Table 3.
Phthalate-induced effects in model animals across generations.
| Species | Sex | Exposure | Dose | Effects across Generations | Reference |
|---|---|---|---|---|---|
| Mouse | Male | DEHP from E7 to E14 |
500 mg/kg | F1–F4: disruption of testicular germ cell association; reduced sperm motility F3: alteration of spermatogonial stem cell function |
[103] |
| Mouse | Male | DEHP from E11 until birth |
20, 200 μg/kg/day | F3: decreased fertility (20 µg/kg); reduced testicular steroidogenic capacity (20 and 200 μg/kg); impaired spermatogenesis (20 and 200 μg/kg); decreased sperm concentration (20 and 200 μg/kg); decreased sperm motility (20 and 200 μg/kg); alteration of BTB integrity (20 and 200 μg/kg); alteration of Y genes expression (20 and 200 μg/kg) in the testis | [104] |
| Rat | Male | DBP from E8 to E14 |
500 mg/kg | F1–F3: spermatogenesis failure; altered reproduction; decrease sperm count; reduced Sertoli cells number; metabolic changes in the testis (increase level of betaine; drop of betaine homocysteine S-methyltransferase); DNA hypomethylation (in TM-4 cells, an immortalized cell line derived from mouse testis). | [105] |
| Mouse | Female | DEHP Adult (12 weeks old) |
80 mg/kg/day | F0–F2: reduced expression of Esr1 in the ovary | [110] |
| Rat | Female | DEHP from PN day 1 to 21 |
1, 10, and 100 mg/kg/BW * | F0: decrease of estradiol (all doses), testosterone and progesterone levels (10 and 100 mg/kg) F1: altered mRNA expression of follicle-stimulating (10 and 100 mg/kg), androgen (100 mg/kg), estrogen (100 mg/kg), progesterone (all doses) and peroxisome proliferator-activated (all doses) receptors, 3β hydroxysteroid dehydrogenase (all doses), aromatase and steroidogenic acute regulatory proteins (all doses) in the ovary; accelerated rate of follicle recruitment (10 and 100 mg/kg) |
[111] |
| Mouse | Female | DEHP from E11 until birth |
20, 200 µg/kg/day 500, 750 mg/kg/day |
F1: estrous cyclicity impairment (750 mg/kg); increased ovarian cysts number (750 mg/kg); total follicle number decrease (750 mg/kg); increased estradiol levels (500 and 750 mg/kg); decreased testosterone (500 mg/kg), inhibin B (750 mg/kg) and FSH levels (500 mg/kg); increased LH levels (20 µg/kg) F2: altered follicle numbers (200 µg/kg and 500 mg/kg); decreased testosterone (20 µg/kg); decreased progesterone (200 µg/kg) F3: estrous cyclicity impairment (20 and 200 µg/kg and 500 and 750 mg/kg); decreased follicle numbers (200 µg/kg/d and 500 mg/kg); increased estradiol levels (20 µg/kg); decreased testosterone (20 µg/kg and 500 mg/kg); decreased inhibin B levels (500 mg/kg); increased FSH (500 mg/kg) and LH levels (500 mg/kg) |
[107] |
| Mouse | Female | DEHP from E10.5 until birth |
20 and 200 μg/kg/day 500, and 750 mg/kg/day |
F1: accelerated puberty onset (200 µg/kg); disrupted estrous cyclicity (200 µg and 500 mg/kg); altered folliculogenesis (20 and 200 µg/kg); increased Dnmt expression in the ovary (750 mg/kg); increased presence of 5-mC in the ovary (20 µg/kg). F2: accelerated puberty onset (500 mg/kg); disrupted estrous cyclicity (20 and 200 µg/kg); increased 17β-estradiol levels (20 μg/kg); decreased expression of steroidogenic enzymes in the ovary (20 μg/kg); dysregulation of PI3K factors in the ovary (20 and 200 µg/kg; 750 mg/kg); decreased Tet expression in the ovary (all doses). F3: accelerated puberty onset (20, 200 µg, and 500 mg/kg); disrupted estrous cyclicity (20 µg/kg/day); decreased expression of steroidogenic enzymes in the ovary; decreased Dnmt in the ovary (all doses) and Tet expression in the ovary (200 μg/kg; 500 and 750 mg/kg) and 5-mC levels in the ovary (500 and 750 mg/kg) |
[85,112] |
| Mouse | Female | From E10 to birth | Mixture of 20 and 200 μg/kg/day—200 and 500 mg/kg/day [DEP (35.22%), DEHP (21.03%), DBP (14.91%), DiBP (8.61%), DiNP (15.10 %), and BzBP (5.13 %)] | F1: decreased FSH (500 mg/kg), estradiol (20 µg/kg; 200 and 500 mg/kg) testosterone (200 µg/kg; 200 and 500 mg/kg levels) and progesterone (500 mg/kg) levels; decreased steroidogenesis (20 and 200 µg/kg; 500 mg/kg); altered transition among follicle types (20 μg/kg and 200 mg/kg); higher incidence of atresia (500 mg/kg) F2 and F3: increased number of cystic ovaries (all doses); breeding, pregnancy and delivery complications (20 µg/kg and 500 mg/kg) |
[106,107,108] |
| Mouse | Female | DEHP from E0.5 to PND + 21 |
0.05, 5 mg/kg/day | F1-F3: accelerated follicular recruitment (all doses); reduction of primordial follicular reserve (all doses); increased pre-antral follicles number (all doses); diminished oocyte quality (0.05 mg/kg); diminished embryonic developmental competence (0.05 mg/kg); altered expression profile of ovarian and pre-implantation embryonic genes, observed in the ovary and in blastocysts, respectively (all doses) | [113] |
+ PND: postnatal day; * BW: body weight.