Environmental Toxins and Infertility

Issues of Concern

Endocrine-Disrupting Chemicals 

Endocrine-disrupting chemicals are exogenous chemicals that, when exposed, specifically in utero or puberty, can contribute to both female and male infertility. The Endocrine Society defines EDC as an exogenous (non-natural) chemical, or a mixture of chemicals, that interferes with any aspect of hormone action.[4] 

Endocrine-disrupting chemicals derive from various sources, including plant phytoestrogens, such as soy products; industrial chemicals, such as flame retardants, pesticides, and lubricants; household consumables, such as bisphenol A products and phthalates; perfluoroalkyl chemicals; and pharmaceutical products, such as diethylstilbestrol. Endocrine-disrupting chemicals are ubiquitously found in the environment, and exposure occurs through skin, inhalation, and water and food consumption.[4]

Diethylstilbestrol is the most infamous of these compounds. Diethylstilbestrol was used primarily in the 1950s and 1960s to prevent miscarriages in pregnant mothers. However, it was later determined that diethylstilbestrol exposure in utero was associated with the development of vaginal clear cell adenocarcinoma in female children. Exposure in offspring resulted in congenital anomalies in the reproductive tract and adverse pregnancy outcomes, rendering affected women infertile or subfertile (see Image. Classic T-Shaped Uterus on a Hysterosalpingogram). Although most of these women are past reproductive age at this point, its historical use is still relevant for the increased risk for clear cell adenocarcinoma and cervical cancer.[5][6]  

Endocrine-disrupting chemicals disrupt the human endocrine system by either increasing or decreasing the production of endogenous hormones or altering the peripheral distribution of endogenous hormones.[7] These chemicals can act as both agonists and antagonists, disrupting hormonal biosynthesis, signaling, and metabolism. This disruption may occur through several proposed molecular pathways, with the nuclear receptor pathway being the most well-established. In this pathway, endocrine-disrupting chemicals bind to the hormone receptors for estrogens, progestins, androgens, and thyroid hormones, either disrupting or augmenting their cellular activity.[8] Other proposed mechanisms exist, including the likelihood of prenatal and early exposure leading to epigenetic effects, predisposing individuals to various diseases, such as rare cancers, obesity, and endocrine disorders, including diabetes.[9][10]

Common endocrine-disrupting chemicals include the following:

• Bisphenols
• Phthalates
  • Diethyl phthalate
  • Dibutyl phthalate
  • Diisobutyl phthalate
  • Di-(2-ethylhexyl) phthalate
  • Diisononyl phthalate
  • Perfluorooctanoate
  • DDT
  • Polybrominated diphenyl ether
  • Bis(triphenyltin) oxide
  • Tributyltin
• Parabens
• Persistent organic pollutants
• Pesticides, herbicides, and insecticides
• Heavy metals (aluminum, arsenic, cadmium, chromium, lead, and mercury) [4]

Endocrine-disrupting chemicals have been associated with reproductive developmental disorders, ovarian dysfunction, subfertility, and polycystic ovary syndrome (PCOS) in women. Hormonal imbalances caused by these chemicals can lead to earlier menopause, increased risk of miscarriage, and longer menstrual cycles. In addition, endocrine-disrupting chemicals can decrease the quality of sperm and eggs and cause DNA damage in sperm. Animal studies have suggested an association between bisphenol A exposure and reproductive conditions, such as ovarian cysts, uterine polyps, vaginal adenosis, and impaired implantation in in vitro fertilization (IVF) patients.[11][12] 

Bisphenol A is used to manufacture plastics, cash register receipts, plastic baby bottles, toys, pacifiers, computers, cell phones, reusable food containers, epoxy resins, and canned food liners. Elevated serum bisphenol A concentrations have been observed in women with PCOS, with increasing evidence of insulin resistance and hyperandrogenism associated with increasing bisphenol A concentrations.[13] Bisphenol A exposure has also been shown to affect embryo development and implantation, oocyte quality, and placentation.[14]

Other endocrine-disrupting chemicals are associated with ovarian dysfunction and infertility. Exposure to polychlorinated biphenyls, 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.[15][16] Increased exposure to phthalates, commonly found in plastics, has been demonstrated to be associated with lower antral follicle counts and fewer mature oocyte numbers in patients undergoing IVF.[17][18] Beyond reproductive organs, endocrine-disrupting chemicals disrupt other components of the endocrine system, such as the thyroid. These disruptions can lead to abnormalities in hormone metabolism and transport, contributing to conditions like hypothyroidism, which further impair fertility.[19]

Endocrine-disrupting chemicals have also been associated with male infertility. For example, DDT, a pesticide metabolite no longer used in the United States but still in use globally, has been shown to decrease sperm concentration, impair normal sperm morphology, and reduce motility in semen analyses.[20] Similarly, bisphenol A exposure has been shown to negatively affect sperm quality in epidemiological studies.[21]  

Organochlorine compounds found in pesticides can disrupt reproductive function. Women with the highest levels of these compounds had the lowest fertility. Methylparaben primarily affects fertility in women, whereas phthalates and benzophenone-2 primarily affect fertility in men. Perfluoroalkyl chemicals are chemicals that are resistant to water and grease and can be found in drinking water, nonstick cookware, food packaging, paints, personal care products, waterproof clothing, and stain-resistant coatings on carpets and upholstery. Perfluoroalkyl chemicals, such as perfluorodecanoic acid, perfluoroheptanoic acid, perfluorooctanesulfonic acid, and perfluorooctanoic acid, have been individually linked to reduced fertility, as they can disrupt fertility hormones. Some studies also link perfluoroalkyl chemicals to endometriosis and PCOS.

Heavy Metals 

Exposure to heavy metals has been linked to infertility. Sources of exposure can include both natural and occupational environments. Heavy metals such as lead, mercury, cadmium, and arsenic have been associated with infertility.

Lead: Lead exposure is observed in battery factory workers, immigrants, individuals handling lead-glazed pottery, those involved in jewelry making, users of lead-containing toys, and women with pica.[14] Individuals can be exposed to lead from a variety of sources, including, but not limited to, lead paints—used in houses built before 1978—water from lead pipes, cosmetics, construction sites, and herbal supplements. A venous blood level can be collected in patients identified as high risk based on exposure. A lead level >15.47 ppb is associated with a 2-fold infertility risk compared to individuals below that threshold.[22] Increased lead exposure has also been associated with an increased risk of spontaneous abortion and preterm birth.[23][24] Treatment for elevated blood lead levels during the preconception period involves identifying and eliminating environmental exposures or, in severe cases, administering chelation therapy.

Mercury: Mercury is a byproduct of coal combustion, waste burning, and incineration processes. Mercury accumulates in fish after leaching into the water. Exposure typically comes from diet, primarily from predatory fish consumption. Mercury enters the seascape through industrial waste sources and accumulates in these predatory fish. Other less common sources are broken thermometers, fluorescent lamp factories, dental supplies, gold mining activities, and some skin-lightening creams.[14][25] Although mercury toxicity in pregnant women is typically linked to neurodevelopmental disorders in offspring, there is also an association with female infertility.[26][27] Treatment during the preconception period focuses on identifying and eliminating exposure and chelation only in cases of very high levels of mercury toxicity. The United States Environmental Protection Agency recommends that women of reproductive age consume fish with lower mercury content and consult local advisories for fish caught and consumed from specific areas.[14]

Cadmium: Cadmium exposure primarily originates from sources such as rechargeable batteries, certain paints, and plastics. The United States produces approximately 600 tons of cadmium annually.[14] This heavy metal can enter the food supply through resorption in the soil, leading to its presence in various foods, including rice, wheat, potatoes, leafy vegetables, and shellfish.[28] Cigarette smoking is another significant source of cadmium exposure (discussed below). Cadmium accumulates in the ovaries and testes, potentially impacting reproductive health. In a small prospective study involving infertile couples undergoing in-vitro fertilization, decreased oocyte fertilization rates and implantation rates were noted in patients with high cadmium levels, though further research is needed.[29][30] Treatment during the preconception period of elevated cadmium levels is again the identification and elimination of exposure and chelation in cases of very high toxicity levels.  

Arsenic: Arsenic exposure is most commonly linked to specific groundwater sources, though it can also stem from certain pesticides and industrial exposures. Arsenic is primarily associated with otherwise unexplained male factor infertility.[31] Treatment focuses on eliminating exposure, as arsenic is rapidly cleared from the bloodstream.

Smoking 

Smoking is a significant modifiable environmental factor that influences fertility. Cigarette smoking is an important environmental toxin to consider.[32] Nearly 20% of adults in the United States reported using tobacco products in 2022, including cigarettes, cigars, cigarillos, vapes, and other smokeless tobacco products. Cigarette smoking during pregnancy is associated with various adverse pregnancy outcomes, such as preterm birth and placental abruption. However, cigarette smoking has also been shown to affect fertility in a dose-dependent manner.[33] The accumulation of cadmium and cotinine—a major nicotine metabolite—in ovarian follicular fluid compromises oocyte quality, thus resulting in infertility. Notably, nonsmoking females exposed to secondhand smoke may also exhibit elevated cotinine levels.[34][35]

Tobacco use in females is associated with increased risks of spontaneous abortion, ectopic pregnancy, and impaired fecundity. Likewise, tobacco use is associated with negative assisted reproductive technology outcomes. The findings are similar in individuals overexposed to tobacco smoke, even if they are not smokers themselves.

In the United States, cigarette smoking has declined over the past decades, and smokers are smoking fewer cigarettes each day. Smoking in men has been associated with reduced sperm concentration and motility. In animal studies, smoking was noted to reduce sperm's ability to bind to the zona pellucida for fertilization.[36] A meta-analysis of 7 studies revealed in patients undergoing assisted reproduction, such as IVF, smokers require twice as many IVF cycles to achieve conception compared to nonsmokers.[37]

Aerosol in electronic nicotine delivery systems has been found to contain heavy metals, such as chromium, nickel, and lead, which are linked to male infertility. Additional contents include formaldehyde, glyoxal, acrolein, and acetaldehyde, which are carbonyls that are linked to infertility and miscarriage. There are no studies yet that assess the effects of electronic nicotine delivery systems on fertility treatment outcomes.[38]

The American College of Obstetrics and Gynecology and the American College of Pediatricians do not recommend marijuana during the preconception period, although evidence supporting this recommendation is mainly theoretical. Despite these recommendations, up to 17% of males and 12% of females use marijuana during this period. No associations between marijuana use and female reproductive hormones have been found except for a possible suppression of luteinizing hormone. Investigations into the association between marijuana use and fecundability are conflicting. Research shows that marijuana use does not affect fecundity, time to pregnancy, semen parameters, or assisted reproductive technology outcomes.[38]

Air Pollution

Elevated air pollution, including ozone, nitrogen dioxide, and sulfate compounds, has been associated with a high risk of pregnancy loss.[39] Some have suggested that air pollution causes inflammation and oxidative stress. A systematic review noted that couples living close to major highways had decreased fertility due to exposure to air pollutants.[40]

Clinical Significance

Understanding the impact of environmental toxins on fertility is clinically significant, as it is preventable and, in some instances, modifiable once exposed. Strategies to reduce toxin exposure include avoiding the following:

• Smoking and vaping in the home or vehicle 
• Consuming raw or undercooked meat, poultry, eggs, and seafood
• Consuming soft cheeses, such as feta, brie, and Roquefort
• Consuming cold lunch meats, such as hot dogs and deli meats
• Consuming fish high in mercury levels, such as shark, swordfish, king mackerel, tilefish, and albacore tuna
• Consuming unwashed fruits and vegetables

Treatment and Prevention

Toxicity can sometimes be treated, particularly in cases of heavy metal exposure. In addition, with cigarette smoking, a return to normal fecundity is noted with smoking cessation, making cessation counseling of utmost importance during an evaluation for infertility.[41] In other cases, such as exposure to EDC, prevention is the primary aim. 

The prevention of environmental toxin exposure comes from individual action and community and policy-level change. Reproductive health professionals are especially poised for exposure prevention, as they can identify at-risk patients during preconception counseling, perhaps even preventing prenatal exposure. Clinicians can avoid 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 individual should be referred to occupational medicine programs or an environmental health specialty unit.[42]

Several regulatory bodies have been involved with regulations on controlling endocrine-disrupting chemicals. Examples include the European Food Safety Authority and the European Chemicals Regulation in the European Union. In the United States, a regulatory program called the Endocrine Disruptor Screening Program has helped control the use and exposure to endocrine-disrupting chemicals. The Canadian Environmental Protection Act and the Japanese environmental regulations are other examples of regulatory and screening investigations.[4] 

Large-scale prevention may 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 government agencies to analyze substances made available to the public for their effect on human health. Certain measures have already been implemented to reduce specific exposures, including the Food and Drug Administration's ban on certain endocrine-disrupting chemicals, such as diethylstilbestrol. Bisphenol A has also been regulated by banning its use in various early-life products, such as baby bottles and infant formula.[43]

Patient education is crucial in minimizing exposure and can be achieved through counseling and distributing educational materials. A specific example includes a research study showing that transitioning a child's food consumption to an organic diet significantly reduced organophosphate pesticide metabolite concentration in the urine.[44] Another study found that avoiding sources of bisphenol A, such as canned food, significantly reduced bisphenol A levels in study participants.[45] Based on these findings, dietary recommendations to reduce environmental toxin exposure include adopting a diet rich in fruits, vegetables, and whole grains, minimizing processed and fast foods, and avoiding products that contain endocrine-disrupting chemicals, such as bisphenol A.

Phthalate use has increased in recent years, as these toxins are extensively used in plastic products and released into the environment. Multiple exposure pathways, such as inhalation and absorption through skin, have been observed. Although the health risks caused by phthalates are not clear, the oxidative stress and inflammation they cause may result in a prolonged time to achieve pregnancy in women. This effect was not associated with women receiving folic acid supplementation, suggesting that folic acid may regulate the infertility associated with phthalate exposure. Similarly, vitamin C may have antagonistic effects on the ovarian damage induced by dibutyl phthalate.[46] 

To reduce exposure to environmental toxins, fruits and vegetables should be washed thoroughly to remove pesticide residues. Patients should be recommended to opt for fresh foods over processed or canned items to avoid endocrine-disrupting chemicals from plastic packaging and can linings. Oily fish and fatty meats should be avoided, as these can accumulate pesticides and heavy metals. Individuals are advised to drink from glass or hard plastic bottles rather than soft plastics, as flexible plastics can release endocrine-disrupting chemicals into beverages. Food should be heated in glass or china containers rather than soft plastic, and cling wrap should be avoided to prevent endocrine-disrupting chemicals from leaching into fatty foods. Indoor air quality is improved by opening windows and avoiding air fresheners, strong chemicals, and heavily scented products. Non-toxic, eco-friendly alternatives for gardening and household cleaning should be chosen, and labels on personal care items read, selecting products without parabens and other harmful additives. Finally, patients must be warned about products marketed as bisphenol A-free, as they may contain chemicals similar to BPS.

Other Issues

Environmental disparities must be carefully considered when identifying high-risk patients during screening evaluations for exposure to environmental toxins. Studies in the United States have shown that various toxins, such as air pollutants, lead, and pesticides, are increased in communities with a lower socioeconomic status.[47] In addition, socioeconomically disadvantaged populations, such as low-wage immigrants, are more likely to have occupational exposures, such as organophosphate pesticides.[48] For patients identified as high risk based on their community, socioeconomic status, or occupation, a comprehensive screening evaluation of environmental exposures is crucial when assessing potential etiologies of infertility.[49]

Enhancing Healthcare Team Outcomes

Environmental toxins, including pesticides, heavy metals, and endocrine-disrupting chemicals, are linked to fertility issues, including decreased sperm quality, ovulatory dysfunction, and overall reproductive health concerns. The role of healthcare teams in addressing these risks is crucial, especially as patients increasingly seek information on how environmental exposures may affect their fertility and overall health. Clinicians, advanced practitioners,  pharmacists, and other healthcare providers play a central role in assessing, educating, and coordinating care to mitigate the impact of these environmental toxins. This collaborative model underscores the importance of each healthcare professional's contribution to patient-centered care. Interprofessional continuing education activities reinforce the importance of each discipline, ultimately enhancing team performance and patient-centered outcomes.

Clinicians often lead the evaluation by identifying possible environmental risk factors and counseling patients about avoidance strategies. Advanced practitioners collaborate by supporting patient education on lifestyle changes and monitoring exposure symptoms. Nurses are essential in coordinating follow-ups, providing education, and ensuring patients feel supported in discussing concerns about environmental exposures. Pharmacists contribute by reviewing and educating on potential interactions between fertility treatments and environmental toxins, such as endocrine-disrupting chemicals. Other healthcare providers, including dietitians and social workers, can help patients build sustainable dietary practices and access community resources to minimize toxin exposure.

To optimize patient-centered care, the interprofessional team collaborates to develop clear communication pathways and workflows that integrate each professional's expertise. Team members participate in case discussions and share insights on toxicology, prevention strategies, and health monitoring tailored to each patient's circumstances. The team uses shared decision-making, offering patients comprehensive information to help them make informed choices about their health. Each discipline's input is valued equally to foster a non-hierarchical structure, supporting the patient's safety and empowerment. By implementing streamlined protocols and consistent communication, the team promotes patient safety, improved health outcomes, and a holistic approach to managing infertility risks associated with environmental toxins.