Prenatal exposure to an environmentally relevant phthalate mixture disrupts reproduction in F1 female mice

Abstract

Phthalates are used in a large variety of products, such as building materials, medical devices, and personal care products. Most previous studies on the toxicity of phthalates have focused on single phthalates, but it is also important to study the effects of phthalate mixtures because humans are exposed to phthalate mixtures. Thus, we tested the hypothesis that prenatal exposure to an environmentally relevant phthalate mixture adversely affects female reproduction in mice. To test this hypothesis, pregnant CD-1 dams were orally dosed with vehicle (tocopherol-stripped corn oil) or a phthalate mixture (20 and 200 μg/kg/day, 200 and 500 mg/kg/day) daily from gestational day 10 to birth. The mixture was based on the composition of phthalates detected in urine samples from pregnant women in Illinois. The mixture included 35% diethyl phthalate, 21% di(2-ethylhexyl) phthalate, 15% dibutyl phthalate, 15% diisononyl phthalate, 8% diisobutyl phthalate, and 5% benzylbutyl phthalate. Female mice born to the exposed dams were subjected to tissue collections and fertility tests at different ages. Our results indicate that prenatal exposure to the phthalate mixture significantly increased uterine weight and decreased anogenital distance on postnatal days 8 and 60, induced cystic ovaries at 13 months, disrupted estrous cyclicity, reduced fertility-related indices, and caused some breeding complications at 3, 6, and 9 months of age. Collectively, our data suggest that prenatal exposure to an environmentally relevant phthalate mixture disrupts aspects of female reproduction in mice.

Effects and Mechanisms of Phthalates’ Action on Reproductive Processes and Reproductive Health: A Literature Review

“…In addition, DEHP disturbed the maturation and activation of oocytes before fertilization via meiotic maturation inhibition and oxidative stress [ 129 ]. Exposure to DEHP at 25 mg/m 3 by inhalation [ 130 ] and prenatal exposure to a mixture of DEP, DEHP, DnBP, DiNP, DiBP, and BBzP at 20, 200 and 500 mg/kg [ 131 ] impaired the estral cycle, particularly ovulation and estradiol synthesis in rats and mice, as well [ 130 , 131 ]. The imbalance of the hypothalamic–pituitary–ovarian axis furthermore negatively affected the development and function of the reproductive system of female progeny [ 132 ].…”

“…The imbalance of the hypothalamic–pituitary–ovarian axis furthermore negatively affected the development and function of the reproductive system of female progeny [ 132 ]. These effects of exposure to the mixture of phthalates were observed in the second and third generation of the progeny of mice [ 131 ]. The similar results occurred in the progeny of Caenorhabditis elegans after the prenatal exposure to DEHP at 20 mg/L [ 133 ].…”

“…The similar results occurred in the progeny of Caenorhabditis elegans after the prenatal exposure to DEHP at 20 mg/L [ 133 ]. Therefore, we can assume that phthalate exposure has a transgenerational as well as a multigenerational effect on fertility in female animal models [ 131 ].…”

Phthalates mixtures in bottled water in Iran: human health risk assessment using direct and indirect exposure assessment

“…The spectrum of effects in animals (male rats) is known as the phthalate syndrome which covers different reproductive abnormalities in male offspring of rats exposed during pregnancy including inhibition of fetal testosterone production, reduced male anogenital distance, decreased gene expression related to steroid biosynthesis, increased permanent nipple retention in male offspring, increased incidence of genital malformations (hypospadias and cryptorchidism), delayed puberty onset, reduced semen quality and testicular changes including decreased testes and epididymes weight, tubular atrophy and Leydig cell hyperplasia Zhou et al, 2017). It is well understood that the cause for the Chapter 29 phthalate syndrome is suppression of fetal androgen action (Kortenkamp, Evans et al 2012).…”

“…Although information on the effects of a mixture of phthalates on reproduction and prenatal development is limited it is important to note that a mixture of phthalates such as DEHP, DBP and BBP tested for anti-androgenic properties in vivo, acted together in line with the dose addition approach which is the mixture effect prediction approach for chemicals acting by the same mechanism of action (NRC 2009;Kortenkamp et al, 2011;Zhou et al, 2017;Conley et al, 2018).…”