Endocrine Disruptors: M6_L2 PDF

Endocrine disruptors  Leaning objectives 1. Understand what constitutes as endocrine disruption. 2. Understand the different mechanisms by which endocrine disruptors act on cells. 3. Know the variables which contribute to endocrine disruption. 4. Understand the impact of ea...

Endocrine disruptors  Leaning objectives 1. Understand what constitutes as endocrine disruption. 2. Understand the different mechanisms by which endocrine disruptors act on cells. 3. Know the variables which contribute to endocrine disruption. 4. Understand the impact of early exposure on the long term health outcomes of endocrine disruptors. 5. Understand the challenges with reducing exposures to potential endocrine disruptors.  What is an Endocrine disruptor ? “..exogenous agent that interferes with the synthesis, secretion, transport, binding, action or elimination of natural hormones in the body that is responsible for the maintenance of homeostasis, reproduction, development and/or behaviour" (USEPA:United States Environmental Protection Agency, 1997). "exogenous substance that causes adverse health effects in an intact organism or its progeny, subsequent to changes in endocrine function” (EC:European Commission, 1997). Difficult to define a 'typical' endocrine disrupter Range of biophysical/biochemical characteristics Chemical mixtures Indeed, epigenetic changes, such as DNA methylation and/or acetylation and histone modifications, appear to be involved in mechanisms related to endocrine disruption.  Endocrine disruptors https://www.endocrine.org/-/media/endocrine/files/patient- engagement/hormones-and- series/hormones_and_edcs_what_you_need_to_know.pdf  Examples of endocrine disruptors Bisphenol A (BPA) — used to make polycarbonate plastics and epoxy resins, which are found in many plastic products including food storage containers Dioxins — produced as a byproduct in herbicide production and paper bleaching, they are also released into the environment during waste burning and wildfires Perfluoroalkyl and Polyfluoroalkyl Substances (PFAS) — used widely in industrial applications, such as firefighting foams and non-stick pan, paper, and textile coatings Phthalates — used to make plastics more flexible, they are also found in some food packaging, cosmetics, children’s toys, and medical devices Phytoestrogens — naturally occurring substances in plants that have hormone-like activity, such as genistein and daidzein that are in soy products, like tofu or soy milk Polybrominated diphenyl ethers (PBDE) — used to make flame retardants for household products such as furniture foam and carpets Polychlorinated biphenyls (PCB) — used to make electrical equipment like transformers, and in hydraulic fluids, heat transfer fluids, lubricants, and plasticizers Triclosan — may be found in some anti-microbial and personal care products, like liquid body wash https://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm The endocrine system Endocrine organs regulate body's growth and development control function of various tissues support pregnancy and other reproductive functions regulate metabolism  Endocrine disruption hormone hormone 1. Too much hormone disease or dysfunction 2. Too little hormone disease or dysfunction https://endocrinedisruption.org/interactive-tools/fact-sheet https://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm  Endocrine disruptors Many chemicals, both natural and man-made, may mimic or interfere with the body’s hormones, known as the endocrine system These chemicals are linked with developmental, reproductive, brain, immune, and other problems. Endocrine disruptors are found in many everyday products, including some plastic bottles and containers, liners of metal food cans, detergents, flame retardants, food, toys, cosmetics, and pesticides. Some endocrine-disrupting chemicals are slow to break-down in the environment. That characteristic makes them potentially hazardous over time. Endocrine disrupting chemicals cause adverse effects in animals. But limited scientific information exists on potential health problems in humans. Because people are typically exposed to multiple endocrine disruptors at the same time, assessing public health effects is difficult. https://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm Endocrine disruptors in development Human Health impact of endocrine disruptors Development Reproductive Cancers male reproductive tract breast cancer abnormalities endometrial cancer (cryptorchidism/hypospadias) ovarian cancer precocious puberty prostate cancer spontaneous abortion testicular cancer Fertility Other Endocrine Disorders endometriosis thyroid disease infertility immune dysfunction decreased semen quality diabetes https://www.epa.gov/endocrine-disruption/what-endocrine-disruption  Exposure pathways Policy Implications Occupational Environmental Safety Exposures Air, soil, water – Emission Standards Food Safety – Food labelling – Pesticides “Take-home pathway” Occupational health & safety – personal protective Food/water Direct soil contact equipment (PPE) – Family safety Endocrine disruptors - sources Diabetologia volume 62, pages1811–1822(2019)  Routes of exposures Four “classic” route of exposure 1.Inhalation 2.Ingestion 3.Injection 4.Absorption (dermal) Should also add 5. Trans-placental 6. Lactation  Indigenous People –Environmental Research Hypothesis: people living far from urban industrial centers would have low levels of polychlorinated biphenyls (PCB) chemicals in their bodies late 1980s, in the Canadian Arctic, scientists measured the breast milk of Inuit women for the presence of environmental chemicals, particularly PCBs  PCBs levels measured in Indigenous peoples’ breast milk were the highest ever reported (Dewailly et al., 1994).  PCB concentrations in Inuit women’s breast milk 7x southern Québec women (Dewailly et al., 1993) Caused by ‘traditional diet’ nutrient rich foods such as marine mammals, fish, and terrestrial wild game, bioaccumulation (toxins build up in higher concentrations as they move up through the food web)  Human Dose Assessment Biomonitoring Assessment/measurements of chemicals and metabolites in human tissue compartments Tissues sampled may include: Blood reflect recent exposures Urine Hair: long-term exposure Saliva: non-invasive Biomonitoring has become essential in public health as it reveals the 'body burden' of chemicals in the population.  Dose response curves Dose- Response Curves Simple monotonic dose-response relationships More complex U-shaped NOAEL (No Observable Adverse Effect Level) LOAEL (Lowest Observable Adverse Effect Level) Windows of susceptibility https://www.riskcom.ca/Issues/environment/endocrine.shtml endocrine-disrupting chemicals (EDCs) https://www.sciencedirect.com/science/article/abs/pii/S1532045621000296  Mechanisms of action EDCs' effects on EDCs can disrupt hormonal pathways multiple systems simultaneously Michele A. La Merrill et al., Nature Reviews Endocrinology volume 16, pages45–57(2020) Looking at some examples  Phthalates Phthalates are a group of chemicals used in hundreds of products, such as toys, vinyl flooring and wall covering, detergents, lubricating oils, food packaging, pharmaceuticals, blood bags and tubing, and personal care products, such as nail polish, hair sprays, aftershave lotions, soaps, shampoos, perfumes and other fragrance preparations. They are used to make plastics more flexible and harder to break. They are often called plasticizers. Exposure of foetuses to such a substance may cause negative health effects when they reach adulthood. These effects could also be inherited by future generations. Phthalates Metabolites are often the active component  Phthalates – Adverse effects Phthalates are demonstrated reproductive toxicants in laboratory animals intrauterine deaths, testicular atrophy, and teratogenicity Particular effects on male offspring exposed in utero reduced anogenital distance, areola and nipple retention, undescended testes Laboratory studies, phthalate exposure produces effects on reproductive, neurodevelopment, and respiratory systems Human studies Infertility, Poor semen quality, male subfertility carcinogenic effects and influenced neurodevelopment in early life. Prolonged time to pregnancy Environmental Research 160 (2018) 239– 246  Global Semen Quality Carlsen et al. (1992) wrote that: ‘There has been a genuine decline in semen quality over the past 50 years’. Many studies examined the issue of global semen quality parameters. Recent student supports the original study meta-analysis of data collected between 1973 and 2011 finds that among men from Western countries, sperm concentration declined by more than 50%, with no evidence of a 'leveling off' in recent years Possible causes? Obesity Environmental factors, EDCs  Testicular Dysgenesis Syndrome Cryptorchidism One/both testicles fail to move into the scrotum prior to birth. Undescended testicles have an increased likelihood of developing cancer regardless of whether or not they are brought down into the scrotum. Hypospadias Opening of the urethra is on the underside, rather than at the end, of the penis. A relatively common abnormality (3 in 1,000 newborn boys). Testicular Dysgenesis Syndrome http://ourstolenfuture.com/newscience/reproduction/TDS/2001skakkebaeketal.htm  Phthalate Syndrome Laboratory animals Urogenital malformations Reduced anogenital distance infertility Humans prenatal phthalate exposure (Swan et al. 2005; 2008; Latini et al. 2003) reduced anogenital distance shorter penile length undescended testis shorter gestational age at birth Overall, weight of evidence is not conclusive for humans https://www.frontiersin.org/articles/10.3389/fpubh.2020.00366/full Dr. Ron Saulnier HSS 4102 Fall 2020  DES –Background/history DES- diethylstilbestrol One of the most potent xenoestrogens Higher ER binding affinity vs. 17-β estradiol Prescribed to pregnant women in the 1950’s to Dr. Ron Saulnier manage morning sickness HSS 4102 Fall 2020 1940-early 1970s, DES was given to ~ 2 million pregnant women in the US alone DES did not reduce the incidence of spontaneous abortion, prematurity or post-maturity. DES actually appears to enhance premature labor.  Diethylstilbestrol (DES) Diethylstilbestrol (DES), can cause abnormalities or cancer of the uterus, vagina, and cervix in girls older than 14 when the mother was exposed during the first trimester. No malignancies in males but evidence of genital lesions (epididymal cysts, hypotrophic testes) or pathologic changes in the Dr. Ron Saulnier spermatozoa. HSS 4102 Fall 2020 32 33  DES -Mechanisms of action DES inhibits Hoxa10 expression two putative ERE within the 5’ regulatory regions of the Hoxa10 gene estrogens regulate Hoxa10 through ER binding both ERα and ERβ bind the Hoxa10 ERE Homeobox-a10 (Hoxa10) Dr. Ron Saulnier participates in developmental patterning of the male and female reproductive HSS 4102 Fall 2020 systems under the regulation of estrogens. Males- development and descent of the testes Hoxa10 knockout mice are characterized by infertility and cryptorchidism. Females- endometrial decidualization Hoxa10 knockout mice exhibit significant reproductive defects including implantation failure and increased embryo resorptions. Cold Spring Harb Perspect Med. 2016 Jan; 6(1): DES -Mechanisms of action Cold Spring Harb Perspect Med. 2016 Jan; 6(1):  DES -Mechanisms of action DES Normal Wnt7a Wnt7a X X X Hoxa10, Hoxa11 Wnt5a Hoxa10, Hoxa11 Wnt5a X X Cell specification Cell proliferation Normal glandular tissue and Improper cell specialization, smooth muscle disorganized smooth muscle tissue  DES –Adverse effects- females DES Mothers Prescribed DES during pregnancy Miscarriage history prior to DES use Risk of breast cancer one in six women prescribed DES will develop breast cancer, vs one in eight women in the general population (not exposed to DES) Note, cancer models estimate cancer rates may require 20-40 y post- DES exposure to manifest Animal Studies Adult, orally-exposed mice -cancer of the mammary gland, ovary, cervix, uterus, vagina, testes, and bone  DES- Daughters DES Daughters Women exposed to DES in utero Clear cell adenocarcinoma (CCA) of the vagina and cervix which is a very rare cancer Relative risk 40x higher in DES Daughters vs. unexposed women. ~1- 1.5 in 1,000 DES Daughters will develop CCA of the vagina and/or cervix peak incidence of CCA occurs in the late teens and early 20s, some in 30s and 40s In the absence of DES exposure, CCA occurs in the postmenopausal years. DES daughters have 2x risk of breast cancer after age 40 compared to unexposed women of the same age.  DES sons DES Sons Men exposed to DES in utero Consistent evidence for increased risk for non-cancerous epididymal cysts, which are growths on the testicles 15%-32% of DES Sons experience hypospadias, cryptorchidism or microphallus vs 5%-8% of unexposed men Effects of gestational DES exposure on male urogenital development still unclear, evidence not consistent Infertility- probably no increased risk but evidence unclear  The Beginning- DDT Discovered in 1939 U.S. used in WWII Control vectors of malaria and typhus 1945 - Agricultural pesticide 1.3 billion pounds used 1959 – use declined greatly 1974 – banned 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  DDT DDT is still used in some developing countries  DDT TOXIC EFFECTS Insects Death Fish Reproductive effects Neurotoxin effects Birds Eggshell thinning Mammals Localized liver and kidney damage Neurotoxin effects Teratogenic effects (mice) Carcinogenic effects are likely – Breast cancer in women  DDT Wildlife bird populations declined bald eagle, brown pelican, peregrine falcon and osprey Eggshell thinning Mechanism- DDT metabolites p,p’- DDE inhibits Ca2+-ATPase, reduced calcium transport  reduced Ca2+ content in egg shell  Atrazine Most widely used pesticide in the United States Inexpensive and cost-effective as both an herbicide and a pesticide Commonly found in the groundwater of states that use minimal amounts of the herbicide Tyrone Hayes’ discovery of atrazine’s endocrine-disrupting properties exposure to atrazine caused male frogs to become hermaphrodites low doses of atrazine, these deformed frogs had multiple sets of both male and female sexual organs 15 European Union countries announced in October 2003 atrazine ban  Atrazine Frog larval atrazine exposure: Induced hermaphroditism and demasculinized the larynges of exposed males ~ 1ppb 10-fold decrease in testosterone levels ~ 25 ppb Demasculinized (chemically castrated) and completely feminized as adults. FB, fatbody; K, kidney; O, ovary(ies); T, testis(es). 10% genetic males developed into functional females that copulated with unexposed males and produced viable eggs. PNAS, 2002, 99( 8): 5476–5480 PNAS 2010, 107(10):4612–4617 Atrazine-Mechanism https://www.equiterre.org/sites/fichiers/backgrounder_atrazine_en.pdf  The Case of the Plastic Water Bottles Mystery: reproductive biologist noticed one day that her control mice suddenly started producing aneuploid oocytes Note: this is bad news when your control mice start having problems… time to INVESTIGATE NORMAL ABNORMAL  The Case of the Plastic Water Bottles Possible problems? Mouse environment Mouse food Mouse water Mouse strain/infection, illness  The Case of the Plastic Water Bottles Finally, Dr. Hunt identified source… the animal care facility had recently switched to a new detergent, Bisphenol A the combination of high temperature sterilization degradation of the plastic by the detergent leeching of bisphenol A (BPA) into the mouse drinking water.  The Case of the Plastic Water Bottles Like all good scientists, Dr. Hunt was methodical.. She tested the water from the bottles She exposed different mice to the water contaminated with BPA She exposed oocytes in culture to BPA added to culture media Each time… the result was oocyte aneuploidy NORMAL ABNORMAL  BPA One of the highest volume chemicals produced worldwide. xenoestrogen, weak estrogens, binds ER-α and ER-β human exposure via inhalation (dust), ingestion (plastics, can lining), dermal (thermal cash receipts) Demonstrated reproductive toxic effects in laboratory animals Ovulatory defects Impaired preimplantation embryo development Decreased semen quality, testis morphology Infertility  BPA BPA binds ERs  alterations tissues, cells, and gene expression Cell/gene changes  estrogen-target organs brain, mammary gland, ovary, and uterus etc Changes in one target organ can lead to secondary alterations in other organs Non-estrogen sensitive organs can also be dysregulated in a cascade effect  BPA-mechanism BPA can interact with nuclear estrogen receptors (ERs), cytoplasmic ERs, membrane-bound ERs and GPR30 receptors, inducing mammary epithelial cell proliferation Recall, ER activation produces proliferative effects, including tumorigenesis **note proto-oncogenes: Myc, BCl2, TGFα, VEGF (these last two are growth factors) BPA-mechanism  BPA-mechanism Researchers fed pregnant yellow mice a methyl-rich diet, most of her pups were brown and stayed healthy for life BPA  reduced methylation of Agouti gene BPA + methyl-rich foods  normal methylation of Agouti gene BPA inhibits transcription of DNA DNA methyltransferases (DNMTs) are a methyltransferase genes (DNMTs) conserved family of cytosine methylases with a key role in epigenetic regulation  BPA 2008- Canada became the first nation in the world to ban BPA in both the manufacture and importation of baby bottles 2010-Canada first jurisdiction in the world to declare the everyday plastic- making compound bisphenol A to be toxic  BPA- Green Marketing 2008- label “BPA Free” emerged large-scale government-funded studies confirmed that BPA was leaching out of bottles and baby bottles. 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.  Bisphenol A Alterations in gene expression upon chemical exposure may result in phenotypic changes that relate to the mode of action of that chemical and any associated toxicity.  Precautionary Principle “when an activity raises threats of harm to human health or the environment, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically” Central components of the principle: 1. taking preventive action in the face of uncertainty 2. shifting the burden of proof to the proponents of an activity; 3. exploring a wide range of alternatives to possibly harmful actions; 4. increasing public participation in decision making  EDCs- Childhood-Adult Onset Endpoints Neurodevelopmental disorders autism spectrum disorder (ASD) attention-deficit hyperactivity disorder (ADHD) associations between maternal environmental toxicant exposure (e.g. pesticides, phthalates, PCBs, solvents, heavy metals or other pollutants) and ASD or ADHD (Rossignol and Frye, 2012; de Cock et al., 2012) Puberty Delayed andrenarche (Ferguson et al., 2014; Grandjean et al., 2012; Humblet et al., 2011) Early menarche (DES; D’Aloiso et al., 2013) Obesity Positive associations between prenatal exposures and BMI (de Cock and van der Bor, 2014) PCBs/ DDE + maternal obesity positively associated with girls’ BMI (Tang-Péronard et al., 2014) OBELIX project- Obesogenic Endocrine disrupting chemicals: Linking prenatal exposure to the development of obesity later in life  Obesogens https://e360.yale.edu/digest/many-household-products-contain-obesity-promoting-chemicals-research-finds  Obesogen - mechanisms https://www.researchgate.net/figure/Mechanisms- of-obesogen-actions_fig2_350089269 https://blumberg-lab.bio.uci.edu/reprints/egusquiza-2020a.pdf  EDCs Key points Fetal growth largely depends on endocrine factors, and nutritional deficiency or excess determines important variations. Different EDCs were found in the placenta (pesticides, personal care products, polybrominated diphenyl ethers, bisphenol, A.; polychlorinated biphenyls), and their concentration could be associated with fetal growth restriction, thyroid dysfunction, and neurological disorders. Exposure during the prenatal period may result in epigenetic alterations modifying fetal programming and increasing, during postnatal life, the risk of some non-communicable diseases as suggested by the Developmental Origins of Health and Disease (DOHaD) hypothesis.  EDCs Key points Recent data point out that exposure to EDCs during development can not only cause direct damage to the exposed individual, but also to the individual’s offspring and to future generations— a process that is called transgenerational inheritance. It is now clear that hypothalamus-pituitary gland-thyroid (HPT), hypothalamus-pituitary gland-gonads (HPG), hypothalamus-pituitary gland- adrenal (HPA) represent the main targets of EDCs  Additional resources https://ec.europa.eu/environment/chemicals/endocrine/definitions/endodis_en.htm https://www.endocrine.org/topics/edc https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218126/