Introduction
Infertility is defined as the inability to conceive following a year of regular unprotected intercourse or donor insemination. This definition is reduced to 6 months for women over 35 or with other known risk factors for infertility.[1] In the United States, 13.1% percent of women aged 15 to 49 have known infertility based on 2015 through 2017 national survey data.[2] Numerous etiologies for infertility exist, including ovulatory dysfunction, diminished ovarian reserve, tubal factor, male factor, multifactorial etiologies, and unexplained infertility.
Environmental toxins are ubiquitous and sometimes implicated in infertility development, either through anatomical abnormalities or endocrinological dysfunction. Based on a National Health and Nutrition Survey from 2003 through 2004, pregnant women in the United States are exposed to 43 or more different potential chemical toxins.[3] Knowledge and experience in evaluating exposure to environmental toxins are critical for any reproductive endocrinology and infertility specialist.
Environmental toxins affect individuals throughout the lifespan, including prenatally, and can have various effects, from increasing cancer risk to ovulatory dysfunction to altered semen quality. This article is a focused review on the specific toxins known to influence fertility and the recommended evaluation, treatment, and prognosis for these patients.
Issues of Concern
Environmental Toxins Associated with Infertility
Endocrine Disrupting Chemicals
Endocrine Disrupting Chemicals (EDCs) are exogenous chemicals that, when exposed, specifically in utero or puberty, can contribute to both female and male infertility and predispose to the development of other diseases that affect fertility as obesity, diabetes, and endocrine cancers (Birnbaum).
EDCs derive from various sources, including plant-derived phytoestrogens (such as soy products), industrial chemicals (such as flame retardants, pesticides, and lubricants), household consumables (such as bisphenol A [BPA] products, phthalates, tea, and lavender oils), and pharmaceutical products (such as diethylstilbestrol [DES] and estradiol).
DES may be the most infamous of these compounds. DES was used primarily in the 1950s and 1960s in pregnant mothers for miscarriage prevention until DES exposure in utero was associated with developing vaginal clear cell adenocarcinoma (CCA) in female children. Exposure in offspring resulted in congenital anomalies in the reproductive tract and adverse pregnancy outcomes rendering affected women infertile or sub-fertile (Figure 1). Though most of these women are past reproductive age at this point, its historical use is still relevant for the increased risk for CCA and cervical cancer.[4][5]
EDCs disrupt the human endocrine system by either increasing or decreasing the production of endogenous hormones or altering the peripheral distribution of endogenous hormones.[6] This may happen through several proposed molecular pathways, though the nuclear receptor pathway is the most established. In this pathway, EDCs bind to the hormone receptors for estrogens, progestins, androgens, and thyroid hormones, either disrupting or augmenting their cellular activity.[7] Other proposed mechanisms exist, including the likelihood of prenatal and early exposure leading to epigenetic effects, predisposing individuals to various disease processes such as rare cancers, obesity, and endocrine disorders such as diabetes.[8][9]
In terms of fertility concerns specifically, EDCs have been linked with reproductive development disorders, ovarian dysfunction, subfertility, and polycystic ovarian syndrome (PCOS) in women. As far as reproductive development, the most striking example is DES as above. However, animal models have suggested an association of BPA with ovarian cysts, uterine polyps, vaginal adenosis, and impaired implantation in in-vitro fertilization (IVF) patients.[10][11]
Higher serum BPA concentrations were seen in women with PCOS, with increasing evidence of insulin resistance and hyperandrogenism associated with increasing BPA concentrations.[12] Other EDCs have also been associated with ovarian dysfunction and infertility as well. Exposure to polychlorinated biphenyls (PCBs), used in electrical equipment, has been associated with a more extended period of trying to conceive before achieving pregnancy and worse fertilization rates in those undergoing IVF.[13][14] Increased exposure to phthalates, commonly found in plastics, has been demonstrated to be associated with lower antral follicle counts and mature oocyte numbers in patients undergoing IVF.[15][16]
EDCs have also been associated with male infertility. Dichlorodiphenyltrichloroethane (DDT), for example, is a metabolite of a pesticide no longer used in the United States but still in use globally, has been shown to reduce sperm concentration, normal morphology, and motility in semen analyses.[17] Similarly, BPA exposure has been shown to negatively affect sperm quality in epidemiological studies.[18]
Beyond reproductive organs, EDCs also affect other aspects of the endocrine system that also impact fertility, such as the thyroid, including abnormalities in metabolism and transport, resulting in an association with hypothyroidism.[19]
Heavy Metals
Heavy metal exposure has also been implicated in infertility. Exposure can come from the natural environment and housing/work environments, as in the case of lead exposure through paint or mercury and arsenic exposure through food and water supply. Heavy metals that have been found to affect reproductive activity include lead, mercury, cadmium, and arsenic.
Individuals can be exposed to lead from a variety of sources, including, but not limited to, lead paints, water from lead pipes, cosmetics, construction sites, and herbal supplements. In patients identified as high risk based on exposure, a venous blood level can be collected. A lead level >15.47 ppb is associated with a twofold infertility risk compared to individuals below that threshold.[20] Increased lead exposure has also been associated with an increased risk for spontaneous abortion and preterm birth.[21][22] Treatment of elevated blood leads levels during the preconception period either entails identifying and eliminating environmental exposures or chelation in severe cases.
Mercury exposure usually comes from diet, primarily from predatory fish consumption. Mercury enters the seascape via industrial waste sources and accumulates in predatory fish. Other less common sources are women exposed to gold mining and some skin-lightening creams.[23] While mercury toxicity in pregnant women is usually linked with neurodevelopmental disorders in offspring, there is also an association with female infertility.[24][25] Treatment in the preconception period of elevated mercury levels again hinges on identifying and eliminating exposure and chelation only in cases of very high levels of mercury toxicity.
Cadmium exposure can stem from rechargeable batteries and certain paints and plastics. It can enter the food supply through resorption in the soil, resulting in cadmium exposure in various foods, including rice, wheat, leafy vegetables, and shellfish.[26] Increased cadmium levels are also noted in cigarette smokers (discussed below). In a small prospective study of infertile couples undergoing IVF, decreased oocyte fertilization rates and implantation rates were noted in patients with increased cadmium levels, though further research is needed.[27][28] Treatment in the preconception period of elevated cadmium levels is again identification and elimination of exposure and chelation in cases of very high toxicity levels.
Arsenic exposure usually comes from certain groundwater sources, though it can also stem from certain pesticides and industrial exposures. Arsenic is primarily associated with otherwise unexplained male factor infertility.[29] Treatment involves exposure elimination only, as it quickly clears from the bloodstream.
Smoking
Smoking is a known environmental exposure that is modifiable, that influences fertility. Cigarette smoking is an important environmental toxin to consider, as 17.8% of adults in the United States smoke.[30] Cigarette smoking is most frequently considered prenatally associated with various adverse pregnancy outcomes such as preterm birth and placental abruption. However, it has also been shown to affect fertility in a dose-dependent manner.[31] It is theorized that the accumulation of cadmium and cotinine (a major nicotine metabolite) in follicular fluid in the ovaries compromises oocyte quality, thus resulting in infertility. It is worth noting that even when the female herself is a nonsmoker but lives with a smoker, cotinine levels are still elevated.[32][33]
In smoking men, there is evidence of reduced sperm concentration and motility, as well as evidence in animal studies that smoking may reduce sperm’s ability to bind to the zona pellucida for fertilization.[34]
In a meta-analysis of seven studies, it was noteworthy that in patients undergoing assisted reproduction, such as IVF, smokers require twice as many IVF cycles before conception compared to nonsmokers.[35]
Clinical Significance
Understanding environmental toxins' effect on infertility is clinically significant, as it is preventable, and in some instances, modifiable once already exposed.
Treatment and Prevention
In certain cases, toxicity can be treated, such as in the case of heavy metal exposure. Additionally, with cigarette smoking, return to normal fecundity is noted with smoking cessation, making cessation counseling of utmost importance during an evaluation for infertility.[36] In other cases, such as exposure to EDCs, prevention is the primary aim.
Prevention of environmental toxin exposure comes from individual action and community and policy level change. Reproductive health providers are especially poised for exposure prevention, as they can identify at-risk patients during pre-conception counseling and pregnancy, perhaps even preventing prenatal exposure. Providers can prevent exposure through appropriate reporting and patient education. If a patient is found to have an exposure-related illness or suspected exposure based on screening, the case should be referred to occupational medicine programs or an Environmental Health Specialty Unit.[37]
Patient education is extremely important and can be done easily through counseling and education pamphlets to prevent or minimize exposure. A specific example of this includes a research study that showed that transitioning a child's food consumption to an organic diet significantly reduces organophosphate pesticide metabolite concentration in the urine.[38]
Another study found that avoiding sources of bisphenol A, such as canned food, reduced levels of bisphenol A in study participants.[39] Based on this literature, dietary recommendations for patients to reduce environmental toxin exposure primarily involve moving towards a diet dominated by fruit, vegetables, and whole grains, avoiding processed foods and fast foods, and avoiding products containing known EDCs like BPA.
Large-scale prevention will ultimately involve policy change. Several academic societies, including the American Society of Reproductive Medicine and the Endocrine Society, have called for public policy change to regulate environmental toxin exposure. These statements urge the United States Environmental Protection Agency and other involved government agencies to analyze substances made available to the public for their effect on human health.
Certain actions have already been taken to reduce specific exposures, such as banning certain EDCs like DES by the Food and Drug Administration. BPA has also been regulated by banning its presence in various early life products such as baby bottles and infant formula.[40]
Other Issues
It is important to consider environmental disparities in the process of identifying high-risk patients in a screening evaluation for exposure to environmental toxins. Studies in the United States have shown that the presence of various toxins such as air pollutants, lead, and pesticides are increased in communities with a lower socioeconomic status.[41] Additionally, socioeconomically disadvantaged populations, such as low-wage immigrants, are more likely to have occupational exposures, such as organophosphate pesticides.[42]
For patients identified as high risk based on their community, socioeconomic status, or occupation, it is necessary to include a comprehensive screening evaluation of environmental exposures when evaluating for etiologies of infertility if it is not already routine.[43]
Enhancing Healthcare Team Outcomes
Screening, treatment, and prevention of fertility-altering environmental toxins requires action amongst women’s health providers and reproductive infertility specialists and their ancillary staff and requires cooperation and active management by local government, environmental agencies, and public policymakers. By enacting treatment and change in environmental exposures from the individual to government level, the effects of environmental toxins on infertility can be minimized and ideally even be entirely prevented.[1]
