Table 1.
Model | Exposure dose (mg/kg/day) | Lowest effective dose (mg/kg/day)* | Exposure window | Route** | OT*** | Outcome assessment (age) | Outcome type | Reference |
---|---|---|---|---|---|---|---|---|
Rhesus macaque | 0.4 | 0.4 | E50-100 | po to dams | -- | E100 | Histology, ERα, PR, Ki-67 immunohistochemistry, all genome gene expression | [54] |
0.4 | E100-165 | E165 | ||||||
White Leghorn hens | 67, 134 | 134 | E4 | in ovo | -- | P147 | Histopathology, ERα expression | [55] |
CD-1 mice | 5 | 5 | E9-E16 | ip to dams | -- | P14, P42 | Expression and methylation of Hoxa10 | [56] |
Eker rats | 50 | 50 | P10-P12 | sc | -- | P12 | Expression of 18 ERE genes | [57] |
50 | P10-P12 | sc | -- | P480 | Expression of 18 ERE genes | |||
-- | P10-P12 | sc | -- | P90, P480 | Tumor incidence, non-genomic ER signaling, activity of EZH2, histopathology | |||
Eker rats | 0.00005, 0.05, 50 | -- | P12 | sc | -- | P12 | non-genomic ER signaling | |
Sprague-Dawley rats | 0.00005, 0.01 0.05, 50 | -- | P12 | sc | -- | P12 | non-genomic ER signaling | |
Sprague-Dawley rats | 0.0004–0.05 | -- | P12 | po | -- | P12 | non-genomic ER signaling | |
Sprague-Dawley rats | 200, 400, 600 | 600 | P1-P5 | sc to dams | -- | P6 | CaBP-9k expression | [58] |
Sprague-Dawley rats | 5, 50, 400 | 5 | E11-E20 | sc to dams | -- | E20 | Transcriptome of uterus pooled with ovaries | [59] |
Wistar-derived rats | 0.05, 20 | 0.05 | P1, P3, P5, P7 | sc | -- | P8 | Hoxa10, Hoxa11 expression | [60] |
0.05, 20 | 0.05 | P1, P3, P5, P7 | sc | P80 | P93 (after hormonal stimulation) | ERα, PR, Hoxa10, Hoxa11, SMRT, SPC-3 expression, DNA synthesis, Hoxa10 promoter methylation | ||
Donryu rats | 0.006, 6 | -- | E2-P21 | po to dams | -- | P14, 21, 28, 56 | Uterus weight | [62] |
-- | P10, 14, 21, 28 | Uterus gland development, ERα immunohistochemistry | ||||||
-- | ~ P30-56 | Cyclicity | ||||||
-- | P77-450 | Carcinogenicity after N-ethyl-N′-nitro-N-nitrosoguanidine intrauterine administration | ||||||
Sprague-Dawley rats | 200, 400, 600 | 600 | E17-19 | sc to dams | -- | P5 | CaBP-9k expression | [63] |
Sprague-Dawley rats | 600 | 600 | P14-P16 | sc to dams | -- | P17 | Transcriptome | [64] |
CD-1 mice | 0.5, 1, 5, 50, 200 | 0.5 | E9-E16 | ip to dams | -- | P14, P42 | Hoxa10 immunohistochemistry | [65] |
Wistar-derived rats | 0.05, 20 | 0.05 | P1, P3, P5, P7 | sc | -- | > P80 at pregnancy | Reproductive performance, PR, ERα immunohistochemistry, and gene expression | [66] |
Crj: CD (SD) IGS rats | 0.0002, 0.002, 0.02, 0.2 | 0.02 | E1-∞ | po | -- | >P70 | Cyclicity of F1 and F2 | [76] |
-- | Fertility of F1, uterus weight, histology F1-F2 | |||||||
CD-1 mice | ~ 0.003, 0.03, 0.3, 5, 50, 600 | -- | E1-∞ | po | -- | ~ P56-112 (F1) | Cyclicity (for 3 weeks), fertility | [74] |
-- | P21 (F1, F2) | Uterus weight, histopathology | ||||||
Sprague-Dawley rats | ~ 0.001, 0.02, 0.3, 5, 50, 500 | 500 | E1-∞ | po | -- | ~ P70-117 | Fertility (F2) | [75] |
-- | ~ P70-117 | Cyclicity (for 3 weeks, F1-F3), Fertility (F1) | ||||||
-- | P21 (F1, F2) | Uterus weight | ||||||
500 | F1-2 dams after weaning | Uterus weight | ||||||
-- | F1-3 dams | Histopathology | ||||||
Sprague-Dawley, Alderley Park (Wistar derived) rats | 0.02, 0.1, 50 | -- | E6-E21 | po to dams | -- | P98 | Uterus weight | [77] |
50 | Cycle onset | |||||||
Sprague-Dawley rats | 231.8 at gestation, and 384.4 at lactation | -- | E15-P10 | po to dams | -- | P77 at diestrus | Cyclicity (P48-P77), histology, uterus weight | [78] |
Sprague-Dawley rats | 0.0025, 0.008, 0.025, 0.08, 0.26, 0.84, 2.7, 100, 300 | 100 | E6-P90 | po | -- | VO****+10 days, P69-90, P150-170 | Cyclicity | [79] |
n/a | P21, P90 at estrus | Uterus weight | ||||||
0.008 | P90 | Histopathology | ||||||
CD-1 mice | 0.5, 10 | 0.5 | E15-19 | sc to dams | -- | P63-77 | Cyclicity | [80] |
-- | P28, 56, 84, 112 | Histopathology | ||||||
Sprague-Dawley rats | 4.35±1.85, 43.75±18.75 | 43.75±18.75 | P1-P10 | sc | -- | P60-120 | Cyclicity | [81] |
ICR/Jcl mice | 0.02, 0.2 | 0.02 | E11-17 | sc to dams | -- | P26-56 | Cyclicity | [82] |
-- | P90-120 | Fertility (pups number) | ||||||
Crl:CD BR Sprague-Dawley rats | 3.2, 32, or 320 | -- | E11-P20 | po | -- | P120-142 | Cyclicity | [83] |
Wistar rats | 1.2 | 1.2 | E6-P21 | po to dams | -- | P120, at estrus | Cyclicity, ERα immunohistochemistry, histopathology | [84] |
Sprague-Dawley rats | ~0.1, 1.2 | -- | E6-P21 | po to dams | -- | P1, 240, 360–480 | Macroscopic abnormalities | [85] |
1.2 | P120-138 | Cyclicity | ||||||
ICR/Jcl mice | 10, 100 | -- | E10-E18 | sc to dams | P30 | P40 | Histopathology | [86] |
~ 10, 100 | ~ 100 | P1-P5 | sc | P30 | P40, P90 | Histopathology | ||
~ 10 | -- | P61-P90 | Cyclicity | |||||
-- | F1 dams after weaning (~13 week) | Uterus weight, histopathology | ||||||
FVB mice | 0.0005, 0.02, 0.05 | 0.0005 | E11-E21 | po to dams | -- | VO***+30 days | Cyclicity | [87] |
0.0005 | 3, 6, 9 months | Fertility | ||||||
Wistar-derived rats | 0.0005, 0.05 | 0.0005 | E9-P21 | po to dams | -- | P90, 360 in estrus | Histology, α SMA, vimentin, immunohistochemistry, proliferative, apoptotic activity | [88] |
n/a | P70-90, 340-360 | Cycling | ||||||
0.0005 | P360 | P460 | Histology, ERα, ERβ and PR immunohistochemistry, expression of IGF1, IGFR, p63 | |||||
Sprague-Dawley rats | 0.44±0.19, 4.35±1.85, 43.75±18.75 | 4.35±1.85 | P1-P10 | sc | -- | P120-150 | Fertility | [89] |
CD-1 mice | 0.000025, 0.00025, 0.025 | 0.000025 | E8-P16 | pump to dams | -- | P60 | Number of pups and pregnancies | [91] |
Long-Evans rats | 0.02, 0.2 | -- | E7-P18 | po to dams | -- | P23-143 | Fertility and fecundity | [92] |
Sprague-Dawley rats | 0.1, 50 | 0.1 | E6-E21 | po to dams | -- | P120 at estrus | Histopathology, ERα and ERβ immunohistochemistry | [93] |
Balb-C mice | 0.1, 1 | 0.1 | E1-P7 | sc to dams | -- | P90 | Histopathology, ectopic endometrium | [94] |
Wistar rats | 0.05, 20 | 0.05 | P1, P3, P5, P7 | sc | P80 | P93 | Vegf expression, endothelial proliferation | [96] |
CD-1 mice | 0.000025, 0.00025 | 0.000025 | E9-P4 | pump to dams | -- | P90, at proestrus | ERα, PR expression, histopathology, DNA synthesis | [97] |
CD-1 mice | 0.0001, 0.001, 0.01, 0.1, 1 | 0.001 | E9-E16 | sc to dams | -- | P540 | Histopathology | [99] |
Wistar rats | 0.025, 0.25, 5, 50 | -- | E7-P22 | po to dams | P16 | Uterus weight | [112] | |
CD-1 mice | 0.01, 0.1, 1 | 0.01 | P1-P5 | sc | -- | P540 | Histopathology | [126] |
(n/c) – no conclusive results
ip – intraperitoneal injection, sc – subcutaneous injection, po – per oral administration, pump – osmotic pumps implanted subcutaneous
OT - Ovariectomy
VO – day of vaginal opening