The effects of short-term and long-term phthalate exposures on ovarian follicle growth dynamics and hormone levels in female mice†

Biol Reprod. 2024 Jan 13;110(1):198-210. doi: 10.1093/biolre/ioad137.


Di(2-ethylhexyl) phthalate and diisononyl phthalate are widely used as plasticizers in polyvinyl chloride products. Short-term exposures to phthalates affect hormone levels, ovarian follicle populations, and ovarian gene expression. However, limited data exist regarding the effects of long-term exposure to phthalates on reproductive functions. Thus, this study tested the hypothesis that short-term and long-term exposure to di(2-ethylhexyl) phthalate or diisononyl phthalate disrupts follicle dynamics, ovarian and pituitary gene expression, and hormone levels in female mice. Adult CD-1 female mice were exposed to vehicle, di(2-ethylhexyl) phthalate, or diisononyl phthalate (0.15 ppm, 1.5 ppm, or 1500 ppm) via the chow for 1 or 6 months. Short-term exposure to di(2-ethylhexyl) phthalate (0.15 ppm) and diisononyl phthalate (1.5 ppm) decreased serum follicle-stimulating hormone levels compared to control. Long-term exposure to di(2-ethylhexyl) phthalate and diisononyl phthalate (1500 ppm) increased the percentage of primordial follicles and decreased the percentages of preantral and antral follicles compared to control. Both phthalates increased follicle-stimulating hormone levels (di(2-ethylhexyl) phthalate at 1500 ppm; diisononyl phthalate at 1.5 ppm) and decreased luteinizing hormone levels (di(2-ethylhexyl) phthalate at 0.15 and 1.5 ppm; diisononyl phthalate at 1.5 ppm and 1500 ppm) compared to control. Furthermore, both phthalates altered the expression of pituitary gonadotropin subunit genes (Cga, Fshb, and Lhb) and a transcription factor (Nr5a1) that regulates gonadotropin synthesis. These data indicate that long-term exposure to di(2-ethylhexyl) phthalate and diisononyl phthalate alters follicle growth dynamics in the ovary and the expression of gonadotropin subunit genes in the pituitary and consequently luteinizing hormone and follicle-stimulating hormone synthesis.

Keywords: di(2-ethylhexyl) phthalate; diisononyl phthalate; follicle-stimulating hormone synthesis; luteinizing hormone synthesis; ovarian follicles; phthalates; pituitary; toxicity.

MeSH terms

  • Animals
  • Diethylhexyl Phthalate* / toxicity
  • Female
  • Follicle Stimulating Hormone / pharmacology
  • Luteinizing Hormone / metabolism
  • Mice
  • Ovarian Follicle / metabolism
  • Phthalic Acids* / toxicity


  • diisononyl phthalate
  • phthalic acid
  • Phthalic Acids
  • Diethylhexyl Phthalate
  • Follicle Stimulating Hormone
  • Luteinizing Hormone