By Robert W. Rebar, MD

Professor and Chair, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo

Dr. Rebar reports no financial relationships relevant to this field of study.

SYNOPSIS: The endocrine-disrupting chemicals diphenyl-dichloroethene and phthalates appear to contribute substantially to the incidence of the most common reproductive disorders in women, endometriosis and fibroids, and lead to total costs of 1.5 billion euros in the European Union.

SOURCE: Hunt PA, Sathyanarayana S, Fowler PA, Trasande L. Female reproductive disorders, diseases, and costs of exposure to endocrine disrupting chemicals in the European Union. J Clin Endocrinol Metab 2016;101:1562-1570.

Endocrine-disrupting chemicals (EDCs) have been defined as chemicals that may interfere with the body’s endocrine system and produce adverse developmental, reproductive, neurological, and immune effects in both humans and wildlife. A recent statement from the Endocrine Society concluded that evidence for the effects of a number of EDCs, including bisphenol A, phthalates, pesticides, and persistent organic pollutants (POPs), on the developing ovary and reproductive tract is compelling.1 Plasticizers used primarily to soften polyvinyl chloride, phthalates are found in a wide range of common products and are released into the environment; most individuals have measurable levels of phthalates in their bodies. Pesticides are commonly organophosphates and their breakdown products are common in the environment.

For this study, the Endocrine Society selected an expert panel to calculate the associated combined healthcare and economic costs attributable to the effects of adult diphenyl-dichloroethene (DDE, a breakdown product of the pesticide dichlorodiphenyltrichloroethane [DDT]) exposure on fibroids and adult phthalate exposure on endometriosis. The panel selected these specific exposure-outcome relationships because of the availability of well-conducted observational human studies of these EDCs on female reproductive disorders. Exposure-response relationships were assessed from the peer-reviewed literature to assess European exposure and approximate the burden of disease in 2010. DDE exposure was estimated from 12 European birth cohorts in which maternal and cord blood levels were measured and assumed that women of reproductive age had similar levels. Phthalate exposure was estimated from a study assessing phthalate metabolites in urine samples from a general population and extrapolated to women of reproductive age. The frequencies of fibroids and endometriosis in reproductive aged women were estimated from other peer-reviewed population studies.

Despite careful use of the best available data, the panel concluded that the strength of the epidemiological evidence is low and the toxicological evidence is moderate. The panel further concluded that the EDCs studied accounted for disease in 20-39% of women affected with fibroids and endometriosis. The investigators calculated that in 2010, an estimated incremental 56,700 women with fibroids causally related to DDE underwent interventions for fibroids requiring surgery at an estimated cost of 163 million euros. The analysis also suggested that in 2010, there were 145,000 incremental cases of endometriosis attributable to phthalates among 20- to 44-year-old women in the European Union, with associated costs of 1.25 billion euros.

The panel noted that these estimates represent only direct costs and only EDCs for which there were sufficient epidemiologic studies and those with the highest probability of causation. Moreover, the analysis focused only on adult exposures, despite growing experimental evidence that EDC exposure during fetal development leads to reproductive aberrations in the adult. Because of the wide variety of reproductive disorders that might be affected by EDCs and the number of EDCs already identified, the panel concluded that its analysis likely represents just the “tip of the iceberg.”

COMMENTARY

This is admittedly an unusual choice to summarize for this publication. Why do so? This article received worldwide coverage in the press and suggests the need for clinicians to be knowledgeable about the potential effects of EDCs. The Endocrine Society, which supported this study, has lobbied Congress about the potential dangers of EDCs. The use of DDT (the parent compound of DDE) is now banned except in certain third-world countries, and the use of bisphenol A, another EDC, commonly found in plastics, has been sharply curtailed. I have been asked by a number of patients about EDCs. While it is true that little can be done to completely eliminate exposure, individuals can select containers for foodstuffs that are “BPA- and phthalate-free.” Moreover, it is worthwhile summarizing what is now known, while simultaneously recognizing that more data exist regarding environmental exposures during pregnancy than in adult life. Teasing out the effects of individual EDCs is difficult considering the variety of chemicals humans are now exposed to daily.

The pesticide DDT first attracted attention in the late 1950s for causing eggshell thinning in certain bird species, including the bald eagle and brown pelican, and leading to their rapid population decline.2 DDT and its various breakdown products, including DDE, are known to have both estrogenic activity and be androgen-receptor antagonists. Breakdown products of DDT have been found in 99% of adults tested by the CDC. The myriad detrimental effects of DDT and its breakdown products led to the creation of the U.S. Environmental Protection Agency and to the worldwide ban of DDT for agricultural uses in 2001 by the Stockholm Convention on Persistent Organic Pollutants. It is still used today in many third-world countries in an effort to control the spread of malaria. It is now recognized that exposure to this pesticide early in life leads to increased risk for subsequent breast cancer, and it has also been linked to increased risks for miscarriage, low birth weight in subsequent pregnancies, and male infertility.

Perhaps the first EDC studied in detail in humans was diethylstilbestrol (DES). An increased incidence of clear cell adenocarcinoma of the vagina was noted among women exposed to DES in utero, and other reproductive abnormalities included infertility and increased incidences of ectopic pregnancy, spontaneous abortion, and preterm delivery.3 Men exposed to DES in utero have an increased incidence of cryptorchidism (relative risk [RR], 2.5; 95% confidence interval [CI], 1.5-4.3) and epididymal cysts (RR, 2.4; 95% CI, 1.54-4.0).3 More recently, it has become apparent that the sons (odds ratio [OR], 1.53; 95% CI, 1.04-2.23) and the daughters (OR, 2.35; 95% CI, 1.44-3.82) of mothers exposed to DES in utero have increased risks of birth defects.4 The mechanisms have yet to be elucidated, but given emerging data involving other EDCs, they may well involve epigenetic changes in the germ line.

First trimester exposure to phthalates affects male genital development, which researchers demonstrated in a study documenting decreased anogenital distance in newborn males.5 A large epidemiologic study published in 2015 extended these observations by documenting that, after control for genetic mutation, parental occupational and environmental exposure to a number of EDCs increased the risk of hypospadias in male children.6

How all EDCs might affect reproductive changes has been suggested by elegant studies in rodents involving the EDC vinclozolin, an antiandrogenic agricultural fertilizer.7 Vinclozolin and the pesticide methoxychlor have been shown to promote the epigenetic transgenerational inheritance of reduced male fertility.8 Germ-line alterations have included changes in DNA methylation, histone modifications, and alterations in chromatin structure; these alterations are mitotically stable and can regulate genome activity independent of DNA sequence. This nongenetic form of inheritance is altering our understanding of how EDCs can affect reproduction across generations.

Studies involving the American alligator have shown recently that these epigenetic changes are not limited to rodents. A number of studies have demonstrated that alligators from lakes containing a variety of environmental EDCs have significant developmental and reproductive impairments; the presence of EDCs in lakes can even alter the ratio of male-to-female alligators present and affect the reproductive potential of the males. Recently, alterations in DNA methylation in alligators was observed in comparing samples from alligators from pristine and contaminated Florida lakes.8

In summary, it now is of great concern as to whether many EDCs common in our everyday lives not only can cause reproductive abnormalities in affected adults, like those detailed in the article itself, but also can alter the human genome through epigenetic changes in the germ line and affect the future reproductive potential of humans. Just how many of the reproductive disorders that we treat today have been caused at least in part by EDCs? The answer is unknown, but the evidence is mounting.

REFERENCES

  1. Gore AC, Chappell VA, Fenton SE, et al. EDC-2: The Endocrine Society’s second annual scientific statement on endocrine-disrupting chemicals. Endocr Rev 2015;36:E1-E150.
  2. Horada T, Takeda M, Kojima S, Tomiyama N. Toxicity and carcinogenicity of dichlorodiphenyltrichloroethane (DDT). Toxicol Res 2016;32:21-33.
  3. Goldberg JM, Falcone T. Effect of diethylstilbestrol on reproductive function. Fertil Steril 1999;72:1-7.
  4. Titus-Ernstoff L, Troisi R, Hatch EE, et al. Birth defects in the sons and daughters of women who were exposed in utero to diethylstilbestrol (DES). Int J Androl 2010;33:377-384.
  5. Swan SH, Sathyanarayana S, Barrett ES, et al. et al. First trimester phthalate exposure and anogenital distance in newborns. Hum Reprod 2015;30:963-972.
  6. Kalfa N, Paris F, Philibert P, et al. Is hypospadias associated with prenatal exposure to endocrine disruptors? A French collaborative controlled study of a cohort of 300 consecutive children without genetic defect. Eur Urol 2015;68:1023-1030.
  7. Skinner MK. Endocrine disruptors in 2015. Epigenetic transgenerational inheritance. Nat Rev Endocrinol 2016;12:68-70.
  8. Guillette LJ Jr, Parrott BB, Nilsson E, et al. Epigenetic programming alterations in alligators from environmentally contaminated lakes. Gen Comp Endocrinol 2016; doi: 10.1016/j.ygcen.2016.04.012.