Subchronic Exposure to Di(2-ethylhexyl) Phthalate and Diisononyl Phthalate during Adulthood Has Immediate and Long-Term Reproductive Consequences in Female Mice

Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer used in a variety of consumer products. This is concerning because DEHP is an endocrine disruptor and ovarian toxicant. Diisononyl phthalate (DiNP) is a DEHP replacement that is a rising human toxicant due to its increased use as a DEHP substitute. However, little is known about the effects of DEHP or DiNP exposure during adulthood on female reproduction. Thus, this study tested the hypothesis that DEHP or DiNP exposure during adulthood has long-term consequences for female reproduction in mice. Adult female CD-1 mice (39-40 days) were orally dosed with vehicle control (corn oil), DEHP (20 μg/kg/day-200 mg/kg/day), or DiNP (20 μg/kg/day-200 mg/kg/day) for 10 days. Females were paired with untreated male mice for breeding trials immediately post-dosing and again at 3 and 9 months post-dosing. Immediately post-dosing, DEHP and DiNP did not affect fertility. At 3 months post-dosing, DiNP (20 and 100 μg/kg/day and 200 mg/kg/day) significantly disrupted estrous cyclicity, and DiNP and DEHP (20 μg/kg/day) significantly reduced the ability of females to get pregnant. At 9 months post-dosing, DiNP significantly disrupted estrous cyclicity (100 μg/kg/day), reduced time to mating (100 μg/kg/day-200 mg/kg/day), and borderline reduced percent of females who produced offspring (20 mg/kg/day). At 9 months post-dosing, DEHP (200 μg/kg/day and 200 mg/kg/day) and DiNP (100 μg/kg/day and 20 and 200 mg/kg/day) increased numbers of male-biased litters. These data show that DEHP and DiNP exposure has long-term consequences for female reproduction, even long after cessation of exposure.