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

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 Rats Ovarian theca- interstitial (T-I) obtained from Sprague– Dawley rats 28–30 days old In vitro administration 72 h BPA low concentration 10–7 M and high concentration from 10 to 4 M to 10–6M After 72 h Increase 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 10–4M Ovarian theca- interstitial (T-I) obtained from Sprague– Dawley rats Zhou 2008 [28]
Rats Granulosa cells obtained from Sprague– Dawley rats 28–30 days old In vitro administration 72 h from 10 to 4 M to 10–7M After 72 h Increased 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 10–4M Granulosa cells obtained from Sprague– Dawley rats Zhou 2008 [28]
Mice FVB Adult female Ex vivo administration in antral follicles PND32 4.4, 44, and 440 μM 120 h Decreased 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 μM Antral follicules of adult female mice Peretz 2011 [32]
Human Luteinized granulosa cells Fertile and infertile patients < 38 years old In vitro Administration 48 h 0.2, 0.02,2.0, 20 μg/ml After 48 h P and E2 reduced secretion in cell media. P450scc, 3ß-HSD and aromatase mRNA expression reduced at BPA higher concentrations. Luteinized granulosa cells Mansur 2016 [33]
Mice CD-1 Antral follicles PND32-PND35 In vitro administration 24h-96h 1.0. 10, 100μg/ml 24h-96h Lack of cholesterol conversion to Pregnenologne and consequently decreased of CYP11a1 and StAR expression. Decrease of androsteneidione, T, and E2 levels Antral follicles Peretz 2013 [34]
Experimental studies in vivo Mouse CD-1 Adult pregnant mice Oral gavage Cohort A: From GD1 to PND20 12, 25 and 50 mg/kg bw/day PND50 Increased 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 phase Female offspring (F1) in adulthood Xi 2011 [29]
Mouse CD-1 Female pups (F1) Oral gavage Cohort B: From PND20 to PND49 25 and 50 mg/kg bw/day PND50 Increased serum E2 levels wherease no change in CYP mRNA expression at proestrus phase Female offspring (F1) in adulthood Xi 2011 [29]
Rat Sprague- Dawley 8-week-old Oral gavage 90 days 0.001 or 0.1 mg/kg bw/day After 90 days of exposure during estrus Decreased 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/day The same adult female rats (8-week- old) Lee 2013 [30]
Rat Wistar Adult pregnant rats Oral administration (drinking water) From GD1 to PND21 3 μg/kg bw/day PND30 Increased serum E2 levels Female offspring (F1) in prepubertal phase Gamez 2015 [31]
Mice ICR Adult Female mice Oral administration 6h 20μg/kg bw/ day Diestrus, proestrus and estrus Increased serum E2 levels during proestrus The same adult mice Wang 2014 [78]
Mice ICR Adult female mice Injection into the right lateral ventricle 6h 0.02, 0.2, 2,20 and 200 nM/3μl Diestrus, proestrus and estrus Increased serum E2 levels during proestrus The same adult mice Wang 2014 [78]
Rat Sprague-Dawley Female pups Subcutaneous Injection From PND1 to PND10 6.2–2.5 mg/kg bw/day and 62.5–25.0 mg/
kg bw/day
PND13 Increased levels of serum E2 and T, and decreased P serum levels The same rats in adulthood Fernandez 2010 [80]
Rats Sprague-Dawley Adult female Oral administration After two classic estrous cycles 50 mg/kg bw/ day 6 consecutive weeks Increased mRNA and protein expression of FSHR The same adult female rats Zhou 2014 [86]
Mice C57BL/6 J 39 days old Oral administration 12–15 days (first 3 reproductive cycle) 50 μg/kg bw/ day At third proestrus No significant change in serum E2 levels The same adult female mice (39-days-old) Moore-Ambriz 2015 [87]
Ewes Suffolk N.R. Injection From GD30 to GD90 0.5 mg/k From GD30 to GD90 Prenatal 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 genes Female offspring at fetal day 65 and at fetal day 90 Veiga- Lopez 2013 [90]
Rat Sprague- Dawley 28 days-old Oral gavage 42 days 10 mg/kg bw/ day After the last treatment day, during diestrus Slight but not significant increase of E2 serum levels and reduction of P serum levels The same adult female rats (70-days-old) Zaid 2018 [88]
Mouse C57BL/6 J Adult second- pregnancy mice Oral gavage Pregnancy GD15) and lactation (PND21) period 0.05 and 5 mg/kg bw/day During diestrus 5 weeks after BPA administration Increased serum E2 levels in diestrus Female offspring in adulthood Naule 2014 [81]
  1. N.R not reported