PHAR 303 Lecture 18 Endocrine

the endocrine system

-any tissue that secretes a molecule that circulates in the blood and is meant to act at a distant site is considered an endocrine tissue

-endocrine system has targets all over the body

anterior pituitary

Anterior Pituitary (Master Gland)

• Master gland and central coordinator

• Receives input from the brain and feedback from circulation

• Hormones produced by the anterior pituitary enter the central circulation

• Target other tissues, which then produce their own hormones

Anterior Pituitary Hormones

• TSH → acts on the thyroid → stimulates production of T3 and T4

• LH and FSH → act on the ovaries/testes

  • Stimulate production of progesterone, testosterone, and estradiol

• Prolactin → acts on the ovaries/testes

main steroidal glands and the hypothalamus

• Ovaries, testes, and adrenal glands are the 3 main steroidal glands in the body.

• The hypothalamus (HT) releases:

  • GnRH

  • TRH

  • CRH

• These hormones travel through the portal circulation to the anterior pituitary.

Hypothalamic Hormones

• TRH → stimulates TSH release from the anterior pituitary.

• GnRH → stimulates LH and FSH release from the anterior pituitary.

• CRH → stimulates ACTH release from the anterior pituitary.

• Dopamine → suppresses prolactin release.

• TRH, GnRH, and CRH are positive stimulators of anterior pituitary hormone release.

• If hypothalamic input is removed, only prolactin is secreted because dopamine normally inhibits its release.

regulation in the endocrine sys

• Small molecules/steroids produced by tissues can feed back to the:

  • Anterior pituitary

  • Hypothalamus (HT)

• This feedback makes the endocrine system sensitive to exogenous factors.

• Endocrine disruptors often interfere with these regulatory mechanisms.

Negative Feedback

• The primary driver of endocrine regulation is negative feedback.

Hypothalamic Regulation of the Anterior Pituitary

• Almost all peptide hormones released by the anterior pituitary are under positive regulation by the hypothalamus.

• Prolactin is the exception:

  • It is primarily under inhibitory control by dopamine from the hypothalamus.

(-) feedback ex//

• LH stimulates production of testosterone and estradiol.

• Increased testosterone and estradiol raise their blood concentrations.

• High concentrations of testosterone and estradiol exert negative feedback on the anterior pituitary.

• Negative feedback decreases LH production.

• When testosterone and estradiol levels decrease, the anterior pituitary produces more LH.

steroid pyramid

• Refers to the concentrations of different steroid hormones.

• Cholesterol acts as the precursor for steroid hormones.

• Cholesterol is present in all cell types.

Relative Steroid Concentrations

• 10⁻³: Progestins

  • Includes progesterone and pregnenolone.

• 10⁻⁸: Androgens

  • Precursors for testosterone and DHEA.

• 10⁻⁹: Testosterone.

• 10⁻¹¹: Estrogens.

Key Point

• Estrogen receptors are particularly sensitive.

• Because estrogens are present at very low concentrations, low concentrations of toxins are more likely to affect estrogen signaling.

endocrine disrupting chemicals

WHO Definition of an Endocrine Disruptor

• An endocrine disruptor is an exogenous substance or mixture that alters the function of the endocrine system.

• Consequently causes adverse health effects in:

  • An organism, or its progeny

historical perspective

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ECDs in everyday environments

Endocrine Disruptors (EDCs)

• Infants and pregnant women are the most vulnerable.

• Effects are most striking when exposure occurs:

  • Late in gestation.

  • Early in postnatal life.

Common Household EDCs

• PAHs

• Bisphenol A (BPA)

• Plasticizers

• Cleaning products

• Air particulates

• Ozone

• Flame retardants

• Metals

• Microplastics

• Pharmaceuticals containing phthalates

• Pesticides

mechanism of action of endocrine disruptors

Mechanisms of Endocrine Disruptors

• Mimic natural hormones and act as agonists.

• Block natural hormones and act as antagonists.

• Directly stimulate or inhibit the endocrine system.

• Cause overproduction or underproduction of hormones.

where prominent effects of ECDs are seen

Effects of Endocrine Disruptors (EDCs)

• Can affect:

  • Obesity

  • Fertility

  • Thyroid

  • Immune system

  • Brain development and function

  • Embryo and child development

Reproductive Effects

• EDCs can alter:

  • Composition of sperm

  • Gametes

  • Embryo and fetal development

Long-Term Effects

• Individuals exposed to EDCs may not see effects until adulthood.

developmental origins of health and disease DOHaD

Developmental Origins of Disease

• Evidence suggests that the roots of many diseases and dysfunctions occur early in life:

  • Embryo

  • Fetus

  • Infant

  • Child

Early Life Influences

• Parental nutrition can influence the likelihood of children developing metabolic disorders later in life.

  • Overnutrition or undernutrition in parents can affect offspring health.

Endocrine Disruptor Vulnerability

• The CNS and endocrine systems are vulnerable to disruption.

• Even low doses of endocrine-disrupting chemicals (EDCs) can cause effects.

ideating study

Developmental Effects of Endocrine Disruptors (EDCs)

• Studies based on food intake during WWII showed that:

  • Towns where mothers experienced starvation had children with altered metabolism.

  • These children had increased risk of:

    • Cardiovascular disease

    • Diabetes

    • Obesity

    • Breast cancer

    • Prostate cancer

Parental Effects on Offspring

• Obesity in fathers can increase the risk of:

  • Obesity in children

  • Cardiovascular disease in children

• Differences were thought to be due to exposure to endocrine disruptors.

• EDCs can modify epigenetic marks, causing changes that may appear later in adulthood.

Epigenetic Effects of EDCs

• EDCs can modify:

  • DNA methylation

  • Histone coding

  • Non-coding RNA

• These changes can disrupt normal gene regulation.

• Effects can be transmitted across generations (transgenerational effects), potentially up to the F4 generation.

flame retard - brominated

lame Retardants and Endocrine Disruptors

• Used to prevent fire hazards in:

  • Laptops

  • Clothing

Polybrominated Biphenyls (PBBs)

• Used as flame retardants.

• Removed from the market in the 2000s because they were toxic.

Polybrominated Diphenyl Ethers (PBDEs)

• Introduced as substitutes for PBBs.

• Later banned due to toxicity concerns.

Tetrabromobisphenol A (TBBPA)

• One of the most commonly used brominated flame retardants (BFRs).

• Use increased after the PBDE ban.

Replacement Problem

• When a flame retardant is banned, industry often creates a chemically similar replacement.

• New replacements do not always need to prove safety before use.

• This can lead to continued exposure to potentially harmful chemicals.

organophosphate flame retardants

Flame Retardants / Plasticizers

• Act as both:

  • Flame retardants

  • Plasticizers

Sources of Exposure

• Found in:

  • Furniture

  • Plastics

• Humans are highly exposed.

• Detected in:

  • Blood

  • Urine

  • Hair

Toxic Effects

• Neurotoxicity

• Thyroid toxicity

• Liver effects

• Adrenal effects

• Effects on:

  • Fat tissue

  • Bone

  • Reproductive system

• Developmental toxicity

Exposure Levels

• High levels can be found in homes.

2 types of OPEs and high-content imagining

Flame Retardant Types

1. Triaryl-containing

• Contains 3 aromatic rings.

• Lipophilic → better absorbed into cells.

2. Non-aryl-containing

• Does not contain aromatic rings.

Testing Methods

• High-content imaging:

  • Uses 96-well plates.

  • Different organelles can be examined using fluorescent markers.

  • Allows analysis of cellular changes after exposure.

Benchmark Dose Analysis (BMC10)

• BMC10 = Benchmark Concentration causing a 10% biological response.

• Used to determine what happens at a 10% effect level or lower.

• Requires calculating a dose-response curve.

• Computer programs fit the collected data to determine the dose-response relationship.

Cellular Effects Observed

• Some compounds show no effects on cellular endpoints.

• Others cause: TMPP

  • Decreased cell counts

  • Increased lysosomes

  • Increased reactive oxygen species (ROS)

  • Lipid changes

phthalates overview & effect on male reproductive system

lasticizers:

• Added to plastics to make them pliable/flexible.

DEHP:

• Most widely used plasticizer.

• Accounts for 79% of worldwide plasticizer consumption.

Male reproductive system effects:

• Changes serum levels of:

  • LH

  • FSH

  • Estradiol

  • Testosterone

Developmental effects:

• Reduced anogenital distance in males.

• Anogenital distance is directly correlated with the androgen:estrogen ratio during gestation.

• More androgen blockade during gestation → shorter anogenital distance.

Reproductive abnormalities:

• Hypospadias:

  • Urethra develops on the shaft instead of the tip.

• Cryptorchidism:

  • Testes fail to descend properly.

  • Blocks sperm production and meiosis because sperm production requires lower temperatures.

Sperm effects:

• Reduced sperm count.

• Reduced sperm production.

• Reduced sperm motility.

phthalates on female reproductive system and M/F endpoints

Female reproductive effects:

• Affects follicle development.

• Reduces oocyte quality.

• Can cause earlier menopause.

Other male/female endpoints:

• Affects adrenal steroid production.

• Increases asthma incidence.

• Associated with higher rates of liver cancer.

• Causes neurobehavioral developmental effects in the CNS (especially in children).

Adverse outcome pathway for phthalate syndrome *APO

Mechanism:

• Not fully known.

• Likely not a single mechanism of action.

• Has multiple molecular targets.

Effects analysis:

• Can examine effects at:

  • Cellular level

  • Tissue level

  • Whole organism level

• This approach helps identify what is known and what is unknown.

APOs:

• About both:

  • The chemical

  • The endpointt

bisphenol A im so gay

Sources of BPA exposure:

• Found in:

  • Baby bottles

  • Teething rings

  • Dental fillings

BPA study findings:

• Washington researcher found control animals had higher levels of aneuploidy than animals treated with the chemical.

• Difference between Washington and Ohio studies:

  • Washington used supplies containing BPA.

  • BPA exposure affected the control animals.

BPA effects:

• Abnormal kidney growth.

• Prostatic hyperplasia.

• Prostate inflammation.

• Decreased sperm count.

• Effects on breast cancer cells.

endpoints of BPA exposure and ban

-major effects occurred on CV system. diabetes, obesity (not fertility and cancer as much)

-canada was 1st to ban BPA in bby products

-USA has only banned in baby bottles not other products

BPA mechanism of action

• Interacts with four estrogen receptor subtypes.

• ERRγ (estrogen-related receptor γ)

  • Strongly activated by BPA.

  • BPA binds ERRγ with greater affinity than estradiol.

• Estrogen-related receptors (ERRs)

  • Can dimerize with ERα and ERβ.

  • Prevent ERα and ERβ from functioning as transcription factors by blocking their translocation to the nucleus.

• ERα

  • BPA is a poor agonist.

• ERβ

  • BPA has a higher affinity than for ERα.

• Dose-response

  • BPA interacts differently with multiple estrogen receptor subtypes depending on the dose.

  • Each receptor individually exhibits a monotonic dose-response.

  • The combined response of all receptor subtypes is nonmonotonic, because receptor activation changes with BPA concentration

BPA continued industry

• BPA has biological effects even at low doses.

• Canada

  • Created a list of BPA alternatives.

  • Many alternatives are not necessarily safer than BPA.

• Europe

  • Designated BPS (bisphenol S), a common BPA replacement, as a chemical of concern.

• Many foods contain BPS.

• Many plastics previously containing BPA are now labeled "BPA-free" or "BPA- and BPS-free", but may still contain other bisphenols.

• When tested in cell lines, many BPA alternatives were found to be more cytotoxic than BPA.

• BPA alternatives also affected steroid hormone secretion by:

  • Leydig cells.

subs for EDCs

• DINCH was introduced as a replacement chemical but can still be harmful.

• Not all replacement chemicals are safer than the chemicals they replace (regrettable substitution).

• A key goal for the future is to make industry responsible for identifying potential harms before chemicals are marketed.

• Design studies to screen large numbers of chemicals and eliminate those with the potential to be harmful.

history

Front:
Key dates in the history of endocrine disruptors

Back:

• 1930–1977: Widespread PCB use in transformers and cutting oils.

• 1941–1954: DES approved for use in humans and animals.

• 1942–1972: Widespread DDT use for malaria control and agriculture.

• 1959: DES found to cause cancer in experimental animals.

• 1962: Silent Spring (Rachel Carson) published → linked DDT to eggshell thinning and decline of birds of prey; led to DDT ban movement.

• 1972: EPA bans DDT; FDA warns against DES use in pregnancy.

• 1977: EPA bans PCBs.

• 1980s: Increased research on environmental estrogens.

• 1995: EPA endocrine disruptor workshop; NAS/NRC panel convenes.

• 1996: Our Stolen Future published.

• 1998: International Conference on Endocrine Disruptors (Kyoto, Japan).

• 1999: NRC publishes Hormonally Active Agents in the Environment.

• 2002: WHO Global Assessment on Endocrine Disruptors.

• 2012: WHO Endocrine Disrupting Chemicals (EDCs) statement released.

• 2015: Endocrine Society publishes position statement on endocrine disruptors.