Table 3 Effects of phthalates on ovarian function

Xu et al., 2010 [41]

Female rats intragastrically exposed to benzo[a]pyrene (B[a]P) 5 and 10 mg/kg, to DEHP 300 and 600 mg/kg and B[a]P + DEHP for 60 days.

⇘ number of primordial follicles (BaP 10 mg/kg ± DEHP 600 mg/kg) and of primary/secondary follicles (DEHP 600 mg/kg ± BaP 10 mg/kg) with granulosa cell apoptosis increased in DEHP, B[a]P and B[a]P + DEHP groups, implying a PPAR-mediated signaling pathway for both. No interaction effect was observed.

Moyer and Hixon, 2012 [31]

Pregnant mice exposed by oral gavage to placebo or 100, 500 or 1000 mg/kg of MEHP during gestational days 17–19.

⇘ by 1 month of reproductive lifespan in the highest F1 exposure group (9.8 ± 0.4 compared to 11.1 ± 0.6 months in the control F1 females)

Li et al., 2012 [39]

60 randomized adult mice in 4 groups exposed to 0, 125, 500 or 2000 mg/kg of DEHP by gavage for 16 weeks, 6 days/week

DEHP arrested granulosa cells in the G0/G1 phases of the cell cycle and ⇗ apoptosis in granulosa cells at 500 and 2000 mg/kg

Zhang et al., 2013 [35]

Subcutaneous injections of DEHP of 20 and 40 μg/kg in newborn mice

⇘ number of primordial follicles at puberty and adult age by accelerating follicular recruitment

⇘ DNA methylation of maternal imprinted genes (Igf2r, Peg3) in oocytes

Hannon et al., 2014 [40]

Oral exposure of adult mice to DEHP (20 μg at 750 mg/kg/day) every day for 10 or 30 days.

⇘ in the number of primordial follicles and ⇗ in the percentage of primary follicles via dysregulation of PI3K signaling

Li et al., 2014 [33]

Pregnant mice treated with DEHP from 0 to 40 μg/kg/day from 0.5 to the 18.5th day post coitum.

⇘ percentage of CpG sites in the differentially methylated regions of the oocytes in F1 mice, heritable to F2.

Zhang et al., 2015 [32]

Pregnant mice exposed to DEHP, evaluation of the ovarian reserve in offspring generations

Delay of meiosis initiation in F1 fetal ovaries with Stra8 gene hypermethylation and underexpression

Acceleration of follicular recruitment in the F1 and F2 generations responsible for depletion in the primordial follicle pool.

Niermann et al., 2015 [34]

Pregnant mice exposed to DEHP from 20 μg to 750 mg/kg/day. Evaluation of the number of follicles at D8 and D21 and fertility at 3 and 9 months.

⇗ number of pre-antral follicles at D21 with a non-monotonic dose-effect

22.2% of mice exposed in utero to 20 μg/kg/day took more than 5 days to become pregnant at 3 months

Sen et al., 2015 [38]

Mice exposed to DBP at 0.01, 0.1 and 1000 mg/kg/day for 10 days.

⇘ number of antral follicles ⇗ mRNA coding for pro-apoptosis genes

Li et al., 2016 [36]

Intraperitoneal injection of DEHP in newborn mice, 20 to 40 μg/kg, every 5 days.

⇘ percentage of antral follicles.

⇗ mRNA of apoptosis genes. Accumulation of ROS.

Hannon et al., 2016 [37]

Oral exposure of adult mice to DEHP (20 or 500 mg/kg/day) every day for 10 days

⇗ BAX/BCL2 ratio in primordial follicles, ⇘ number of primordial follicles, 9 months after exposure.

Messerlian et al., 2016 [42]

Assay of phthalate metabolites in urine and antral follicle count, prospective study on 215 patients between 2004 and 2012

⇘ antral follicle count in patients whose metabolite assay was in the higher quartiles compared to lower concentrations