Environmental Factors and Reproduction

Developmental Origins of Adult Health and Disease

The concept of developmental origins of adult health and disease describes links between the in utero environment, the external environment, an individual’s genes, and the propensity to develop disease or dysfunction later in life. ^{, ,} The central nervous system, cardiovascular system, various endocrine systems, and the immune system are particularly vulnerable to adverse effects during development, and neurodevelopmental disorders and some cancers can be initiated before birth or during early postnatal life. ^{, ,}

The Fetus Can Be Uniquely Sensitive to Chemical Exposures: Thalidomide and Other Agents of Concern

The embryo, fetus, and developing human are highly vulnerable to exposure from even small amounts of environmental toxicants. This vulnerability is due to the unique and rapidly changing physiology, growth, and development of humans (i.e., high mitotic indices and cellular differentiation in developing organs; high metabolic rate; and an underdeveloped immune system, blood-brain barrier, and liver detoxifying mechanisms).

A critical window of susceptibility occurs when exposures to environmental contaminants can disrupt or interfere with the physiology of a targeted cell, tissue, or organ. Exposures that occur during this time can lead to permanent and lifelong health effects and can be transmitted to subsequent generations via epigenetic mechanisms (see below). Sensitive windows of susceptibility can still permit development of disease, with less intensity and severity, compared with those occurring in a critical window. Critical and sensitive windows occur during times of rapid development and cellular differentiation and proliferation such as those that occur during gametogenesis, embryogenesis, implantation, pregnancy, infancy, childhood, puberty, and lactation.

In the 1960s, the drug thalidomide was given to pregnant women to prevent morning sickness. While women who took the drug did not experience ill health effects, their children experienced a high rate of congenital limb and gastrointestinal malformations, particularly when their mother took the drug during the period of the 28th through the 42nd day after conception, which is the critical period of limb development. More than 10,000 children in 46 countries that approved the drug were born with deformities as a consequence of their mothers being prescribed the drug during pregnancy.

Intergenerational Harm Can Result From In Utero Exposure to Exogenous Chemicals: Diethylstilbestrol

Environmental chemical exposures can affect first generation (F0 [parental]) and second generation (F1 [offspring] and F2, germ cells of offspring) ( Fig. 20.1 ). To determine whether alterations are transmitted transgenerationally, the F3 generation (without direct exposure to the insult) must be studied.

Adverse health impacts of in utero exposure to environmental chemicals may appear at birth, such as with methyl mercury and severe neurologic effects (see below), and may also be delayed and/or manifest in future generations. The latter outcome is exemplified by the pharmaceutical diethylstilbestrol (DES), an estrogen that was prescribed in up to 10 million pregnancies from 1938 to 1971 with the intent to prevent miscarriage (though it was later proved ineffective for this) with no immediate adverse health impacts observed in the mother or newborn. Reproductive tract abnormalities began to emerge at puberty in the daughters and sons of DES-exposed women and continued to emerge 40 years after the index pregnancies and long after its use ended. ^, Delayed health impacts of in utero exposure to DES in adult women include clear cell adenocarcinoma of the vagina and cervix, structural reproductive tract anomalies, infertility, irregular menses, amenorrhea, poor pregnancy outcomes, and breast cancer. Hypospadias and cryptorchidism have been reported among sons and grandsons of women and men exposed to DES in utero . This is a remarkable example of transgenerational inheritance, and mechanisms specifically underlying this process strongly endorse the involvement of the epigenome (see below).

The Placenta Does Not Protect the Fetus From Damaging Environmental Chemicals: Methyl Mercury

Environmental chemicals can cross the placenta, and in some cases, such as with methyl mercury, they can bioaccumulate such that the fetal exposure is higher than maternal exposure. ^{, ,} In the 1950s, waste discharge from a chemical factory in Japan polluted Minamata Bay, a primary source of food for the local population. Pregnant women who consumed contaminated fish and shellfish from the Bay were exposed to methyl mercury and subsequently gave birth to children with severe neurologic deficits, comprising a syndrome named Minamata disease. This tragedy established that the placenta does not protect the fetus from exposure to exogenous chemicals. Subsequent research has documented that developmental and cognitive effects can occur in children exposed prenatally to mercury even at low doses that do not result in effects in the mother and that the adverse neurologic effects of methyl mercury exposure may also be delayed. This may also be seen with other chemicals affecting neurodevelopment.

Synthetic Chemicals and Heavy Metals Are Ubiquitous in the Environment

Chemicals in the environment are manufactured for various uses (e.g., synthetic chemicals for consumer and industrial applications). They are also by-products of industrial and human activity and are released through land activities such as mining and fracking (e.g., heavy metals such as lead and mercury). There are over 350,000 chemicals and chemical mixtures registered for production and use worldwide, and thousands of high production volume chemicals in widespread use in the US leading to widespread pollution. ^, In the United States alone, chemicals in commerce increased more than 15-fold over the past 70 years ; in 2012, 9.5 trillion pounds of industrial chemicals were domestically manufactured and imported into the United States, which is the equivalent of 30,000 pounds for every US resident. The vast majority of chemicals in commerce have not been fully tested for reproductive, developmental, or other health effects. ^{, ,} Most chemicals and mixtures have unregulated production and disposal and lack formal data-reporting processes, and there are wide differences across regions and countries. Moreover, of the 350,000 chemicals registered for production and use globally, about 50,000 are publicly unknown (“confidential”) and ∼70,000 are “ambiguously described.”

The thousands of high-volume chemicals in commerce are ubiquitous in the environment, which poses a major challenge to establishing health impacts and implementing effective interventions. They enter humans through ingestion, inhalation, and dermal absorption. The National Health and Nutrition Examination Survey (NHANES) data have demonstrated levels of multiple chemicals measured in urine or blood in up to 100% of the US population. Presented below are classes of chemicals and metals illustrative of the most widespread environmental chemical toxicants. Contaminants specifically in pregnant women are considered in the following section below. Table 20.1 presents where these chemicals and other common chemicals are found and specific health outcomes associated with exposure.

• Persistent organic pollutants (POPs): POPs are chemicals that, due to their physical structure, do not break down easily in the environment and can biomagnify up the food chain, leading to long-term and widespread exposures. These include chemicals such as polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and per- and polyfluoroalkyl substances (PFAS). While certain POPs such as the pesticide dichlorodiphenyl-trichloro-ethane (DDT), its metabolite dichlorodiphenyldichloroethylene (DDE), and PCBs have been banned in the United States for decades, they are still found in virtually the entire population due to their ubiquitous presence in the environment, long half-life, and lipid solubility. Over 90% of the population in the US has detectable levels of pesticides and their metabolites in urine or serum. Most PBDEs in the US have been replaced by alternative flame retardants. However, because these chemicals are lipophilic, they persist in adipose tissue with a half-life of a few months to 12 years. ^,

• Pseudo-persistent compounds: These compounds have short half-lives in the human body but because exposures are frequent, they are found in most human samples. Examples include phthalates, polycyclic aromatic hydrocarbons (PAHs), bisphenol A (BPA), and perchlorate. ^, Detectable levels of BPA in urine are found in 93% of the US population, ^, and several phthalate metabolites are detectable in serum of > 95% of the US adult population.

• Metals: Metals commonly found in the environment include mercury, arsenic, cadmium, and lead. Due to public policy initiatives that removed lead from gasoline, paint, food cans, and other products, blood levels of lead have dropped precipitously in the United States. However, the 2015 discovery of lead in Flint, Michigan’s drinking water reveals that there remain populations within the United States with high blood lead levels, which are often caused by exposure to lead-contaminated paint and lead in water pipes. ^, Cadmium derives from industrial sources and can also enter the food chain through soil absorption of leaking sewage. Moreover, smokers are exposed to cadmium through tobacco smoke and nonsmokers through second-hand smoke. The half-life of cadmium is 10 to 30 years, and there is no efficient way to recycle it. It accumulates in the liver, kidneys, testes, ovaries, and the placenta. ^,

Environmental Chemicals in Pregnant Women

Environmental chemicals permeate the air, water, food, and consumer products; consequently, exposure to environmental chemicals among pregnant women in the United States and around the world ^{, ,} is ubiquitous. A report by the US National Cancer Institute concluded that “to a disturbing extent babies are born ‘ prepolluted.’” In population-based surveys of pregnant women in the United States, specific PCBs, organochlorine pesticides, PFCs, phenols, PBDEs, phthalates, PAHs, and perchlorate were detected in 99% to 100% of pregnant women. Many chemicals were measured at levels similar to those encountered in epidemiologic studies that demonstrate adverse reproductive and developmental outcomes. A recent study reported characterizing the chemical exposome to industrial chemicals in matched maternal and cord blood sample pairs using a high throughput “suspect screening” and nontargeted analysis pipeline and liquid chromatography; quadrupole time-of-flight tandem mass spectrometry (LC-QTOF/MS). The results revealed 557 chemicals in maternal and/or cord blood, including 55 compounds not previously reported in the literature, opening the field to high throughput, nontargeted, simultaneous analyses of large numbers of compounds. Notably, all women and men are exposed to multiple chemicals. Exposure to multiple chemicals that impact the same health endpoint (e.g., brain development) can result in a greater risk than exposure to a single chemical alone.