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Environmental toxicants: hidden players on the reproductive stage

  • Linda C. Giudice
    Correspondence
    Reprint requests: Linda C. Giudice, M.D., Ph.D., Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California.
    Affiliations
    Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California
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      A growing body of evidence suggests that environmental contaminants, including natural gas, endocrine-disrupting chemicals, and air pollution, are posing major threats to human reproductive health. Many chemicals are in commonly used personal care products, linings of food containers, pesticides, and toys, as well as in discarded electronic waste, textile treatments, and indoor and outdoor air and soil. They travel across borders through trade, food, wind, and water. Reproductive and other health effects can be incurred by exposures in utero, in the neonatal or adolescent periods, or in adulthood and can have transgenerational effects. Most chemicals do not undergo the level of evaluation for harm that pharmaceuticals, e.g., do, and they are rarely seen or seriously considered as a danger to human health. Herein, the burden of exposures, challenges in assessing data and populations at risk, models for evaluating harm, and mechanisms of effects are briefly reviewed, ending with a call to action for reproductive health care professionals to advocate for further research, education, and chemical policy reform for the health of this and future generations.

      Key Words

      Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/posts/11407-introduction-environmental-toxicants-hidden-players-on-the-reproductive-stage
      The American Society for Reproductive Medicine and other professional societies including the American College of Obstetricians and Gynecologists (ACOG; www.acog.org), Royal College of Obstetricians and Gynecologists (RCOG; www.rcog.org), International Federation of Gynecologists and Obstetricians (FIGO) (
      • di Renzo G.C.
      • Conry J.A.
      • Blake J.
      • DeFrancesco M.S.
      • DeNicola N.
      • Martin Jr., J.N.
      • et al.
      International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals.
      ), World Health Organization (WHO)/United National Environmental Programme (UNEP) (www.who.int/ceh/publications/endocrine/en/), and The Endocrine Society (
      • Gore A.C.
      • Chappell V.A.
      • Fenton S.E.
      • Flaws J.A.
      • Nadal A.
      • Prins G.S.
      • et al.
      EDC 2: The Endocrine Society's second scientific statement on endocrine-disrupting chemicals.
      ) have made formal statements that the environment can adversely affect human reproductive health. For this supplement on Environment and Reproduction, I asked colleagues in reproductive medicine, science, and toxicology to think critically about new knowledge accrued over time, as the science continues to unfold about specific environmental contaminants—natural gas, endocrine-disrupting chemicals (EDCs), and outdoor air pollution—posing major challenges to human reproductive health. Herein, the authors have focused on germ cells, gonadal steroidogenesis, sperm quality, female and male fertility, placental function, pregnancy outcomes, polycystic ovarian syndrome, endometriosis, uterine fibroids, and menopause. They found supporting data for adverse impacts on some processes and conflicting data for others, and where possible they describe underlying mechanisms or plausible mechanisms for the results observed. Although nonhuman animal data overwhelmingly support environmental toxicants as detrimental to reproductive tract development and function (
      • Gore A.C.
      • Chappell V.A.
      • Fenton S.E.
      • Flaws J.A.
      • Nadal A.
      • Prins G.S.
      • et al.
      EDC 2: The Endocrine Society's second scientific statement on endocrine-disrupting chemicals.
      ), human data are challenging because of inherent limitations of epidemiologic and clinical studies. To give context to the papers that follow in this supplement, in this preface I present a brief overview of the magnitude of the burden that confronts human reproductive health, insights into EDCs and their mechanisms of action relevant to reproduction, and some challenges in experimental and epidemiologic studies in the reproductive environmental health space. I conclude with an eye to the future and a call for action to protect the reproductive health and capacity of this and subsequent generations.

      Global health trends and environmental chemicals

      A growing body of scientific evidence suggests that reproductive health and ultimately reproductive capacity are under strain globally. Indicators of such adversity over the past 60 years include increased rates of obesity, cardiovascular disease, hormone-dependent cancers, developmental disorders, chronic childhood diseases, early pubertal onset, poor birth outcomes, altered sex ratios, and longer time to pregnancy (
      • Crain D.A.
      • Janssen S.J.
      • Edwards T.M.
      • Jeindel J.
      • Ho S.M.
      • Hunt P.
      • et al.
      Female reproductive disorders: the roles of endocrine-disrupting compounds and developmental timing.
      ). Because these changes have occurred in a relatively short time frame, they are unlikely to be explained solely by genetic mutations, therefore warranting consideration of other causes, including the environment, i.e., environmental toxicants (chemicals and heavy metals) and indoor and outdoor air pollution (
      • di Renzo G.C.
      • Conry J.A.
      • Blake J.
      • DeFrancesco M.S.
      • DeNicola N.
      • Martin Jr., J.N.
      • et al.
      International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals.
      ).
      Chemical production increased 23.5-fold from 1947 to 2007, and in 2012 in the U.S. alone, 9.5 trillion pounds of industrial chemicals (e.g., pesticides, plastics, and chemicals in drugs and personal care products) were domestically manufactured or imported, amounting to ∼30,000 pounds/person (www2.epa.gov). In the face of limited safety testing and ethically impermissible randomized controlled trials in people to determine the safety of even very low doses (parts per billion) of environmental chemicals, they have been characterized to “act like uncontrolled medicines” for humans (
      • Birnbaum L.S.
      When environmental chemicals act like uncontrolled medicine.
      ).
      Environmental chemicals cross borders through trade, food, wind, and water, and individuals are exposed through ingestion, transdermally, inhalation, and absorption through mucus membranes. Effects on reproductive (and other health) outcomes of these agents depend on timing of exposures (critical “windows of susceptibility” such as in utero, adolescence, adulthood), dose, duration of exposure, and interactions with other chemicals, as mixtures of chemicals are found in all populations tested (
      • di Renzo G.C.
      • Conry J.A.
      • Blake J.
      • DeFrancesco M.S.
      • DeNicola N.
      • Martin Jr., J.N.
      • et al.
      International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals.
      ,
      • Gore A.C.
      • Chappell V.A.
      • Fenton S.E.
      • Flaws J.A.
      • Nadal A.
      • Prins G.S.
      • et al.
      EDC 2: The Endocrine Society's second scientific statement on endocrine-disrupting chemicals.
      ). In a study of pregnant women representative of the U.S. population, contaminants were ubiquitously found and included environmental tobacco smoke, lead, mercury, phthalates, bisphenol A, perfluorinated compounds, and perchlorate (http://ehp.niehs.nih.gov/wp-content/uploads/119/6/ehp.1002727), underscoring the magnitude of the issue potentially affecting reproductive health. Figure 1 shows windows of susceptibility for several reproductive disorders wherein chemical exposures result in reproductive dysfunction.
      Figure thumbnail gr1
      Figure 1Sensitive developmental periods when exposures to endocrine-disrupting chemicals greatly increase the risk of female reproductive disorders. Data are derived from studies conducted in mice, rats, lamb, sheep, and humans. Adapted from Crain et al. [
      • Crain D.A.
      • Janssen S.J.
      • Edwards T.M.
      • Jeindel J.
      • Ho S.M.
      • Hunt P.
      • et al.
      Female reproductive disorders: the roles of endocrine-disrupting compounds and developmental timing.
      ], with permission. PCOS = polycystic ovary syndrome.

      Endocrine-disrupting chemicals

      Endocrine-disrupting chemicals have received by far the greatest focus, because of their widespread use and broad exposures (
      • Gore A.C.
      • Chappell V.A.
      • Fenton S.E.
      • Flaws J.A.
      • Nadal A.
      • Prins G.S.
      • et al.
      EDC 2: The Endocrine Society's second scientific statement on endocrine-disrupting chemicals.
      ). EDCs are chemicals or mixtures of chemicals that interfere with any aspect of hormone action at any time of development and/or during the life course. These include pesticides (e.g., dichlorodiphenyltrichloro-ethane [DDT], chlorpyrifos, atrazine, 2,4-dichlorophenoxyacetic acid [2,4-D]), children's products (containing lead, phthalates, cadmium), food contact material (e.g., linings of cans or plastic bottles with bisphenol A, phthalates, phenol), electronics and building materials (e.g., brominated flame retardants), personal care products and tubing (e.g., phthalates), antibacterials (e.g., triclosan), and textiles and clothing (e.g., perfluorochemicals) (
      • Gore A.C.
      • Chappell V.A.
      • Fenton S.E.
      • Flaws J.A.
      • Nadal A.
      • Prins G.S.
      • et al.
      EDC 2: The Endocrine Society's second scientific statement on endocrine-disrupting chemicals.
      ). Emerging evidence supports EDCs as obesogens, diabetogens, reproductive disrupters, thyroid disrupters, and neurodevelopmental disrupters (
      • Gore A.C.
      • Chappell V.A.
      • Fenton S.E.
      • Flaws J.A.
      • Nadal A.
      • Prins G.S.
      • et al.
      EDC 2: The Endocrine Society's second scientific statement on endocrine-disrupting chemicals.
      ).
      There is a connection between adult diseases (e.g., obesity, cardiovascular disease, type 2 diabetes, some cancers, neurodevelopmental abnormalities, mental illnesses, impaired fertility, poor pregnancy outcomes, and urogenital abnormalities) and preconceptual, periconceptual, and prenatal environmental exposures (
      • Birnbaum L.S.
      When environmental chemicals act like uncontrolled medicine.
      ). Environmental chemicals can modify multiple biologic processes, including interfering with any aspect of hormone action (as with EDCs [2]), and thus have potential to markedly affect steroid hormone–dependent human reproductive tract development and adult reproductive function. EDCs can change cellular processes by binding to steroid hormone nuclear receptors and activating genomic and nongenomic pathways, activate ion channels, induce proinflammatory cytokines and chemokines, promote oxidative stress, and alter cell proliferation and differentiation (
      • Gore A.C.
      • Chappell V.A.
      • Fenton S.E.
      • Flaws J.A.
      • Nadal A.
      • Prins G.S.
      • et al.
      EDC 2: The Endocrine Society's second scientific statement on endocrine-disrupting chemicals.
      ). They can also act through nonsteroid hormone receptors (e.g., the thyroid receptor ThR and GPR30), and increasing evidence suggests that epigenetic mechanisms, including DNA methylation, histone modifications, and micro-RNA expression are involved (
      • Gore A.C.
      • Chappell V.A.
      • Fenton S.E.
      • Flaws J.A.
      • Nadal A.
      • Prins G.S.
      • et al.
      EDC 2: The Endocrine Society's second scientific statement on endocrine-disrupting chemicals.
      ). These in turn affect gene expression, cell and tissue function, and disease risk. Considering the methylation/demethylation changes that occur normally during gametogenesis and embryogenesis (Fig. 2) (
      • Perera F.
      • Herbstman J.
      Prenatal environmental exposures, epigenetics, and disease.
      ), the impact of EDCs can be significant for reproductive success across generations.
      Figure thumbnail gr2
      Figure 2Multiple periods when environmental exposures can affect first-generation (F0 [parental]) and second-generation (F1 [offspring] and F2 [germ cells of offspring]) DNA methylation status, potentially affecting phenotype. To demonstrate whether epigenetic alterations are transmitted transgenerationally, the F3 generation must be studied.
      From Perera and Herbstma [
      • Perera F.
      • Herbstman J.
      Prenatal environmental exposures, epigenetics, and disease.
      ], with permission.

      Challenges in experimental and epidemiologic studies in environmental health

      Much of the information we have about effects of various chemicals in the environment and particulate matter in the air derive from nonhuman animal models, occupational exposures, environmental accidents, and epidemiologic data from various populations. Challenges in animal studies include different results or directionality of effects (increased or decreased) observed with the use of different species or strains within a species and differences of age at exposure, duration of exposure, and doses used in the studies (
      • Gore A.C.
      • Chappell V.A.
      • Fenton S.E.
      • Flaws J.A.
      • Nadal A.
      • Prins G.S.
      • et al.
      EDC 2: The Endocrine Society's second scientific statement on endocrine-disrupting chemicals.
      ).
      Challenges in epidemiologic and clinical observational studies include precise definition of study populations (e.g., fertile vs. subfertile), sample sizes, study design (e.g., cross-sectional vs. prospective), controlling for multiple variables, including lifestyle, body mass index, smoking, and other confounders of epigenetic modifications, and different chemical quantification approaches and which congeners are assayed. Other challenges are evaluating exposure levels of specific chemicals (occupational, casual, chronic), study procedures used to collect and measure compounds, which compartments to study (urine, adipose tissue, blood, saliva), and measurements (e.g., one urine sample to characterize exposure or multiple samples).
      Systematic reviews in environmental health sciences are challenging and have lagged behind those in clinical medicine by nearly 20 years. Recently, Woodruff et al. developed the Navigation Guide Systematic Review methodology (http://content.healthaffairs.org/content/30/5/931.full.pdf+html?ijkey=z58MCEPW2X49.&keytype=ref&siteid=healthaff), building on best practices in research synthesis in evidence-based medicine and environmental health, providing a rigorous and transparent approach to translate environmental health science into better outcomes. These are important to studies in environmental health and equally to reproductive environmental health.

      Moving forward

      Environmental contaminants can be insidious and lack the level of data for evaluating harm that is applied to pharmaceutical drugs, resulting in the burden of proof of harm being left to those affected (
      • Birnbaum L.S.
      When environmental chemicals act like uncontrolled medicine.
      ). Many are unaware of their potential effects on human health, and some dismiss their potential for harm in the face of lack of data. Lack of data about a chemical's health hazard does not imply it is safe, but merely indicates that no data are available to indicate harm or not. However, if there are sufficient data to suggest plausibility of harm, the precautionary principle is advocated, i.e., minimizing exposures within the capabilities of those exposed.
      Although the field of reproductive environmental health is still in its infancy, the stakes are high. Effective protection from chemical exposures requires leadership, environmental education, civic participation, and social action. Science has an important role to help us continue to identify exposures and harms that may be occurring in the population, and in partnership with physicians, community leaders also can make positive change. Scientists and health care professionals are well positioned to collaborate with other stakeholders to promote protection and to advocate for improved chemical policies focused on industrial chemical production, disposal, tracking, and recycling and testing for reproductive health outcomes. Professional organizations, including WHO/UNEP, ACOG, ASRM, RCOG, FIGO, and the University of California, San Francisco, Program on Reproductive Health and the Environment (prhe.ucsf.edu) have spoken out to raise awareness of risks among the population at large and for health care professionals to advocate for improved industrial chemical regulation and a safe food supply nationally and globally. As learned by the lesson of reducing blood levels of lead after its removal from house paint and gasoline, reducing risk of disease, infertility, or developmental abnormalities may be achieved through environmental chemical policy reform. Although environmental toxicants are hidden players on the reproductive stage, scientific evidence for their harm shows that the time has come to minimize their effects on our reproductive capacity and outcomes and advocate for change for the health and well-being of this and future generations.

      Acknowledgments

      I extend my appreciation to all of the authors for their time and efforts in their individual contributions to this supplement and to the Editors-in-Chief for their vision to include a reproductive environmental health update for the readers of Fertility & Sterility. Furthermore, I thank Nancy Kucik, managing editor, for her editorial support and Nicole Bloom for her administrative support, both of whom contributed greatly to making this supplement a reality.

      References

        • di Renzo G.C.
        • Conry J.A.
        • Blake J.
        • DeFrancesco M.S.
        • DeNicola N.
        • Martin Jr., J.N.
        • et al.
        International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals.
        Int J Gynecol Obstet. 2015; 131: 219-225
        • Gore A.C.
        • Chappell V.A.
        • Fenton S.E.
        • Flaws J.A.
        • Nadal A.
        • Prins G.S.
        • et al.
        EDC 2: The Endocrine Society's second scientific statement on endocrine-disrupting chemicals.
        Endocr Rev. 2015; 36: E1-E150
        • Crain D.A.
        • Janssen S.J.
        • Edwards T.M.
        • Jeindel J.
        • Ho S.M.
        • Hunt P.
        • et al.
        Female reproductive disorders: the roles of endocrine-disrupting compounds and developmental timing.
        Fertil Steril. 2008; 90: 911-940
        • Birnbaum L.S.
        When environmental chemicals act like uncontrolled medicine.
        Trends Endocrinol Metabl. 2013; 24: 321-323
        • Perera F.
        • Herbstman J.
        Prenatal environmental exposures, epigenetics, and disease.
        Reprod Toxicol. 2011; 31: 363-373