.R.

Gavage

From GD0.5 to 3.5

200, 400, 600, and 800 mg/kg/day

From GD0.5 to 3.5

Increase of eNOS protein expression. Remarkably reduced the number of implantation sites of pregnant mice.

Pan 2015

[37]

Mouse

CD-1

N.R.

In vitro administration

From PDN 0 to PDN 10

0,1, 1 and 10 μM

From PDN 0 to PDN 10

Enhanced primordial follicle recruitment by decreasing Ki-67 and caspase-3 expression and by activating PI3K/AKT pathway.

Zhao 2014

[95]

Mouse

CD-1

PND 0

In vitro administration

For 1–8 days

0.1, 1, 5, and 10 μg/ mL

For 1–8 days

Inhibition of germ cell nest breakdown increasing expressione of Bcl2 and decreasing of FAS and caspase 8

Zhou 2015

[96]

Mouse

C57/Bl6JxCBA/ Ca

12–14 day-old

In vitro administration

At the start of follicle culture and each replenishment for 13 days

3 nM and 300 nM

At the start of follicle culture and each replenishment for 13 days

Accelerated follicle development with an increase in antral follicle growth.

Trapphoff 2013

[35]

Mouse

Sensitivity to FVB

2- to 35-day-old

In vitro administration

24–96 h

1, 10, and 100 μg

24–96 h

Estradiol does not protect follicles from BPA- induced growth inhibition and does not protect follicles from BPA-induced atre sia. BPA up-regulates Cdk4, Ccne1, and Trp53 expression, whereas it down- regulates Ccnd2 expression. BPA also up- regulates Bax and Bcl2 expression while in ducing atresia in antral follicles.

Peretz 2012

[36]

Mouse

CD-1

PND 32–

35

In vitro administration

24–96 h

1.0, 10, and 100 μg/mL

24–96 h

Lack of cholesterol conversion to pregnenolone and consequently decrease of Cyp11a1 and StAR expression. Decrease of androstenedione, testosterone, and estradiol levels.

Peretz 2013

Mouse

C57BL/6

50–54 days old

In vitro administration

24–96 h

0.004, 0.04, 0.44, 4.38, 43.8, 110, 219 and 438 μM

24–96 h

BPA inhibited follicle growth and decreased estradiol levels

Ziv-Gal 2013

[97]

Mouse

C57BL6

2–3 months old

Subcutaneous Injiecton

From GD0.5 to GD3.5.

0, 0.025, 0.5, 10, 40, and 100 mg/kg/day

From GD0.5 to GD3.5.

Females treated with 100 mg/kg/day BPA, did not show implantation sites on day 4.5. In 40 mg/kg/day BPA treated females.

Female offsprings in adulthood

Xiao 2011

[38]

Mouse

CF-1

3–5 months

Subcutaneous Injections

From GD1 to GD4

100, 200, and 300 mg/kg

From GD1 to GD4

Disruption of intrauterine implantation and alteration in uterine morphology. Expansion in uterine luminal area and an increase in luminal epithelial cell height. ER alpha and PR expression was modulated as a non-monotonic function of BPA dose, with some evidence of a rise with the lowest dose and declines with increasing dose.

Adult female mice

Berger 2010

[39]

Rat

Wister-derived

N.R.

Subcutaneous Injections

PND 1, 3, 5, and 7

0.05 mg/kg/day and 20 mg/kg/day

PND 1, 3, 5, and 7

Pregnancgy rate decrease. Decrease in the number of implantation sites. A lower mRNA expression of Hoxa10 and a lower protein expression of ER and PR.

Adult female rats

Varayoud 2011

[40]

Mouse

CD-1

PND56

Subcutaneous injections

N.R.

0, 60, 600 mg/kg/ day

N.R.

Downregulation of PGR and HAND2 expression in uterine stroma upon BPA exposure was associated with enhanced activation of FGF and MAPK signaling in the epithelium, contributed to aberrant proliferation and lack of uterine receptivity

N.R.

Li 2016

[98]

Mouse

Sensitivity to FVB

12 weeks of age

Oral administration

From GD 11 until birth

0.5, 20, and 50 μg/kg

PND 4

Disruption of germ cell nest breakdown and reduce of the size of the primordial follicle pool by altering the expression of pro- and anti-apoptotic factors. Advance of puberty onset and disturb of estrous cyclicity.

Ovaries of female offspring at PND4

Wang 2014

[100]

Mouse

Sensitivity to FVB

12 weeks of age

Feeding Exposure

From GD 11 until birth

0.5, 20, and 50 μg/kg

On PND 4 and PND 21

BPA at 50 μg/kg/day increased expression of the anti-apoptotic factor Bcl2 and BPA at 0.5 μg/kg/day and 20 μg/kg/day decreased expression of the pro- apoptotic Bax compared to control. In the F2 generation, BPA at 0.5 μg/kg/day significantly decreased expression of Bcl2, but it did not significantly affect the expression of Bax compared to control. BPA also did not significantly affect the ratios of these two factors in the F2 ovaries. In the F3 generation, BPA exposure did not significantly affect levels of expression of Bcl2, Bax, or their ratio compared to control. In utero BPA exposure inhibits germ cell nest breakdown in PND 4 ovaries of the F1 generation, but not in the F2 or F3 generations.

Female offspring in adulthood

Berger 2016

[99]

Experimental Mouse studies in vivo

Kunming

N.R.

Gavage

From GD0.5 to GD3.5

200, 400, 600, and 800 mg/kg/day

From GD0.5 to GD3.5.

Delay of the transfer of embryos to the uterus, damaged blastocyst development before implantation, and inhibited embryo implantation.

Adult female mice

Pan 2015

[37]

Mouse

C57BL6

2–3 months old

Subcutaneous Injecton

From GD0.5 to GD3.5

0, 0.025, 0.5, 10, 40, and 100 mg/kg/day

From GD0.5 to GD3.5.

Delayed implantation and increased perinatal lethality of their offspring were observed.

Pregnant female mice

Xiao 2011

[38]

Mouse

CD-1

N.R.

Subcutaneous Injections

GD9–GD16

0.1, 1, 10, 100, or 1000 μg/kg/day

16–18 months

Ovarian cysts increase; increasing in proliferative lesions of the oviduct; squamous metaplasia of the uterus; some evidence of a rise with the lowest dose and declines with increasing dose.

Female offspring in adulthood

Newbold 2009

[101]

Rat

Wister-derived

N.R.

Subcutaneous Injections

PND 1, 3, 5, and 7

0.05 mg/kg/day and 20 mg/kg/day

PND 1, 3, 5, and 7

Pregnancgy rate decrease. Decrease in the number of implantation sites. A lower mRNA expression of Hoxa10 and a lower protein expression of ER and PR.

Adult female rats

Varayoud 2011

[40]

Mouse

CD-1

PND56

Subcutaneous injections

N.R.

0, 60, 600 mg/kg/ day

N.R.

Downregulation of PGR and HAND2 expression in uterine stroma upon BPA exposure was associated with enhanced activation of FGF and MAPK signaling in the epithelium, contributed to aberrant proliferation and lack of uterine receptivity

N.R.

Li 2016

[98]

Mouse

Sensitivity to FVB

12 weeks of age

Oral administration

From GD 11 until birth

0.5, 20, and 50 μg/kg

PND 4

Disruption of germ cell nest breakdown and reduce of the size of the primordial follicle pool by altering the expression of pro- and anti-apoptotic factors. Advance of puberty onset and disturb of estrous cyclicity.

Ovaries of female offspring at PND4

Wang 2014

[100]

Mouse

Sensitivity to FVB

12 weeks of age

Feeding Exposure

From GD 11 until birth

0.5, 20, and 50 μg/kg

On PND 4 and PND 21

BPA at 50 μg/kg/day increased expression of the anti-apoptotic factor Bcl2 and BPA at 0.5 μg/kg/day and 20 μg/kg/day decreased expression of the pro- apoptotic Bax compared to control. In the F2 generation, BPA at 0.5 μg/kg/day significantly decreased expression of Bcl2, but it did not significantly affect the expression of Bax compared to control. BPA also did not significantly affect the ratios of these two factors in the F2 ovaries. In the F3 generation, BPA exposure did not significantly affect levels of expression of Bcl2, Bax, or their ratio compared to control. In utero BPA exposure inhibits germ cell nest breakdown in PND 4 ovaries of the F1 generation, but not in the F2 or F3 generations.

Female offspring in adulthood

Berger 2016

[99]

Experimental Mouse studies in vivo

Kunming

N.R.

Gavage

From GD0.5 to GD3.5

200, 400, 600, and 800 mg/kg/day

From GD0.5 to GD3.5.

Delay of the transfer of embryos to the uterus, damaged blastocyst development before implantation, and inhibited embryo implantation.

Adult female mice

Pan 2015

[37]

Mouse

C57BL6

2–3 months old

Subcutaneous Injecton

From GD0.5 to GD3.5

0, 0.025, 0.5, 10, 40, and 100 mg/kg/day

From GD0.5 to GD3.5.

Delayed implantation and increased perinatal lethality of their offspring were observed.

Pregnant female mice

Xiao 2011

[38]

Mouse

CD-1

N.R.

Subcutaneous

Injections

GD9–GD16

0.1, 1, 10, 100, or 1000 μg/kg/day

16–18 months

Ovarian cysts increase; increasing in proliferative lesions of the oviduct; squamous metaplasia of the uterus; atypical hyperplasia and stromal polyps of the uterus; sarcoma of the uterine cervix.

Female offspring in adulthood

Newbold 2009

[101]

Mouse

CD-1

N.R.

Subcutaneous injections

PND 1–5

10, 100, or 1000 μg/kg/day

18 months

Significant increase in cystic ovaries and cystic endometrial hyperplasia; progressive proliferative lesion of the oviduct and cystic mesonephric duct remnants; adenomyosis, leiomyomas, atypical hyperplasia, and stromal polyps of the uterus.

Adult female mice

Newbold 2007

[102]

Rat

Wistar

N.R.

Drinking water

GD9-PND21

10 mg/L

3 months

Modification of estrous cyclicity, an increased height of both uterine epithelia and stroma, a reduction in apoptotic cells in both uterine luminal and glandular epithelium and down regulation of ER alpha on estrus days.

Female offspring in adulthood

Mendoza- Rodriguez 2011

[103]

Mouse

CF-1

3–6 months

Subcutaneous injections and Oral administration

From GD1–4

0.000, 0.0005, 0.0015, 0.0046, 0.0143, 0.0416, 0.125, 0.375, 1.125, 3.375, and 10.125 mg BPA/animal/ day

From GD1–4

Subcutaneous injections resulted in a significant decrease in the average number of pups at 3.375 mg/day. At 10.125 mg/day, there was a significant reduction in the number of pregnancies. Uterine implantation sites were also significantly reduced in females sacrificed at day 6 after receiving 10.125 mg/day.

Pregnant female mice

Berger 2007

[104]

Mouse

CF-1

3–6 months old

Subcutaneous Injections

GD1–4

6.75 and 10.125 mg/mL

From GD1 to GD4

In Experiment 1, daily doses of 6.75 and 10.125 mg significantly reduced the number of implantation sites. Urinary progesterone was significantly reduced by the higher dose. In Experiment 2, inseminated females received a single dose of BPA on days 0, 1, or 2 of gestation. A single dose of 10.125 mg reduced the number of implantation sites when given on day 0 or day 1, and 6.75 mg on day 1 also produced fewer implantation sites.

Pregnant female mice

Berger 2008

[105]

Mouse

CD-1

Pregnant mice

Oral administration

0.02, 0.04, 0.08 mg/kg

PND3, 5, 7

BPA exposure level was associated with more oocytes in germ cell cyst and less primordial follicle. Decreased mRNA expression of specific meiotic genes including Stra8, Dmc1, Rec8 and Scp3 were observed.

Female offspring in adulthood

Zhang 2012

[106]

Ewes

Corriedale

2–4 years old

Subcutaneous injections

PND 1–14

5 and 50 μg/kg/ day

PND30

Reduce in ovarian weight and increase in the number of multioocyte follicles. Proliferation of granulosa/theca cells in antral follicles and increase of the number of antral atretic follicles. Reduce in the primordial follicle pool by stimulating their initial recruitment and subsequent follicle development until antral stage. Acceleration of folliculogenesis resulted in increased incidence of atretic follicles.

Female lamb at PND30

Rivera 2011

[107]

Ewes

Corriedale

2–4 years old

Subcutaneous Injections

PND1–14

0.5, 5 and 50 μg/kg/day

PND30 and PND34

Impaired ovarian response to oFSH with a lower number of follicles. AR induction by oFSH disruption in granulosa and theca cells. An increase in GDF9 mRNA expression levels. In contrast, a decrease in BMPR1B was observed.

Ovaries of female lamb at PND30 and after oFSH at PND34

Rivera 2015

[108]

Rat

Wistar

90 days old

Drinking water

GD9-PND21

2.5, 50 and 250 μg/ kg/day

PND90 during estrus

Ovaries showed reduced primordial follicle recruitment and a greater number of corpora lutea. A lower expression of androgen receptor (AR) at different stages of the growing follicle population was demonstrated.

Female offspring in adulthood

Santamaria 2016

[109]

Mouse

CD-1

N.R.

Hypodermical injiection

PND7–14

20 and 40 μg/kg/ day

PND15 and PND 21

BPA promotes the primordial to primary follicle transition, thereby speeding up the depletion of the primordial follicle pool, and suppressed the meiotic maturation of oocytes because of abnormal spindle assembling in meiosis.

Adult female mice

Chao 2012

[110]

Rat

Sprague- Dawley

28 days- old

Oral gavage

42 days

10 mg/kg bw/day

After the last treatment day, during diestrus phase

Higher number of large antral follicles and atretic follicles that did not reached ovulation stage

The same adult female rats (70-days- old)

Zaid 2018

[88]

Rat

Wistar

Female pups

Subcutaneous Injection

From PND 1 to PND 15

25 ng/kg/d and 5 mg/kg/d

90 days after last treatment, during diestrus phase

Decreased number of primordial follicles and increased number of atretic follicle at both tested BPA doses

Female offspring in adulthood (PND 105)

Lòpez-Rodríguez 2019

[89]

Rat

Wistar

Adult female

Subcutaneous Injection

From PND 90 to PND 105

25 ng/kg/d and 5 mg/kg/d

24 h after last treatment, during diestrus phase

Decreased number of antral follicles and increased number of corpora lutea at both tested BPA doses

The same adult female rats (105-days- old)

Lòpez-Rodríguez 2019

[89]