Table 5 Description and supporting evidence of the KEs included in postulated MoA for BPAF in female adult exposure
Brief description of key event | Supporting evidence | |
|---|---|---|
MIE 1 | Estrogen receptor activation (two parallel MIEs are suggested, current knowledge in endocrinology does not provide sufficient knowledge to conclude whether they are indeed parallel or whether one of them precedes the other) | In vitro mechanistic: ■Estrogen receptor binding IDs: 45, 51, 72, 75 ●Estrogen receptor agonist activity IDs: 3, 6, 8, 11–15, 17–18, 20–22, 42–44, 46, 48, 52, 62–65, 78, 81, 86–87 ●Estrogen dependent cellular proliferation IDs: 7–6, 10, 15, 20, 48, 80 ■Estrogen receptor dependent gene/protein expression increased IDs: 9–13, 15, 17–18, 20, 23, 48, 80 In vivo mechanistic: ■Estrogen receptor dependent gene expression increased (adult exposure) IDs: 59, 83 ●Uterus weight increase (adult exposure) IDs: 61–63, 86 ●Uterus histopathology alteration (adult exposure) ID: 63 |
MIE 2 | Altered steroidogenesis | In vitro mechanistic: ●Steroidogenesis alteration IDs: 4–5, 87 In vivo mechanistic: ●Steroidogenesis gene/protein expression alteration (adult exposure) IDs: 55, 58, 83 ●Progesterone level decrease in female (adult exposure) ID: 83 |
KE1 | Ovarian dysfunction | EATS-mediated: â—ŹOvary histopathology alteration (adult exposure) IDs: 83, 88 â—ŹOvary weight decrease (adult exposure) IDs: 83, 88 |
KE2 | Altered estrous cycling | EATS-mediated: â—ŹEstrous cycling disruption (adult exposure) IDs: 60, 83, 88 |
AO | Impaired female fertility | None (no data available, but hypothesized based on current knowledge in endocrinology) |