M6-Lecture2

Question 1

regulate body’s growth and development
control function of various tissues
support pregnancy and other reproductive functions
regulate metabolism

Answer 1

Endocrine glands

Question 2

Endocrine disruptors are exogenous agents that interfere with hormone function, affecting homeostasis, reproduction, development, and behavior.

They can cause health issues by altering endocrine activity, and their effects are linked to epigenetic changes like DNA methylation, acetylation, and histone modifications. These disruptors vary in their characteristics and may include chemical mixtures.

Question 3

Examples:

Answer 3

Metals, pesticides, household products and materials

Solvents

Industrial ingredients

Pharmaceuticals

Question 4

Endocrine disruptors include chemicals like BPA (in plastics),

dioxins (from herbicide production),

PFAS (in firefighting foams),

phthalates (in flexible plastics),

phytoestrogens (in soy products),
PBDEs (in flame retardants),

PCBs (in electrical equipment),

and triclosan (in personal care products), all of which can interfere with hormone function.

Question 5

Endocrine disruptors are chemicals, both natural and man-made, that interfere with hormones and are linked to health issues like developmental, reproductive, brain, and immune problems. Found in everyday products like plastics, food cans, toys, and cosmetics, these chemicals can persist in the environment and may have long-term risks. While they are known to harm animals, their effects on humans are less understood, and multiple exposures make health assessments challenging.

Question 6

Endocrine disruptors - sources

Answer 6

Food production,
industrial activity
Personal and home care
Medical care

Question 7

Too much hormone disease or dysfunction
Too little hormone disease or dysfunction

Question 8

Everyday exposure to EDCs contribute to modern health epidemics.

Question 9

A dose-response curve shows how different doses of a substance affect an organism.

Monotonic curve: The effect increases or decreases consistently with dose.

Non-monotonic curve: The effect changes unpredictably, often showing a reversal (e.g., a low dose has one effect, and a higher dose has a different or opposite effect).

Question 10

Transgenerational effects example:

Answer 10

Mother exposure to EDCs (F0)

IN UTERO EXPOSURE of fetus to EDCs (F1)

Germline of the exposed F1, which will be used for the production of F2

F3 generation if the only generation that has not received direct exposure to EDCs.

However, F3 (and future generations) will not necessarily carry the effects indefinitely. The genetic and epigenetic changes in F1 and F2 may fade over several generations, depending on factors like environmental exposure, genetic repair mechanisms, and whether the effects are stable or reversible. In short, transgenerational effects can persist for some generations, but they don’t automatically continue “endlessly.”

Question 11

Critical windows of sensitivity to endocrine disruption during human female development

Answer 11

Most sensitive during the second trimester, adolescence, and adulthood, particularly affecting the secondary sexual characteristics, ovaries/oocytes, gonads, and mammary glands.
Less sensitive during the first and third trimesters.

Question 12

Endocrine disruptors can impact human health by affecting development, fertility, reproductive cancers, and other endocrine disorders:

Answer 12

Developmental impacts: male reproductive tract abnormalities

Fertility issues: infertility, and decreased semen quality.

Reproductive cancers: breast, endometrial, ovarian, prostate, and testicular cancers.

Other disorders: thyroid disease, immune dysfunction, and diabetes.

Question 13

Environmental Safety
- Emission Standards
Food Safety
- Food labelling
- Pesticides
Occupational health & safety
-PPE
- Family safety

Question 14

Four “classic” route of exposure
Inhalation
Ingestion
Injection
Absorption (dermal)
Should also add
Trans-placental
Lactation

Question 15

In the 1980s, scientists found unexpectedly high levels of PCBs in the breast milk of Inuit women in the Canadian Arctic, due to bioaccumulation from their traditional diet of marine mammals, fish, and wild game, which had higher concentrations of these chemicals compared to women in southern Québec.

Question 16

Assessment/measurements of chemicals and metabolites in human tissue compartments

Answer 16

Biomonitering

Tissue sampled may be:
Blood
Urine
Hair
Saliva

Question 17

EDCs can either stimulate or inhibit hormonal pathways: they may act as hormone receptor agonists, boost hormone production, or increase co-activators, or they can block hormone receptors, inhibit hormone synthesis, or deplete necessary enzymes and co-activators.

Answer 17

See diagram

Question 18

are chemicals used in many products, like toys, packaging, and personal care items, to make plastics flexible. Exposure during fetal development may lead to health issues in adulthood and could be passed to future generations.

Answer 18

Phthalates

Question 19

See diagram

Answer 19

Metabolites are often the active component

Question 20

Phthalates are reproductive toxicants shown to cause issues like testicular atrophy and developmental defects in animals. In humans, they can lead to infertility, poor semen quality, delayed pregnancy, and may affect neurodevelopment and increase cancer risk.

Question 21

A study by Carlsen et al. (1992) noted a decline in semen quality over 50 years, and recent data supports this, showing a more than 50% decline in sperm concentration in men from Western countries. Possible causes include obesity and environmental factors, particularly exposure to endocrine-disrupting chemicals (EDCs).

Question 22

Testicular Dysgenesis Syndrome

Environmental and genetic defects

Answer 22

Testicular Dysgenesis Syndrome includes conditions like cryptorchidism (undescended testicles), reduced semen quality and hypospadias. Cryptorchidism increases the risk of testicular cancer, while hypospadias is a common abnormality where the urethral opening is on the underside of the penis, affecting about 3 in 1,000 newborn boys

Question 23

Prenatal phthalate exposure in laboratory animals causes urogenital malformations, reduced anogenital distance, and infertility. In humans, it has been linked to shorter anogenital distance, shorter penile length, undescended testes, and preterm birth, but the evidence remains inconclusive.

Question 24

Diethylstilbestrol (DES) was a synthetic estrogen prescribed to pregnant women from the 1940s to the early 1970s to prevent miscarriage, but it failed to reduce complications and actually increased the risk of premature labor. It also caused long-term health issues, including reproductive problems and cancers, for those exposed to it.

Question 25

Girls whose mothers took DES during pregnancy may develop abnormalities or cancer of the uterus, vagina, or cervix after age 14. In males, while there are no cancers, DES exposure can cause genital issues like epididymal cysts, smaller testes, or changes in sperm.

Question 26

Estradiol is a naturally occurring estrogen hormone used in hormone replacement therapy to treat menopausal symptoms and hormonal imbalances.

Iso-butylparaben is a synthetic preservative used in cosmetics and personal care products, with potential endocrine-disrupting effects.

Question 27

DES inhibits Hoxa10 expression, regulated by estrogen receptors.

In males, Hoxa10 is crucial for testicular descent; its knockout causes infertility and cryptorchidism.
In females, Hoxa10 is important for implantation; its knockout leads to implantation failure and embryo loss.

Question 28

HOXA9: Affects the fallopian tubes.
HOXA10: Affects the uterus.
HOXA11: Affects the cervix.
HOXA13: Affects the vagina.
These genes regulate the development of structures derived from the paramesonephric duct (Müllerian duct) in females.

Question 29

Wnt7a and Wnt5a regulate cell proliferation, while DES, HOXA10, and HOXA11 influence cell specification. Together, these factors control the development of glandular tissue and smooth muscle, which can result in normal or improper tissue formation.

Question 30

Women who took DES during pregnancy have an increased risk of breast cancer—about 1 in 6 will develop it, compared to 1 in 8 in the general population. Cancer risks may take 20-40 years post-exposure to appear. Animal studies show DES exposure in adult mice leads to cancers in the mammary gland, ovaries, cervix, uterus, vagina, testes, and bones.

Question 31

Women exposed to DES in utero (DES daughters) have a 40x higher risk of developing clear cell adenocarcinoma (CCA) of the vagina and cervix, a rare cancer. About 1-1.5 in 1,000 DES daughters will develop CCA, typically in their late teens to early 30s, whereas CCA usually occurs after menopause in unexposed women. DES daughters also have 2x the risk of breast cancer after age 40.

Question 32

Men exposed to DES in utero (DES sons) have a higher risk of epididymal cysts and genital issues like hypospadias, cryptorchidism, or microphallus (15%-32% vs. 5%-8% in unexposed men).

Question 33

Bioaccumulates in fatty tissues of humans/ animals
Persistent in the environment,
Can travel long distances in the upper atmosphere.
Classified as ‘probably carcinogenic’ to humans

Answer 33

DDT (pesticide), banned

Question 34

DDT is still used in some developing countries

Answer 34

True

Question 35

DDT’s toxic effects

Answer 35

Death, reproductive, neurotoxin effects

Birds: eggshell thinning
Mammals:
- liver & kidney damage
- N effects
- teratogenic effects (mice)
- breast cancer in women.

Question 36

DDT conc. increase up the food chain pyramid.

Question 37

is the most widely used herbicide in the U.S. and is effective and inexpensive, but Tyrone Hayes discovered it disrupts hormones. Exposure to low doses caused male frogs to develop both male and female sexual organs. As a result, the European Union banned atrazine in 2003.

Question 38

Atrazine

Answer 38

Endocrine disruptor

Suspected carcinogen

Reproductive toxicity

Question 39

aromatase is an enzyme that converts testosterone into estradiol, a form of estrogen. Atrazine can affect aromatase activity, potentially increasing estrogen levels and disrupting hormonal balance.

Question 40

Plastic water bottles can pose problems for mice studies due to potential contamination from chemicals like bisphenol A BPA (a plasticizer) leaching into the water, affecting the mice’s health. Mouse environment, food, and water quality, along with mouse strain and possible infections, can all influence the validity of experimental results.

Question 41

BPA is a widely used chemical, binding to estrogen receptors (ER-α and ER-β). Humans are exposed to it through inhalation, ingestion (plastics, can linings), and skin contact (thermal receipts). In lab animals, BPA causes reproductive toxicity, including ovulatory defects, impaired embryo development, decreased semen quality, and infertility, also brain.

Question 42

BPA can bind to nuclear, cytoplasmic, and membrane-bound estrogen receptors (ERs), as well as GPR30 receptors, stimulating mammary cell proliferation. This activation of ERs can lead to tumor growth and tumorigenesis.

Question 43

Maternal exposure to endocrine disruptors can alter gene expression in offspring, leading to ectopic (misplaced) gene expression or changes in normal gene patterns (like IAP, Ivy, or pseudo-agouti).

Under normal conditions, offspring show yellow or mottled fur.

When methyl donors are added, it affects DNA methylation, causing changes in coat color, often resulting in pseudo-agouti or heavily mottled offspring, indicating altered developmental gene regulation.

Answer 43

See diagram

Question 44

Researchers fed pregnant yellow mice a methyl-rich diet, resulting in brown pups with healthy lifespans due to normal Agouti gene methylation.

BPA reduces DNA methylation of the Agouti gene, but when combined with a methyl-rich diet, normal methylation is restored. BPA also inhibits the expression of DNA methyltransferases (DNMTs), which are essential for epigenetic regulation.

Answer 44

Agouti gene (determines coat color)

Question 45

2008, Canada first nation to ban BPA, or toxic

Answer 45

BPA was leaching out of bottles and baby bottles.

Question 46

BPA-free does not mean estrogen-free as, most products labeled BPA-free still have estrogenic activity.

BPA-consumer products represent only one source of BPA exposure.

Question 47

EDCs are linked to health issues like autism, ADHD, delayed puberty, early menarche (e.g., from DES), and obesity. Prenatal exposure to chemicals like PCBs, phthalates, and heavy metals is associated with higher BMI and obesity later in life.

Question 48

Obesogens are chemicals that can disrupt the body’s hormonal system and promote obesity by influencing fat storage, metabolism, and appetite regulation.

Sources:

Answer 48

Bisphenols
Pthalates
Parabens
Non-steriod estrogens
Brominated flame retardants
Polychorinated biphenyls
Oragnotins

Question 49

Obesogens mechanisms:

Answer 49

Epigenetic mechanisms
Activation of homodimers or heterodimers
Activation of PPARy
Interference with hormone or other signalling pathways
Alter gut microbiome composition
Alter chromatin architecture

See more on the effects/outcomes

Question 50

Fetal growth is influenced by endocrine factors, and exposure to EDCs like BPA and PCBs in the placenta can lead to growth restriction, thyroid issues, and neurological disorders. Prenatal exposure may cause epigenetic changes, increasing the risk of chronic diseases later in life.

Question 51

EDC exposure can cause harm to the individual and be passed to future generations through transgenerational inheritance, primarily affecting the HPT, HPG, and HPA axes.