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Table 4 Bisphenol A and reproductive system morphology and functions

From: Bisphenol A: an emerging threat to female fertility

  Source Strain Age Exposure route Time of exposure Doses Time of observation Outcome Outcome observed in Reference n°  
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]
  1. N.R not reported