Skip to main content
. Author manuscript; available in PMC: 2008 Aug 1.
Published in final edited form as: Reprod Toxicol. 2007 Jun 26;24(2):199–224. doi: 10.1016/j.reprotox.2007.06.004

Table 4.

Published papers reporting biological effects in animal studies (excluding aquatic animals) for bisphenol A (BPA) in the low-dose exposure range (<50,000 μg/kg BW/day), sorted by tissue or endpoint examined. The information indicated in the column headings provides information in published studies. If information is not reported, this is indicated by “NR”. Day plug observed = GD 0. Mice GD 19 = PND 1. Rats GD 22 = PND1. Female = “F”; Male = “M”; DES = diethylstilbestrol.

Reference In Other
Sections		 Animal Sex Exposure,
Vehicle		 Time of
Exposure		 Doses Tested,
μg/kg BW/day (*P<0.05)		 Endpoints Age at
Collection		 Other
Chemicals
Tested
Effects on Brain Physiology
Akingbemi,
2004 [41]		 Sex Diff.,
Testost., Metab.		 Long Evans Rat, CRL M Oral,
Oil Oral Gavage		 PND 21-PND 35

GD 12-PND 21		 2.4*, 10(*),100,000, 200,000
2.4*, 10*, 100,000*, 200,000
2.4*		 Serum LH, Testosterone, suppression Serum Estradiol Suppression Pituitary LHβ and ERα mRNA Expression; Body Weight; Seminal Vesicle Weight (see also In Vitro) PND 35

PND 90
Aloisi, 2001 [120] Rat F Oral, Oil adult 40,000* ERα adult
Ceccarelli, 2007 [32] Sprague-Dawley Rat Harlan Italy F, M Oral PND 23 - 30 40* Hypothalamic ERα PND 27 PND 90 ethinylestradiol
Evans, 2004 [39] Sheep, Poll Dorset F Injection, Oil 4 weeks (prepuberty) - 11 weeks 3,500* Tonic LH Secretion; LH Pulse Frequency & Amplitude 11 weeks DES, Octylphenol
Facciolo, 2002 [34] Sprague-Dawley Rat (CRL Italy) F Oral, Oil GD 0 – PND 23 40, 400* GABAA Receptors PND 10, PND 23
Funabashi, 2001 [117] Rat F Injection, s.c. adult 50,000* Hypothalamic Preoptic Area Progesterone Receptors Estradiol, Butyl benzyl phthalate
Funabashi, 2004 [119] Rat F Inection s.c. adult 40,000* Frontal and Temporal Cortex change in Progesterone Receptor mRNA adult Octylphenol Nonylphenol
Funabashi, 2003 [118] Rat F Oral, Oil adult 4, 40, 400*, 4,000* Hypothalamic Progesterone Receptors, POA and VMH adult Estradiol
Kawai, 2007 [33] ICR mice M Oral GD 11-17 2* Change in ERα And ERβ immnoactivity in dorsal raphe nucleus PND 35 PND 63 PND 91
Kawato, 2004 [42] Wistar Rat M Oral, Water GD 11-PND 21 0.1*, 1, 10, 50 mg/L in drinking water Brain Steroidogenesis 4 weeks
Khurana, 2000 [31] Fischer 344 Rat F, M Injection, Oil PND 1 - 5 15,000*, 75,000*
15,000*		 Hyperprolactinemia Pituitary ERα, ERβ Expression PND 10-PND 30 DES, Octylphenol
MacLusky, 2005 [44] Rat F Injection, Oil adult 40*, 120*, 400*
45*		 Hippocampal Pyramidal Neuron Synaptogenesis adult 17β-Estradiol, 17α-Estradiol
Nikaido, 2004 [15] Puberty,
Metab.		 Crj:CD-1 (ICR) Mouse F Injection, DMSO GD15-GD18 500*, 10,000*
500*, 10,000*
500*, 10,000*
500, 10,000*		 Cycle Length, Diestrus Reduced Corpora Lutea Mammary Gland Dev. Age at Vaginal Opening 4,8,12,16 weeks and weeks 9-11 examined for estrous cycles, DES, Genistein, Zearalenone, Resveratrol
Ramos, 2003 [30] Prostate Wistar-derived Rat M Osmotic Minipump GD 7 – 22 25*, 250*
25*, 250*		 Ventral Prostate; HPG Axis ERβ PND 15, 30, 120
Rubin, 2001 [37] Metab. Sprague Dawley Rat, Taconic F Oral, Water GD6 – PND 21 100*, 1,200* Body Wt., Cyclicity, LH BW from PND2-110 Cycles 4 and 6 months
Savabieasfahani, 2006 [40] Suffolk Ewes F Sc injection in cottonseed oil into pregnant dams GD30-GD90 5000* Low birth weight Increased LH levels during 1st two months of postnatal life Extended breeding season Dampened magnitude of LH surge 6weeks-40+ weeks of age Methoxychlor
Steinmetz, 1997 [121] Rat F Implant adult 300* Serum Prolactin; PRF Activity (see also In Vitro) adult Estradiol
Talsness, 2000 [38] Prostate,
Metab.		 Sprague Dawley Rat, Harlan-Winkelmann F, M Oral, Oil GD 6- GD 21 100*, 50,000*
100*, 50,000
100*, 50,000		 Reproductive System Effects Body Weight, Estrus Cycle; AGD in Males adult 3 months PND 3, 15, 21 Ethinylestradiol
Zoeller, 2005 [9] Sprague Dawley Rat, Zivic Miller F, M Oral, Feed Via treated wafer GD 6-duration not defined 1,000*, 10,000*, 50,000* Serum Thyroxin; Dentate Gyrus RC3/Neurogranin Expression PND 4, 8, 15, and 35
Zsarnovszky, 2005 [43] Sprague Dawley Rats F, M Injections into cerebellum PND4- PND19 and adults 250-300g Concentrations of 10-12- 10−6 M BPA were injected into the cerebellum (3ul in PND4-10, 5ul into older animals) Rapidly increased pERK beginning on PND8; Co-administration with E2 inhibited rapid E2 induced ERK1/2 activation. Dose dependent PND4-PND19 and adults Cyclodextrin encapsulated estradiol
Effects on Brain Structure
Kubo, 2001 [45] Sex Diff. Wistar Rat F, M Oral, Water mating to weaning 1,500* Brain, Behavior. Loss of sexual dimorphism in behavior and in size of locus coeruleus 6-12 weeks
Kubo, 2003 [46] Sex Diff.,
Prostate		 Rat F, M Oral, water mating to weaning 30*, 300* Brain/Behavior. Reversal in the sexually dimorphic volume of the locus coeruleus, behavioral changes postnatally, 6, 11-12 and 14 Weeks DES, Resveratrol
Masuo, 2004 [49] Behav.. Wistar Rat M Intracisternal Injection, Oil 10 μl into pups PND 5 Approximately 2, 20*, 200*, 2,000*
2,000*		 Motor Hyperactivity (Spontaneous Motor Activity) Midbrain Gene Expression PND 56 Nonylphenol, Octylphenol, DEHP
Nakamura, 2006 [50] ICR/Jcl Mice F, M sc injection, oil GD 0- collection 20* Altered Neuronal Migration and Gene Expression GD 10.5- GD 16.5
Patisaul, 2006 [48] Sex Diff. Sprague Dawley Rat, CRL F, M SC injection in sesame oil into pups PND1-2 Approximately 75000* Altered AVPV development Altered Sexual dimorphism of Dopamine (TH) neuron number and number of TH/ER expressing Neurons PND 19
Rubin, 2006 [47] CD-1 Mouse F, M Osmotic minipump GD 8- PND 21 0.025, 0.250* Dopamine neuron number in the AVPV reduced/ loss of expected sexual dimorphism PND 24-27
Effects on Behavior
Adriani, 2003 [64] Sprague Dawley Rat (Italy) F, M Oral, Oil GD 0 – PND 26 40* Behavioral Tests, M & F; Amphetamine Response, M PND30-35, PND 70
Aloisi, 2002 [56] Sprague Dawley Rats, CRL F, M Oral, Oil Trained to suck BPA from pipette Dams exposed thru pregnancy and lactation. 2 groups: placental exp suckling exp 40* Pain Behavior; formalin induced nociception 22 weeks of age
Della Seta, 2005 [61] Metab. Rat F Oral, Oil adult 40* Maternal Behavior
Della Seta, 2006 [67] Testost. Sprague Dawley (Italy) M Oral, Oil PND 23- PND 30 40* Decreased Serum Testosterone PND 37, 45, >90 Ethinylestradiol
Dessi-Fulgheri, 2002 [62] Sprague Dawley Rat (Italy) F, M Oral, Oil 40, GD 0- PND 21; 400, GD 14- PND 6 40*, 400*
40*, 400
40, 400*		 Play Behaviors PND 35, 45, 55
Farabollini, 2002 [51] Sprague Dawley Rat (Italy) F, M Oral, Oil GD 0- GD 22; PND1- PND21 40*
40*		 Aggression, Sexual Behavior PND 100
Ishido, 2004 [54] Metab. Wistar Rat M Intracistern al Injection, Oil 10 μl PND5 ≈3, ≈30, ≈300*, ≈3,000*
≈3, ≈30, ≈300, ≈3,000*
(87fmol- 87nmol BPA/rat)- 0.02-20 ug/rat		 Hyperactivity Reduced gene expression of Dopamine Receptor and Dopamine Transporter, reduded midbrain TH- IR 4-8 weeks
Kawai, 2003 [52] Testost. CD-1 Mouse M Oral, Oil GD 11-17 2*, 20* Aggression, Testis Wt. 8, 12, 16 weeks
Laviola, 2005 [66] Sex Diff. CD-1 Mouse CRL F, M Oral, Oil Drink from syringe GD 11-18 10* Amphetamine- Induced Conditioned Place Preference 60 days Methoxychlor
Masuo, 2004 [53] Rat Intracistern al Injection neonatal ~20 μg/kg* Motor Hyperactivity 4-5 weeks
Mizuo, 2004 [55] ddY mice oral, feed GD 0- ~PND 14 0.002, 0.5*, 2* mg/g in food Enhanced Reward Effect and Hyperlocomotion in Response to Morphine adult
Negishi, 2004 [59] F344/N Rat M Oral, Oil (corn) gavage GD3- PND20 100* Behavioral Alterations Active Avoidance Test 8 weeks- 24 weeks Nonylphenol
Nishizawa, 2005 [35, 36] Mouse F, M Oral, Oil GD 6 -13 GD 6-17 0.02*, 2*, 200*, 2,000* Embryonic Brain and Gonad AhR Expression; RARα, RXRα Expression
Palanza, 2002 [60] Metab. CD-1 Mouse, CRL F Oral, Oil GD 14-18 10* Maternal Behaviors In adulthood
Porrini, 2005 [63] Sprague Dawley Rat, CRL Italy F, M Oral, Peanut Oil, micropipette daily from mating to parturition 40* Socio-Sexual Behaviors 35,45,55 days
Razzoli, 2005 [122] Gerbil F Oral, Oil adult 2*, 20
2*, 20*; 2*, 20;
& 2, 20*		 Social Investigative Behavior Free Exploratory Tests Ethinylestradiol
Ryan, 2006 [57] Puberty, Metab. C57Bl6 Mice Ov × F Oral, gavage needle into back of mouth GD3- PND21 2, 200 Accelerated puberty Altered Anxiety Related Behaviors Adult , 6 weeks + Ethinylestradiol
Suzuki, 2003 [65] ddY Mouse M Oral, in Feed GD 0- PND 21 0.002, 0.5, 2 mg/g feed ≈300*, ≈75,000*, ≈300,000* Dopamine D1 Receptor-Mediated Enhanced Induced Abuse State not specified
Effects on Sex Differences in the Brain
Carr, 2003 [68] Fischer 344 Rat F, M Oral, Oil gavage in pups PND1- PND14 100, 250*
100*, 250		 Morris Water Maze; Elimination of Sex Difference Tests begin PND 34 Estradiol
Farabollini, 1999 [58] Sprague Dawley Rat (Italy) F, M Oral, Oil GD 0- PND 21 40*, 400* Exploratory behavior, Activity PND 85
Fujimoto, 2006 [73] Wistar rat F, M Oral, Drinking water GD 0- PND 1 15* Sex differences in open field and forced swimming behavioral tests 7-9 weeks
Funabashi, 2004 [72] Wistar Rat F, M Oral, Drinking water Gestation and lactation, no GD identified ≈2,500*,(2500) Sex Differences in CRH Neurons in Bed Nucleus of the Stria Terminalis 4-7 months
Imanishi, 2003 [70] ICR Mouse F, M Oral, Oil GD 6- GD 17 2* 2* Placental Nuclear Receptor Gene Expression, 9 of 20 examined; Six Non-Nuclear Receptor Genes GD 18
Nishizawa, 2003 [71] ICR Mouse F, M Oral, Oil GD 6 - collection 2* Embryonic Brain and Gonad Retinoid Receptor Expression RARα, RXRα GD 12, 14, 16, or 18
Shibata, 2002 [69] Metab. Wistar Rat M Oral 2 or 4 weeks adulthood 1,500* BPA and sex steroid metabolism in adult male adult DES
Effects on Puberty in Females
Honma, 2002 [13] Metab. ICR/Jcl Mouse F, M sc Injection, Oil GD 11- GD 17 2*, 20*
2*, 20
2, 20*		 BW, Estrous Cycle Length, Male AGD Vaginal Cytology; Female AGD Age of Vaginal Opening, First Estrus up to PND 120 DES
Howdeshell, 1999 [78] Metab. CF-1 Mouse F, M Oral, Oil GD 11- GD 17 2.4* Puberty, BW puberty
Vandenberg, 2007 [79] Mamm. CD-1 Mouse F Alzeet osmotic pump GD 8 -18 0.25* Mammary gland morphology GD 18
Effects on the Mammary Gland
Colerangle, 1997 [85] Rat F Osmotic minipump 4 weeks old administered 11 days 100*, 54,000* Mammary Gland differentiation 5.5 weeks DES
Durando, 2006 [82] Wistar Rat F Osmotic minipump GD 7 -22 25* Mammary Gland Cancer PND 30, 50, 110, 180
Markey, 2001 [80] CD-1 Mouse F Osmotic minipump GD 8- GD 19 25*, 250* Mammary Gland PND 10, 1 month, 6 months
Munoz-de-Toro, 2005 [81] Mouse F Osmotic minipump GD 8 - lactation 0.025*, 0.250* Mammary Gland Morphogenesis, Terminal End Bud Density PND 30 , 120
Murray, 2006 [83] Wistar Rat F Osmotic minipump 2.5*, 25*, 250*, 1000* Mammary Gland Hyperplasia (carcinoma precursor) PND 55, 95
Effects on the Uterus and Vagina
Markey, 2005 [88] Mouse F Osmotic minipump GD 9 - Lactation 0.025*, 0.250* Genital Tract Alterations; ERα and Progesterone Receptor Up- Regulation Developmentally adult
Nagel, 2001 [173] Mouse F Injection, Oil adult 25 (P<0.06), 791*, 25,000* Uterus, gene expression DES
Schönfelder, 2002 [87] Rat F Oral GD 6-21 100*, 50,000* Vaginal ERα Expression Vaginal Histology adult Ethinylestradiol
Schönfelder, 2004 [86] Sprague- DawleyRat F Oral GD 6-21 100*, 50,000*
50,000*
100*, 50,000*		 Uterine Epithelial Histology Uterine ERα Expression Uterine ERβ Expression adult Ethinylestradiol
Suzuki, 2002 [14] Mouse F Injection, Oil GD 10-18 10,000*, 100,000* Uterine and Vaginal Mitotic Indices Following Prenatal Exposure PND 30 DES
Effects on the Ovary, Oocytes and Fertility
Al-Hiyasat, 2004 [90] Mouse F Oral, Water Adult for 28 days 5, 25*, 100*
5, 25, 100*		 Increased Resorptions, Uterine
Weight Ovarian Weight		 adult
Berger, 2007 [92] Mouse F Injection s.c. GD 1-4 3,375*, 10,125* Implantation rate Fecundity GD 5 PND 1
Hunt, 2003 [89] C57BL/6 Mouse F Oral, Oil Peripubertal for 6-8 days 20*, 40*, 100* Disruption of Meiosis; Aneuploidy ~30 days old
Susiarjo, 2007 [91] C57BL/6 Mouse F Oral Injection GD 11 - 18 20* Disruption of chromosomes GD 18
Effects on Testosterone in Males
Takao, 1999 [133] Mouse M Oral, Drinking water adult ≈120, ≈12,000* Plasma Free Testosterone adult
Effects on the Prostate
Gupta, 2000 [10] Mouse M Oral, Oil GD 14-18 50* Prostate Wt., Prostate AR (see also In Vitro) PND 3, 20, 60 DES, Aroclor
Ho, 2006 [29] Sprague- Dawley Rat M Injection s.c. PND 1-5 10* Prostate Cancer (PIN lesions) adult Estradiol
Nagel, 1997 [94] Metab. CF-1Mouse M Oral, Oil GD11- GD17 2*, 20* Prostate Wt. 6 months Octylphenol
Ramos, 2001 [97] Wistar Rat M Osmotic Pump, DMSO GD 7- GD 22 25*, 250* Ventral Prostate PND 30
Stoker, 1999 [100] Wistar Rat M sc injection, oil PND 22- PND 32 50,000* Serum Prolactin, Lateral Prostate Weight PND 29, PND 120 estradiol, pimozide
Timms, 2005 [16] Mouse M Oral, Oil GD 14-18 10* Fetal Development of Prostate and Urethra GD 19 Ethinylestradiol DES
Effects on the Testes, Epididymis, Sperm and Seminal Vesicles
Aikawa, 2004 [102] SHN Mouse M sc Injection, Oil PND 1- PND 5 ≈175*, ≈17,500*
≈175, ≈17,500*		 Abnormal Sperm Decreased Motility 10 weeks Estradiol
Al-Hiyasat, 2002 [129] Metab. Swiss Mouse M Oral Adult For 1 month 5*, 25* 100* Reduced fertility, epididymidal sperm Body weight adult
Chitra, 2003 [131, 132] Metab. Wistar Rat M Oral, Oil Adult For 45 days 0.2*, 2*, 20*
0.2*, 2*, 20*
0.2*, 2*, 20* 0.2, 2*, 20* 0.2*, 2*, 20* 0.2*, 2*, 20*		 Decreased Testis, Epididymis Weight Increased Ventral Prostate Weight Reduced Sperm Motility, Sperm Count Oxidative Stress Enzymes Increased H2O2
Chitra, 2003 [132] Wistar Rat M Oral adult 0.2*, 2*, 20* Decrease in sperm motility Decrease in oxidative stress enzymes adult
Fisher, 1999 [104] Wistar Rat M sc Injection, Oil PND 2- PND 12 37,000* Efferent duct epithelial height PND 10, 18, 25, 35, and 75 DES, Ethinylestradiol, Genistein, Octylphenol, Parabens
Sakaue, 2001 [127] Rat M Oral, Oil adult 0.2, 2, 20*, 200*, 2,000*, 200,000* Sperm Production
Takahashi, 2003 [136] Rat, Mouse M Injection, Propylene glycol adult 2,000, 20,000* BPA Low-Dose Challenge After Extended High- Dose Exposure
Takao, 2003 [134] Mouse M Oral, Drinking Water adult ≈200, ≈20,000* Testicular ERα, ERβ
Thuillier, 2003 [188] Sprague Dawley Rat, CRL M Gavage (BPA); sc Injection (DES) GD 14- GD 22 100, 1,000*, 10,000*, 200,000* Neonatal Testicular Gonocyte PDGFα, PDGFβ GD 21-PND 3 DES, Genistein, Coumestrol
Tohei, 2001 [135] Rat M Injection adult 3,000* Testes & Serum Hormones
Toyama, 2004 [103] ICR Mouse, Wistar Rat M sc Injection, Oil PND 2- PND 12 71, 714*, 3,600*, 7,100*
180, 1,800*, 18,000*		 Spermatogenesis, Mouse Rat 2 – 10 weeks Estradiol, Estradiol benzoate
Toyama, 2004 [130] Mice M Injection Adult For 6 days 20*, 200* Abnormal Sperm morphology adult
vom Saal, 1998 [101] CF-1 Mouse M Oral, Oil GD 11- GD 17 2*, 20*
2, 20*		 Reproductive Organs, Sperm Production 6 months Octylphenol
Wang, 2004 [105] Sprague Dawley Rat, CRL M Oral, Oil GD 14- GD 22 1,000, 10,000*, 200,000*
1,000*, 10,000, 200,000		 Estrogen Receptor- Associated Protein Expr: Hsp90 p23 GD 21, PND 3, PND 21 DES, Genistein, Coumestrol
Wistuba, 2003 [106] Sprague Dawley Rat (Germany) M Oral gavage, Cornstarch suspension GD 6- GD 21 100*, 50,000* Sertoli Cell Number per Testis PND 290- 370 Ethinylestradiol
Effects on Metabolism
Alonso- Magdalena, 2006 [140] OF1 Mice M Injection oil adult 10* Insulin release Insulin sensitivity Estradiol
Kabuto, 2003 [141] ICR Mice M Injection i.p. for 5 days adult 25,000*
50,000*		 Antioxidant scavenging enzymes
Kabuto, 2004 [114] Mouse M Oral, Drinking water GD 1 - lactation 2.5 - 5* Testis Weight Brain Weight Kidney Weight Various Oxidation Markers PND 28
Lemmen, 2004 [189] Mouse F, M Injection, Oil GD 13.5 100, 1,000*, 10,000* Transgenic Embryonic Gene Expression in Whole Embryo Lysates DES, Estradiol propionate
Markey, 2003 [110] Mouse F Osmotic Minipump GD 8 -19 25*, 250*
25*, 250*
25*, 250*		 Estrus Cycle Alterations Blood-Filled Ovarian Bursae Mammary Gland Budding adult
Nunez, 2001 [139] Sprague Dawley Rat F Osmotic Pump adult ≈5,000, 18,000*, 23,000* Body weight Blood and tissue levels of BPA adult
Takai, 2000 [107] B6C3F1 Mouse F, M Ex vivo in culture medium GD 2-4 0.1, 0.3, 1*, 3*, 10, 100,000* nM (0.023, 0.068, 0.23*, 0.68*, 2.3, 23,000* ppb) Increased rate of development at 1 and 3 nM, decreased rate of development at 100,000 nM blastocyst
Takai, 2001 [108] B6C3F1 Mouse F, M During IVF in culture medium GD 0-2 1 nM (0.228 ppb)* Postnatal weight gain increase Weaning
Effects on the Immune System
Lee, 2003 [145] Mouse BALB/c F Injection (i.p.) adult 25,000 * Increased IL-4 production, increased serum antigen-specific immunoglobulin E (IgE) levels adult nonylphenol
Sawai, 2003 [142] Mouse C57BL/6 NZB/WF1 F, M Oral, in Feed PND 35-42 2.5* Decreased IFNγ and IL-10 secretion by splenic mononuclear cells; Decreased IgG2a Production; Protection in Lupus-Prone Mice (see also In vitro) adult
Sugita-Konishi, 2003 [147] Mouse BALB/c F Injection (s.c.), Oil adult 5,000*
5,000*		 Immune Cells and Functions, Reduced IL-6 production and neutrophil phagocytic activity against bacterial infection adult
Tian, 2003 [144] Mouse BALB/cA M Oral, Oil adult ≈370, 1,800*, 9,000*
≈370, 1,800, 9,000*		 IL-10 production
IL-4 production		 adult
Yoshino, 2003 [143] Mouse DBA/1J F, M Oral, Oil adult 3, 30, 300*, 3,000*
3, 30*, 300*, 3,000*		 Increased serum anti-HEL IgG2a Augmentation of cytokine response adult Estradiol
Yoshino, 2004 [116] Mouse DBA/1J F, M Oral, Oil GD 0 -GD 17 3, 30*, 300*, 3,000*
3, 30, 300*, 3,000*		 Increased serum anti-HEL IgG2a
T-Helper Cytokines (both Th1 and Th2) increased		 adult
Yurino, 2004 [148] BWF1 Mice Silastic Capsule 4 weeks 25 ng/ml in blood* IgM antibodies 5 Months Estradiol DES