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

Abstract

Di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) are widely used as plasticizers in polyvinyl chloride products. Short-term exposures to DEHP or DiNP 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 hypothesis that short-term (1 month) and long-term (6 months) exposure to DEHP or DiNP disrupts follicle dynamics, ovarian and pituitary gene expression, and hormone levels in female mice. Adult CD-1 female mice were exposed to vehicle (corn oil), DEHP, or DiNP (0.15 ppm, 1.5 ppm, or 1500 ppm) via the chow for 1 or 6 months. Exposure to DEHP (0.15 ppm) and DiNP (1.5 ppm) for 1 month decreased serum follicle-stimulating hormone (FSH) levels compared to control. Long-term exposure to DEHP and DiNP (1500) ppm increased the percentage of primordial follicles and decreased the percentages of preantral and antral follicles compared to control. Both phthalates increased FSH levels (DEHP at 1500 ppm; DiNP at 1.5 ppm) and decreased LH levels (DEHP at 0.15 and 1.5 ppm; DiNP at 1.5 ppm and 1500 ppm) compared to control. Further, both phthalates altered the expression of pituitary gonadotropin subunit genes (Cga, Fshb, and Lhb) and a transcription factor (Nr5a1) that regulates FSH and LH synthesis. These data indicate that long-term exposure to DEHP and DiNP alters follicle growth dynamics in the ovary and the expression of gonadotropin subunit genes in the pituitary and consequently LH and FSH synthesis.

Phthalates are detected in the follicular fluid of adolescents and oocyte donors with associated changes in the cumulus cell transcriptome

“…In recent decades, growing concerns have emerged regarding the impact of exposure to environmental chemicals on reproductive health. Research studies in both animals and humans highlighted the adverse effects of phthalates on ovaries [14,21,29].…”

“…Phthalates disrupt hormonally mediated processes primarily through interfering with the regulation of hypothalamic-pituitarygonadal (HPG) axis, consequently altering the levels of gonadotropin releasing hormone (GnRH), and luteinizing hormone (LH) and follicle stimulating hormone (FSH) [13]. In mice, long-term dietary exposure (6 months) to di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) has been shown to increase the expression of genes (Nr5a1, Cga, Lhb) that regulate gonadotropin hormones in the pituitary which results in elevated FSH levels and decreased levels of estradiol (E2) and LH compared to controls [14].…”

“…Additionally, long-term exposure to DEHP and DiNP in mice leads to the disruption of ovarian folliculogenesis, manifested by an increase in the number of primordial follicles and a decrease in the number of preantral and antral follicles [14][15][16]. Prenatal exposure to DEHP has been shown to induce transgenerational effects in mice ovaries through presumed epigenetic modifications.…”

Elucidating the mechanisms and mitigation strategies for six-phthalate-induced toxicity in male germ cells

“…Additionally, PAEs can adversely affect female reproductive health by altering ovarian follicle growth and hormone levels. A mixture of PAEs (MP) can even cause multi- and transgenerational effects on the female reproduction system ( Zhou et al, 2017a ; Zhou et al, 2017b ; Alejandra et al, 2024 ; Santacruz-Márquez et al, 2024 ).…”