The phthalate DEHP undermines female fertility in mice

Prenatal exposure to DEHP increases male-to-female sex ratio in the F1 generation

Two studies in mice add to the evidence that the phthalate DEHP, a plasticizing agent used in auto upholstery, baby toys, building materials and many other consumer products, can undermine female reproductive health, in part by disrupting the growth and function of the ovaries.

Image of Jodi-Flaws
Comparative biosciences professor Jodi Flaws and her colleagues linked phthalate exposure during pregnancy to reproductive problems in mice parent and offspring, and to degradation of the function and structure of the ovaries.

2015 1st Study Abstract

This study tested the hypothesis that prenatal DEHP exposure affects female reproduction. To test this hypothesis, pregnant female CD-1 mice were orally dosed daily with tocopherol-stripped corn oil (vehicle control) or DEHP (20 μg/kg/day–750 mg/kg/day) from gestation day 11-birth. Pups were counted, weighed, and sexed at birth, ovaries were subjected to evaluations of follicle numbers on postnatal days (PNDs) 8 and 21, and fertility was evaluated at 3–9 months. The results indicate that prenatal DEHP exposure increased male-to-female ratio compared to controls. Prenatal DEHP exposure also increased preantral follicle numbers at PND 21 compared to controls. Further, 22.2% of the 20 μg/kg/day treated animals took longer than 5 days to get pregnant at 3 months and 28.6% of the 750 mg/kg/day treated animals lost some of their pups at 6 months. Thus, prenatal DEHP exposure alters F1 sex ratio, increases preantral follicle numbers, and causes some breeding abnormalities.

2015 2nd Study Abstract

Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous environmental toxicant found in consumer products that causes ovarian toxicity. Antral follicles are the functional ovarian units and must undergo growth, survival from atresia, and proper regulation of steroidogenesis to ovulate and produce hormones. Previous studies have determined that DEHP inhibits antral follicle growth and decreases estradiol levels in vitro; however, the mechanism by which DEHP elicits these effects is unknown. The present study tested the hypothesis that DEHP directly alters regulators of the cell cycle, apoptosis, and steroidogenesis to inhibit antral follicle functionality. Antral follicles from adult CD-1 mice were cultured with vehicle control or DEHP (1–100 μg/ml) for 24–96 h to establish the temporal effects of DEHP on the follicle. Following 24–96 h of culture, antral follicles were subjected to gene expression analysis, and media were subjected to measurements of hormone levels. DEHP increased the mRNA levels of cyclin D2, cyclin dependent kinase 4, cyclin E1, cyclin A2, and cyclin B1 and decreased the levels of cyclin-dependent kinase inhibitor 1A prior to growth inhibition. Additionally, DEHP increased the mRNA levels of BCL2-associated agonist of cell death, BCL2-associated X protein, BCL2-related ovarian killer protein, B-cell leukemia/lymphoma 2, and Bcl2-like 10, leading to an increase in atresia. Further, DEHP decreased the levels of progesterone, androstenedione, and testosterone prior to the decrease in estradiol levels, with decreased mRNA levels of side-chain cleavage, 17α-hydroxylase-17,20-desmolase, 17β-hydroxysteroid dehydrogenase, and aromatase. Collectively, DEHP directly alters antral follicle functionality by inhibiting growth, inducing atresia, and inhibiting steroidogenesis.

Sources and more information
  • The phthalate DEHP undermines female fertility in mice, news.illinois.edu, 16/04/2015.
  • Prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP) affects reproductive outcomes in female mice, sciencedirect pii/S0890623815000349, doi:10.1016/j.reprotox.2015.02.013, 9 March 2015.
  • Di(2-ethylhexyl) phthalate inhibits antral follicle growth, induces atresia, and inhibits steroid hormone production in cultured mouse antral follicles, sciencedirect pii/S0041008X15000617, doi:10.1016/j.taap.2015.02.010, 18 February 2015.

Medical device-related exposures to phthalates by premature infants much too high

JHU Public Health recommend to use alternative products that don’t contain DEHP as initial step in reducing phthalate exposures during critical care

Hospitalized premature infants are exposed to unsafe levels of a chemical found in numerous medical products used to treat them, raising questions about whether critically ill newborns may be adversely affected by equipment designed to help save their lives.

Abstract

JHU Public Health
JHU Public Health recommend to use alternative products that don’t contain DEHP as initial step in reducing phthalate exposures during critical care.

Objective:
To assess the types and magnitudes of non-endocrine toxic risks to neonates associated with medical device-related exposures to di(2-ethylhexyl)phthalate (DEHP).

Study design:
Dose-response thresholds for DEHP toxicities were determined from published data, as were the magnitudes of DEHP exposures resulting from neonatal contact with polyvinyl chloride (PVC) devices. Standard methods of risk assessment were used to determine safe levels of DEHP exposure in neonates, and hazard quotients were calculated for devices individually and in aggregate.

Result:
Daily intake of DEHP for critically ill preterm infants can reach 16 mg/kg per day, which is on the order of 4000 and 160,000 times higher than desired to avoid reproductive and hepatic toxicities, respectively. The non-endocrine toxicities of DEHP are similar to complications experienced by preterm neonates.

Conclusion:
DEHP exposures in neonatal intensive care are much higher than estimated safe limits, and might contribute to common early and chronic complications of prematurity. Concerns about phthalates should be expanded beyond endocrine disruption.

Sources and more information
  • Phthalates and critically ill neonates: device-related exposures and non-endocrine toxic risks, Journal of Perinatology , doi:10.1038/jp.2014.157, 13 November 2014.
  • Premature Infants Are Exposed to Unsafe Levels of Chemical in Medical Products Used to Save Their Lives, Johns Hopkins Bloomberg School of Public Health, newswise, 10-Nov-2014.

BPA and Phthalate Exposure even when eating Organic Foods

Unexpected results in a randomized dietary trial to reduce phthalate and bisphenol A exposures

Even Eating Organic Foods Can Result In BPA, Phthalate ExposureA study, published by lead author Dr. Sheela Sathyanarayana, addresses how people may be unable to escape exposure to endocrine disruptors  as they are appearing in their diets, even when their individual meals were organic in nature and the foods were prepared, cooked and stored in non-plastic containers. The study also reinforces the notion that the most vulnerable population are our children.

Read Even Eating Organic Foods Can Result In BPA, Phthalate Exposure by Alan McStravick

Abstract

Diet is a primary source of exposure for high-molecular-weight phthalates and bisphenol A (BPA), but little is known about the efficacy of various interventions to reduce exposures. We conducted a randomized trial with 10 families to test the efficacy of a 5-day complete dietary replacement (Arm 1; n=21) versus written recommendations to reduce phthalate and BPA exposures (Arm 2; n=19). We measured phthalate and BPA concentrations in urine samples at baseline, intervention, and post-intervention periods. We used Wilcoxon paired signed-rank tests to assess change in concentrations across time and multi-level mixed effects regression models to assess differences between Arms 1 and 2. Urinary di(2-ethylhexyl) phthalate (DEHP) metabolite concentrations increased unexpectedly from a median of 283.7 nmol/g at baseline to 7027.5 nmol/g during the intervention (P<0.0001) among Arm 1 participants, and no significant changes were observed for Arm 2 participants. We observed a statistically significant increase in total BPA concentration between baseline and intervention periods in Arm 1 but no significant changes in Arm 2. Arm 1 food ingredient testing for DEHP revealed concentrations of 21,400 ng/g in ground coriander and 673 ng/g in milk. Food contamination with DEHP led to unexpected increases in urinary phthalate concentrations in a trial intended to minimize exposure. In the absence of regulation to reduce phthalate and BPA concentrations in food production, it may be difficult to develop effective interventions that are feasible in the general population. An estimate of DEHP daily intake for children in the dietary replacement Arm was above the US Environmental Protection Agency oral reference dose and the European Food Safety Authority’s tolerable daily intake, suggesting that food contamination can be a major source of DEHP exposure.

Dr. Sheela Sathyanarayana study: Unexpected results in a randomized dietary trial to reduce phthalate and bisphenol A exposures, Journal of Exposure Science and Environmental Epidemiology, July/August 2013.