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Table 3 Bisphenol A and hypothalamus-pituitary-ovary (HPO) axis: ovary

From: Bisphenol A: an emerging threat to female fertility

 SourceStrainAgeExposure routeTime of exposureDosesTime of observationOutcomeOutcome observed inReference n° 
Experimental studies in vitro and ex-vivoRatsOvarian theca- interstitial (T-I) obtained from Sprague– Dawley rats28–30 days oldIn vitro administration72 hBPA low concentration 10–7 M and high concentration from 10 to 4 M to 10–6MAfter 72 hIncrease cholesterol side-chain cleavage enzyme (P450scc) and 17 alpha-hydroxylase/17,20 lyase (P450c17) mRNA at all BPA concentrations tested. Increased StAR mRNA expression and T secretion at BPA 10–5 and 10–4MOvarian theca- interstitial (T-I) obtained from Sprague– Dawley ratsZhou 2008[28]
RatsGranulosa cells obtained from Sprague– Dawley rats28–30 days oldIn vitro administration72 hfrom 10 to 4 M to 10–7MAfter 72 hIncreased StAR mRNA and P levels in cell media from BPA 10–7 to 10–5 M. Decreased P levels in cell media at BPA 10–4 M. E2 levels dose-dependently decreased while aromatase mRNA increased after BPA at 10–7 to 10–4MGranulosa cells obtained from Sprague– Dawley ratsZhou 2008[28]
MiceFVBAdult femaleEx vivo administration in antral folliclesPND324.4, 44, and 440 μM120 hDecreased levels of P and E2 in cell media at 440 μM of BPA. Decreased StAR and 3ß-HSD mRNA expression in antral follicules after BPA exposure of 440 μMAntral follicules of adult female micePeretz 2011[32]
HumanLuteinized granulosa cellsFertile and infertile patients < 38 years oldIn vitro Administration48 h0.2, 0.02,2.0, 20 μg/mlAfter 48 hP and E2 reduced secretion in cell media. P450scc, 3ß-HSD and aromatase mRNA expression reduced at BPA higher concentrations.Luteinized granulosa cellsMansur 2016[33]
Mice CD-1Antral folliclesPND32-PND35In vitro administration24h-96h1.0. 10, 100μg/ml24h-96hLack of cholesterol conversion to Pregnenologne and consequently decreased of CYP11a1 and StAR expression. Decrease of androsteneidione, T, and E2 levelsAntral folliclesPeretz 2013[34]
Experimental studies in vivoMouseCD-1Adult pregnant miceOral gavageCohort A: From GD1 to PND2012, 25 and 50 mg/kg bw/dayPND50Increased serum E2 levels associated with mRNA and protein P450scc and aromatase expressions up- regulation after BPA exposure to 12, 25 and 50 mg/kg bw/day in proestrus phaseFemale offspring (F1) in adulthoodXi 2011[29]
MouseCD-1Female pups (F1)Oral gavageCohort B: From PND20 to PND4925 and 50 mg/kg bw/dayPND50Increased serum E2 levels wherease no change in CYP mRNA expression at proestrus phaseFemale offspring (F1) in adulthoodXi 2011[29]
RatSprague- Dawley8-week-oldOral gavage90 days0.001 or 0.1 mg/kg bw/dayAfter 90 days of exposure during estrusDecreased serum E2 levels. Decreased aromatase protein expression in granulosa cells in particular after BPA exposure of 0.001 mg/kg bw/day. Downregulation of StAR protein expression after BPA exposure of 0.001 or 0.1 mg/kg bw/dayThe same adult female rats (8-week- old)Lee 2013[30]
RatWistarAdult pregnant ratsOral administration (drinking water)From GD1 to PND213 μg/kg bw/dayPND30Increased serum E2 levelsFemale offspring (F1) in prepubertal phaseGamez 2015[31]
MiceICRAdult Female miceOral administration6h20μg/kg bw/ dayDiestrus, proestrus and estrusIncreased serum E2 levels during proestrusThe same adult miceWang 2014[78]
MiceICRAdult female miceInjection into the right lateral ventricle6h0.02, 0.2, 2,20 and 200 nM/3μlDiestrus, proestrus and estrusIncreased serum E2 levels during proestrusThe same adult miceWang 2014[78]
RatSprague-DawleyFemale pupsSubcutaneous InjectionFrom PND1 to PND106.2–2.5 mg/kg bw/day and 62.5–25.0 mg/
kg bw/day
PND13Increased levels of serum E2 and T, and decreased P serum levelsThe same rats in adulthoodFernandez 2010[80]
RatsSprague-DawleyAdult femaleOral administrationAfter two classic estrous cycles50 mg/kg bw/ day6 consecutive weeksIncreased mRNA and protein expression of FSHRThe same adult female ratsZhou 2014[86]
MiceC57BL/6 J39 days oldOral administration12–15 days (first 3 reproductive cycle)50 μg/kg bw/ dayAt third proestrusNo significant change in serum E2 levelsThe same adult female mice (39-days-old)Moore-Ambriz 2015[87]
EwesSuffolkN.R.InjectionFrom GD30 to GD900.5 mg/kFrom GD30 to GD90Prenatal BPA increased Cyp19 and 5α-reductase expression in day 65, but not day 90, ovaries. Fetal ovarian microRNA expression was altered by prenatal BPA with 45 down-regulated at day 65 and 11 down-regulated at day 90 of gestation. These included microRNAs targeting Sry- related high-mobility-group box (SOX) family genes, kit ligand, and insulin-related genesFemale offspring at fetal day 65 and at fetal day 90Veiga- Lopez 2013[90]
RatSprague- Dawley28 days-oldOral gavage42 days10 mg/kg bw/ dayAfter the last treatment day, during diestrusSlight but not significant increase of E2 serum levels and reduction of P serum levelsThe same adult female rats (70-days-old)Zaid 2018[88]
MouseC57BL/6 JAdult second- pregnancy miceOral gavagePregnancy GD15) and lactation (PND21) period0.05 and 5 mg/kg bw/dayDuring diestrus 5 weeks after BPA administrationIncreased serum E2 levels in diestrusFemale offspring in adulthoodNaule 2014[81]
  1. N.R not reported