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Table 4 Bisphenol A and reproductive system morphology and functions

From: Bisphenol A: an emerging threat to female fertility

 SourceStrainAgeExposure routeTime of exposureDosesTime of observationOutcomeOutcome observed inReference n° 
Experimental
studies in vitro and ex vivo
MouseSensitivity to FVB32-day-oldIn vitro administration24–120 h4.4, 44, and 440 μM24–120 hBPA inhibits follicle growth and decreases hormone production in mouse ovarian antral follicles. Pregnenolone protected follicles from BPA-induced inhibition of steroidogenesis. Peretz 2011[32]
MouseKunmingN.R.GavageFrom GD0.5 to 3.5200, 400, 600, and 800 mg/kg/dayFrom GD0.5 to 3.5Increase of eNOS protein expression. Remarkably reduced the number of implantation sites of pregnant mice. Pan 2015[37]
MouseCD-1N.R.In vitro administrationFrom PDN 0 to PDN 100,1, 1 and 10 μMFrom PDN 0 to PDN 10Enhanced primordial follicle recruitment by decreasing Ki-67 and caspase-3 expression and by activating PI3K/AKT pathway. Zhao 2014[95]
MouseCD-1PND 0In vitro administrationFor 1–8 days0.1, 1, 5, and 10 μg/ mLFor 1–8 daysInhibition of germ cell nest breakdown increasing expressione of Bcl2 and decreasing of FAS and caspase 8 Zhou 2015[96]
MouseC57/Bl6JxCBA/ Ca12–14 day-oldIn vitro administrationAt the start of follicle culture and each replenishment for 13 days3 nM and 300 nMAt the start of follicle culture and each replenishment for 13 daysAccelerated follicle development with an increase in antral follicle growth. Trapphoff 2013[35]
MouseSensitivity to FVB2- to 35-day-oldIn vitro administration24–96 h1, 10, and 100 μg24–96 hEstradiol 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]
MouseCD-1PND 32–
35
In vitro administration24–96 h1.0, 10, and 100 μg/mL24–96 hLack of cholesterol conversion to pregnenolone and consequently decrease of Cyp11a1 and StAR expression. Decrease of androstenedione, testosterone, and estradiol levels. Peretz 2013 
MouseC57BL/650–54 days oldIn vitro administration24–96 h0.004, 0.04, 0.44, 4.38, 43.8, 110, 219 and 438 μM24–96 hBPA inhibited follicle growth and decreased estradiol levels Ziv-Gal 2013[97]
MouseC57BL62–3 months oldSubcutaneous InjiectonFrom GD0.5 to GD3.5.0, 0.025, 0.5, 10, 40, and 100 mg/kg/dayFrom 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 adulthoodXiao 2011[38]
MouseCF-13–5 monthsSubcutaneous InjectionsFrom GD1 to GD4100, 200, and 300 mg/kgFrom GD1 to GD4Disruption 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 miceBerger 2010[39]
RatWister-derivedN.R.Subcutaneous InjectionsPND 1, 3, 5, and 70.05 mg/kg/day and 20 mg/kg/dayPND 1, 3, 5, and 7Pregnancgy 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 ratsVarayoud 2011[40]
MouseCD-1PND56Subcutaneous injectionsN.R.0, 60, 600 mg/kg/ dayN.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 receptivityN.R.Li 2016[98]
MouseSensitivity to FVB12 weeks of ageOral administrationFrom GD 11 until birth0.5, 20, and 50 μg/kgPND 4Disruption 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 PND4Wang 2014[100]
MouseSensitivity to FVB12 weeks of ageFeeding ExposureFrom GD 11 until birth0.5, 20, and 50 μg/kgOn PND 4 and PND 21BPA 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 adulthoodBerger 2016[99]
Experimental Mouse studies in vivoKunmingN.R.GavageFrom GD0.5 to GD3.5200, 400, 600, and 800 mg/kg/dayFrom 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 micePan 2015[37]
MouseC57BL62–3 months oldSubcutaneous InjectonFrom GD0.5 to GD3.50, 0.025, 0.5, 10, 40, and 100 mg/kg/dayFrom GD0.5 to GD3.5.Delayed implantation and increased perinatal lethality of their offspring were observed.Pregnant female miceXiao 2011[38]
MouseCD-1N.R.Subcutaneous InjectionsGD9–GD160.1, 1, 10, 100, or 1000 μg/kg/day16–18 monthsOvarian 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 adulthoodNewbold 2009[101]
RatWister-derivedN.R.Subcutaneous InjectionsPND 1, 3, 5, and 70.05 mg/kg/day and 20 mg/kg/dayPND 1, 3, 5, and 7Pregnancgy 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 ratsVarayoud 2011[40]
MouseCD-1PND56Subcutaneous injectionsN.R.0, 60, 600 mg/kg/ dayN.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 receptivityN.R.Li 2016[98]
MouseSensitivity to FVB12 weeks of ageOral administrationFrom GD 11 until birth0.5, 20, and 50 μg/kgPND 4Disruption 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 PND4Wang 2014[100]
MouseSensitivity to FVB12 weeks of ageFeeding ExposureFrom GD 11 until birth0.5, 20, and 50 μg/kgOn PND 4 and PND 21BPA 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 adulthoodBerger 2016[99]
Experimental Mouse studies in vivoKunmingN.R.GavageFrom GD0.5 to GD3.5200, 400, 600, and 800 mg/kg/dayFrom 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 micePan 2015[37]
MouseC57BL62–3 months oldSubcutaneous InjectonFrom GD0.5 to GD3.50, 0.025, 0.5, 10, 40, and 100 mg/kg/dayFrom GD0.5 to GD3.5.Delayed implantation and increased perinatal lethality of their offspring were observed.Pregnant female miceXiao 2011[38]
MouseCD-1N.R.Subcutaneous
Injections
GD9–GD160.1, 1, 10, 100, or 1000 μg/kg/day16–18 monthsOvarian 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 adulthoodNewbold 2009[101]
MouseCD-1N.R.Subcutaneous injectionsPND 1–510, 100, or 1000 μg/kg/day18 monthsSignificant 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 miceNewbold 2007[102]
RatWistarN.R.Drinking waterGD9-PND2110 mg/L3 monthsModification 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 adulthoodMendoza- Rodriguez 2011[103]
MouseCF-13–6 monthsSubcutaneous injections and Oral administrationFrom GD1–40.000, 0.0005, 0.0015, 0.0046, 0.0143, 0.0416, 0.125, 0.375, 1.125, 3.375, and 10.125 mg BPA/animal/ dayFrom GD1–4Subcutaneous 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 miceBerger 2007[104]
MouseCF-13–6 months oldSubcutaneous InjectionsGD1–46.75 and 10.125 mg/mLFrom GD1 to GD4In 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 miceBerger 2008[105]
MouseCD-1Pregnant miceOral administration 0.02, 0.04, 0.08 mg/kgPND3, 5, 7BPA 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 adulthoodZhang 2012[106]
EwesCorriedale2–4 years oldSubcutaneous injectionsPND 1–145 and 50 μg/kg/ dayPND30Reduce 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 PND30Rivera 2011[107]
EwesCorriedale2–4 years oldSubcutaneous InjectionsPND1–140.5, 5 and 50 μg/kg/dayPND30 and PND34Impaired 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 PND34Rivera 2015[108]
RatWistar90 days oldDrinking waterGD9-PND212.5, 50 and 250 μg/ kg/dayPND90 during estrusOvaries 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 adulthoodSantamaria 2016[109]
MouseCD-1N.R.Hypodermical injiectionPND7–1420 and 40 μg/kg/ dayPND15 and PND 21BPA 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 miceChao 2012[110]
RatSprague- Dawley28 days- oldOral gavage42 days10 mg/kg bw/dayAfter the last treatment day, during diestrus phaseHigher number of large antral follicles and atretic follicles that did not reached ovulation stageThe same adult female rats (70-days- old)Zaid 2018[88]
RatWistarFemale pupsSubcutaneous InjectionFrom PND 1 to PND 1525 ng/kg/d and 5 mg/kg/d90 days after last treatment, during diestrus phaseDecreased number of primordial follicles and increased number of atretic follicle at both tested BPA dosesFemale offspring in adulthood (PND 105)Lòpez-Rodríguez 2019[89]
RatWistarAdult femaleSubcutaneous InjectionFrom PND 90 to PND 10525 ng/kg/d and 5 mg/kg/d24 h after last treatment, during diestrus phaseDecreased number of antral follicles and increased number of corpora lutea at both tested BPA dosesThe same adult female rats (105-days- old)Lòpez-Rodríguez 2019[89]
  1. N.R not reported