4.5 Endocrine disruption

The endocrine system is a complex network of glands and hormones that regulate vital bodily functions. Endocrine disrupting chemicals (EDCs) are substances that interfere with this delicate system, potentially causing adverse health effects.

EDCs can mimic or block natural hormones, alter hormone synthesis, and disrupt feedback loops. They come from various sources like industrial chemicals, pesticides, and consumer products. Understanding EDCs is crucial for assessing their impact on human health and the environment.

Endocrine system overview

• The endocrine system consists of glands that secrete hormones directly into the bloodstream to regulate various physiological processes throughout the body
• Endocrine glands include the pituitary, thyroid, parathyroid, adrenal, pancreas, and reproductive organs (ovaries and testes)
• Hormones act as chemical messengers that bind to specific receptors on target cells to elicit responses

Major endocrine glands

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• The pituitary gland, located at the base of the brain, is often referred to as the "master gland" as it controls the functions of other endocrine glands
• The thyroid gland secretes thyroxine (T4) and triiodothyronine (T3) which regulate metabolism, growth, and development
• The adrenal glands, situated above the kidneys, produce hormones such as cortisol (stress response), aldosterone (blood pressure regulation), and androgens (male sex characteristics)
• The pancreas secretes insulin and glucagon to regulate blood sugar levels
• The ovaries in females produce estrogens and progesterone, while the testes in males produce testosterone, all of which are essential for reproductive function and development

Hormones and signaling pathways

• Hormones can be classified into three main categories: peptide/protein hormones (insulin), steroid hormones (estrogen), and amino acid derivatives (thyroid hormones)
• Peptide and protein hormones typically bind to cell surface receptors, triggering intracellular signaling cascades that lead to changes in gene expression or cellular function
• Steroid hormones and thyroid hormones can diffuse through the cell membrane and bind to intracellular receptors, forming hormone-receptor complexes that directly interact with DNA to regulate gene transcription
• Signal transduction pathways, such as the cAMP pathway or the phosphoinositide pathway, amplify and propagate the hormonal signal within the cell

Feedback loops and regulation

• Endocrine systems are often regulated by negative feedback loops to maintain homeostasis
• In a negative feedback loop, the end product of a pathway inhibits its own production by suppressing the release of stimulatory hormones from the pituitary or hypothalamus
• For example, high levels of thyroid hormones in the blood inhibit the release of thyroid-stimulating hormone (TSH) from the pituitary, which in turn reduces the production of thyroid hormones by the thyroid gland
• Positive feedback loops also exist, such as the surge in luteinizing hormone (LH) during ovulation, which further stimulates the release of estrogen from the ovaries
• Feedback loops ensure that hormone levels remain within a narrow range to prevent over- or under-stimulation of target tissues

Endocrine disrupting chemicals (EDCs)

Definition and characteristics of EDCs

• Endocrine disrupting chemicals (EDCs) are exogenous substances that interfere with the normal functioning of the endocrine system
• EDCs can mimic, block, or alter the synthesis, metabolism, or transport of natural hormones, leading to adverse health effects
• These chemicals are often persistent in the environment, bioaccumulate in living organisms, and can have effects at very low doses

Classes of EDCs

• EDCs can be classified based on their chemical structure or their source
• Common classes of EDCs include:
  1. Synthetic hormones (ethinyl estradiol in birth control pills)
  2. Industrial chemicals (polychlorinated biphenyls, dioxins)
  3. Pesticides and herbicides (atrazine, DDT)
  4. Plasticizers (phthalates, bisphenol A)
  5. Flame retardants (polybrominated diphenyl ethers)
• Some naturally occurring compounds, such as phytoestrogens found in plants (genistein in soybeans), can also act as EDCs

Sources and routes of exposure

• EDCs can be found in various consumer products, including food packaging, cosmetics, pesticides, and cleaning agents
• Exposure to EDCs can occur through ingestion of contaminated food or water, inhalation of polluted air, or dermal absorption from personal care products
• The developing fetus can be exposed to EDCs through placental transfer, while infants can be exposed through breastfeeding or ingestion of contaminated formula
• Occupational exposure to EDCs is a concern for workers in industries such as agriculture, manufacturing, and waste management

Mechanisms of endocrine disruption

Hormone mimicry and agonism

• Some EDCs can mimic the structure of natural hormones and bind to their receptors, activating the same signaling pathways as the endogenous hormone
• These EDCs are called hormone agonists, as they stimulate the receptor and elicit a biological response
• For example, bisphenol A (BPA) can bind to estrogen receptors and mimic the effects of estrogen in the body, potentially leading to reproductive disorders or cancer

Hormone antagonism and blockade

• Other EDCs can bind to hormone receptors without activating them, preventing the natural hormone from binding and eliciting its normal response
• These EDCs are known as hormone antagonists, as they block the action of the endogenous hormone
• An example of a hormone antagonist is the fungicide vinclozolin, which binds to androgen receptors and inhibits the action of testosterone, leading to feminization of male offspring in exposed animals

Interference with hormone synthesis

• EDCs can disrupt the endocrine system by interfering with the synthesis of natural hormones
• Some EDCs can inhibit the enzymes involved in hormone production, leading to decreased levels of the hormone in the body
• For instance, the herbicide atrazine can inhibit the enzyme aromatase, which converts testosterone to estrogen, resulting in reduced estrogen levels and potential reproductive problems

Alteration of hormone metabolism

• EDCs can also alter the metabolism and elimination of natural hormones, leading to changes in their circulating levels or duration of action
• Certain EDCs can induce or inhibit the liver enzymes responsible for hormone metabolism, such as cytochrome P450 enzymes
• The pesticide DDT and its metabolite DDE can inhibit the enzyme 11β-hydroxysteroid dehydrogenase type 2, which normally inactivates cortisol, leading to increased cortisol levels and potential metabolic disorders

Disruption of feedback loops

• EDCs can interfere with the normal feedback loops that regulate hormone production and secretion
• By disrupting the balance between hormone levels and the signals sent to the hypothalamus and pituitary gland, EDCs can cause over- or under-production of hormones
• For example, the industrial chemical PCB-153 can inhibit the negative feedback of thyroid hormones on the hypothalamus and pituitary, leading to continual stimulation of the thyroid gland and potentially causing thyroid disorders

Health effects of EDCs

Reproductive system disorders

• EDCs can cause a range of reproductive disorders in both males and females
• In males, exposure to EDCs has been linked to decreased sperm count and quality, testicular cancer, and reproductive tract abnormalities (hypospadias, cryptorchidism)
• In females, EDCs can lead to ovarian dysfunction, polycystic ovary syndrome (PCOS), endometriosis, and uterine fibroids
• EDCs can also contribute to infertility and adverse pregnancy outcomes, such as preterm birth and low birth weight

Developmental and birth defects

• Exposure to EDCs during critical windows of development, such as in utero or during early childhood, can result in birth defects and developmental disorders
• EDCs can interfere with the normal hormonal signaling that guides embryonic and fetal development, leading to structural and functional abnormalities
• Examples of developmental effects associated with EDC exposure include neural tube defects, cleft palate, and altered brain development
• The synthetic estrogen diethylstilbestrol (DES), prescribed to pregnant women in the past, caused reproductive tract abnormalities and increased cancer risk in their offspring

Neurological and behavioral changes

• EDCs can impact the development and function of the nervous system, leading to neurological and behavioral changes
• Exposure to EDCs during brain development has been associated with cognitive deficits, learning disabilities, and attention deficit hyperactivity disorder (ADHD)
• Some EDCs, such as polybrominated diphenyl ethers (PBDEs) used as flame retardants, can interfere with thyroid hormone signaling, which is crucial for proper brain development
• Prenatal exposure to phthalates, found in plastics and personal care products, has been linked to lower IQ scores and behavioral problems in children

Metabolic syndrome and obesity

• EDCs have been implicated in the development of metabolic disorders, such as obesity, insulin resistance, and type 2 diabetes
• These chemicals can interfere with the hormonal regulation of metabolism, appetite, and fat storage
• Some EDCs, known as "obesogens," can promote adipogenesis (the formation of fat cells) and increase the risk of obesity
• Bisphenol A (BPA) and some phthalates have been associated with increased body weight, insulin resistance, and altered glucose metabolism in animal studies and human epidemiological research

Cancer risk and progression

• Exposure to EDCs has been linked to an increased risk of certain types of cancer, particularly hormone-sensitive cancers such as breast, prostate, and thyroid cancer
• EDCs can promote cancer development by stimulating cell proliferation, inhibiting apoptosis (programmed cell death), or altering gene expression
• Some EDCs, like BPA and certain pesticides, can act as estrogen mimics and stimulate the growth of estrogen-responsive tumors
• Dioxins and PCBs have been classified as human carcinogens by the International Agency for Research on Cancer (IARC) due to their ability to promote tumor formation in various tissues

Specific EDCs and their effects

Bisphenol A (BPA)

• BPA is a synthetic compound widely used in the production of polycarbonate plastics and epoxy resins, found in food and beverage containers, thermal paper receipts, and dental sealants
• BPA can leach from these products and enter the human body through ingestion, inhalation, or dermal absorption
• As an endocrine disruptor, BPA can mimic estrogen and interfere with normal hormonal signaling
• Exposure to BPA has been associated with a range of health effects, including reproductive disorders, developmental problems, metabolic dysfunction, and increased cancer risk

Phthalates

• Phthalates are a group of chemicals used as plasticizers to increase the flexibility and durability of various consumer products, such as toys, cosmetics, and food packaging
• These compounds can easily leach from products and enter the human body through ingestion, inhalation, or dermal absorption
• Phthalates can interfere with the production and function of androgens (male hormones), leading to reproductive and developmental disorders
• Exposure to phthalates has been linked to decreased sperm quality, reproductive tract abnormalities, and neurodevelopmental problems in children

Polychlorinated biphenyls (PCBs)

• PCBs are synthetic organic chemicals that were widely used in electrical equipment, hydraulic fluids, and plasticizers until their production was banned in the 1970s
• Despite the ban, PCBs persist in the environment and can bioaccumulate in the food chain, leading to human exposure through contaminated fish, meat, and dairy products
• PCBs can interfere with thyroid hormone signaling, leading to developmental and neurological problems
• Exposure to PCBs has also been associated with increased risk of certain cancers, such as breast and liver cancer

Dioxins and furans

• Dioxins and furans are highly toxic, persistent organic pollutants that are formed as byproducts of industrial processes, such as waste incineration and pesticide manufacturing
• These compounds can enter the human body through ingestion of contaminated food, particularly animal fats, as well as through inhalation and dermal absorption
• Dioxins and furans can interfere with the aryl hydrocarbon receptor (AhR), a transcription factor involved in the regulation of various biological processes, including hormone signaling and cell growth
• Exposure to dioxins and furans has been linked to a range of health effects, including developmental and reproductive disorders, immune system dysfunction, and increased cancer risk

Pesticides and herbicides

• Pesticides and herbicides are chemicals used to control insects, weeds, and other pests in agriculture and landscaping
• Many of these compounds can act as endocrine disruptors, interfering with the normal function of hormones in the body
• Examples of endocrine-disrupting pesticides include DDT, atrazine, and glyphosate
• Exposure to these chemicals has been associated with various health effects, such as reproductive disorders, developmental problems, neurological issues, and increased cancer risk
• Agricultural workers and people living in rural areas near farms may be at higher risk of exposure to these EDCs

Assessing EDC toxicity

In vitro and in vivo testing methods

• In vitro methods involve testing the effects of EDCs on isolated cells, tissues, or biochemical pathways in a laboratory setting
• These methods can provide valuable information on the mechanisms of action and potential toxicity of EDCs
• Examples of in vitro assays include receptor binding assays, gene expression analysis, and cell proliferation or apoptosis assays
• In vivo methods involve testing the effects of EDCs on whole organisms, typically using animal models such as rodents or fish
• These studies can provide information on the systemic effects of EDCs, including developmental, reproductive, and neurological outcomes
• In vivo studies are crucial for understanding the complex interactions between EDCs and the endocrine system in a living organism

Dose-response relationships

• Dose-response relationships describe how the magnitude of an effect changes with increasing doses of an EDC
• Traditional toxicology assumes a monotonic dose-response curve, where the effect increases with increasing dose, and there is a threshold below which no adverse effects are observed
• However, many EDCs exhibit non-monotonic dose-response curves, where the effect may be greater at lower doses than at higher doses, or there may be different effects at different dose ranges
• Non-monotonic dose-response curves can make it challenging to determine safe exposure levels for EDCs and may require a reevaluation of traditional risk assessment methods

Low-dose effects and non-monotonic curves

• Many EDCs have been shown to exert effects at very low doses, often below the levels considered safe by regulatory agencies
• These low-dose effects can be particularly concerning because they may occur at environmentally relevant concentrations and can impact sensitive populations, such as developing fetuses or infants
• Non-monotonic dose-response curves, where the effect does not follow a linear pattern with increasing dose, are common for EDCs
• Examples of non-monotonic dose-response curves include U-shaped curves, where the effect is greater at low and high doses than at intermediate doses, and inverted U-shaped curves, where the effect is greatest at intermediate doses
• The mechanisms underlying non-monotonic dose-response curves are not fully understood but may involve multiple receptors, feedback loops, or competing pathways

Mixtures and cocktail effects

• In real-world scenarios, humans are exposed to a complex mixture of EDCs, rather than single chemicals
• The combined effects of multiple EDCs, known as mixture or cocktail effects, can be additive, synergistic (greater than additive), or antagonistic (less than additive)
• Assessing the toxicity of EDC mixtures is challenging because the interactions between chemicals can be difficult to predict based on their individual effects
• Some studies have shown that mixtures of EDCs can produce significant effects even when each individual chemical is present at levels considered safe
• Current risk assessment methods often focus on single chemicals and may underestimate the risks associated with exposure to EDC mixtures

Challenges in risk assessment

• Assessing the risks posed by EDCs is complicated by several factors, including low-dose effects, non-monotonic dose-response curves, and mixture effects
• Traditional risk assessment methods, which rely on identifying a no-observed-adverse-effect level (NOAEL) and applying safety factors, may not be appropriate for EDCs
• The long latency period between exposure and the manifestation of health effects, particularly for developmental and reproductive disorders, can make it difficult to establish causal relationships
• Interindividual variability in susceptibility to EDCs, based on factors such as age, sex, and genetic background, can further complicate risk assessment
• There is a need for novel approaches to EDC risk assessment that take into account the unique properties of these chemicals and the complexity of the endocrine system

Regulatory aspects of EDCs

Current regulations and guidelines

• Regulations and guidelines for EDCs vary across countries and regions
• In the United States, the Environmental Protection Agency (EPA) has the authority to regulate chemicals under the Toxic Substances Control Act (TSCA)
• The European Union has implemented the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) regulation, which requires manufacturers and importers to assess the risks of chemicals and manage them appropriately
• Some countries, such as Japan and South Korea, have specific regulations for endocrine-disrupting chemicals
• International organizations, such as the World Health Organization (WHO) and the Organisation for Economic Co-operation and Development (OECD), have developed guidelines and testing frameworks for assessing EDCs

Limitations and controversies

• Despite existing regulations, there are limitations and controversies surrounding the management of EDCs
• One major challenge is the lack of standardized testing methods and criteria for identifying EDCs
• The current regulatory framework often relies on a chemical-by-chemical approach, which may not adequately address the cumulative effects of EDC mixtures
• There are debates about the appropriate level of evidence required to regulate ED