ENDOCRINE DISRUPTORS Prepared by Lobna Nabil Christeen Medhat
ENDOCRINE DISRUPTORS Prepared by: Lobna Nabil Christeen Medhat
Outlines Definition of endocrine disruptors. History of endocrine disruptors. Most common classes and sources of endocrine disruptors. Potential diseases originating from exposure to EDs and vulnerable groups. Mechanisms of endocrine disruption. Endocrine disruption and obesity. Epigenetic effects of EDs. Endocrine disruption and cancer. Managing the risk incurred by EDs.
DEFINITION : The definition according to the WHO (2002) and it is now widely accepted scientifically “An endocrine disruptor is an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny or (sub)populations. ” Endocrine Disruptors: from Scientific Evidence to Human Health Protection, Updated version, May 2019
A SHORT HISTORY OF THE DISCOVERY OF ENDOCRINE DISRUPTORS (ENDOCRINE DISRUPTING CHEMICALS EDCS)
THE DRUG DIETHYLSTILBOESTROL (DES) : • DES was developed as a synthetic oestrogen. • It was prescribed from the 1940 s onwards as it prevents miscarriage and other pregnancy complications. • In 1971, the (FDA) advised against its use due to vaginal cancers occurrence in girls born to mothers who had used DES Endocrine Disruptors: from Scientific Evidence to Human Health Protection, Updated version, May 2019
Epidemiology shows that the in utero DES exposure causes : *Vaginal cancer *Reproductive tract disorders *Infertility *Spontaneous abortion in the daughters. *Genital abnormalities *Increased risks of prostate cancer *Increased risk of testicular cancer in the sons Endocrine Disruptors: from Scientific Evidence to Human Health Protection, Updated version, May 2019
THE INSECTICIDE DDT : In 1962, a book published by Rachel Carson took the attention to the population losses in fish and birds due to accumulation of DDT (and its metabolites) in their organs. She also predicted that humans would be contaminated through their food, and their health would be affected. Endocrine Disruptors: from Scientific Evidence to Human Health Protection, Updated version, May 2019
Half a century later, it was reported that girls (female foetuses) who had been exposed to DDT in utero during the 1960 s have an increased risk of breast cancer in the following 50 years. Recent studies suggest DDT may inhibit the proper development of female reproductive system, marked decrease in fertility in adult males and Most recently, it has been suggested that it can increase a child's risk of childhood obesity. DDT is still used as anti-malarial insecticide in Africa and parts of Southeast Asia in limited quantities. Endocrine Disruptors: from Scientific Evidence to Human Health Protection, Updated version, May 2019
The Wingspread conference (1991) defined and detailed the global problem of endocrine disruption in both wildlife and humans. One of the early papers on the phenomenon was by Theo Colborn in 1993. . Endocrine Disruptors: from Scientific Evidence to Human Health Protection, Updated version, May 2019
A number of scientific reviews and reports on endocrine disruption have been published since 2010, underlining the importance, the concern and the rapid growth of the field. Endocrine Disruptors: from Scientific Evidence to Human Health Protection, Updated version, May 2019
LET’S GO THROUGH SOME OF THE WELL STUDIED ENDOCRINE DISRUPTING CHEMICALS (EDCS) : PCBs (Polychlorinated biphenyls ) Dioxins • Found in: Pesticides. • Combustion processes: waste incineration. Parabens • Found in: food additives, cosmetics and sunscreens Pthalates • Found in: Plastics, food packaging, cosmetics, cleaning agents. • Bis(2 -ethylhexyl) phthalate (DEHP) used in medical tubing, catheters and blood bags.
Flame retardants • Polybrominated diphenyl ethers (PBDE) Found in: Plastics, paint, furniture, electronics and food. BPA bisphenol A • Found in: Plastics, food packaging, the lining of many food/beverage containers. Triclosan Organotins • Found in: Personal care products, antimicrobial products. • Disinfectants, Anti-fouling paints. Endocrine Disruptors: from Scientific Evidence to Human Health Protection, Updated version, May 2019
ROUTES OF EXPOSURE TO EDCS Introduction to endocrine disrupting chemicals (EDCs) 2014
What EDC do ? Endocrine disrupting chemicals (EDCs) mimic block, or interfere with natural hormones in the body's endocrine system. Endocrine Disruptors: from Scientific Evidence to Human Health Protection, Updated version, May 2019
THE COCKTAIL EFFECTS OF EDCS : The exposure to multiple compounds may generate a “cocktail” of effects with unknown consequences , those effects may be: cumulative, inhibitory and/or synergic effects. Rosa lauretta et al, 2019
NON-LINEAR RESPONSES ARE SEEN FOR ENDOGENOUS RESPONSES AND IN ENDOCRINE DISRUPTION Endogenous Hormones EDCs Non-linearity Non-monotonic dose response curves U- shaped dose response curves
This contradicts the standard 'dose makes the poison' rule of toxicology. * Their doses are measured in part per million (ppm) , part per billion (ppb) and even part per trillion (ppt) as they act at extremely low doses. Endocrine Disruptors: from Scientific Evidence to Human Health Protection, Updated version, May 2019
Who is most at risk? According to the WHO : Pregnant women � The developing fetus � Early postnatal life � Endocrine Disruptors: from Scientific Evidence to Human Health Protection, Updated version, May 2019
Examples of potential diseases and dysfunctions originating from early exposures to EDCs State of the Science of Endocrine Disrupting Chemicals – 2012
Developmental exposure and windows Of vulnerability Stockholm University, Stockholm, Sweden 2012
Mechanisms of endocrine disruption Hypothalamic /pituitary/gonad axis Hypothalamic /pituitary/thyroid axis Interference with the estrogen or androgen binding to their receptors Interference with thyroid hormone distribution in the blood Affecting aromatase action Interference with iodine uptake by the thyroid gland. Interference with thyroid receptor activation. Other nuclear receptors (PPARs)
Mechanisms of endocrine disruption Hypothalamic /pituitary/gonad axis Hypothalamic /pituitary/thyroid axis Interference with the estrogen or androgen binding to their receptors Interference with thyroid hormone distribution in the blood Affecting aromatase action Interference with iodine uptake by the thyroid gland. Interference with thyroid receptor activation. Other nuclear receptors (PPARs)
Mechanisms of endocrine disruption Hypothalamic /pituitary/gonad axis Hypothalamic /pituitary/thyroid axis Interference with the estrogen or androgen binding to their receptors Interference with thyroid hormone distribution in the blood Affecting aromatase action Interference with iodine uptake by the thyroid gland. Interference with thyroid receptor activation. Other nuclear receptors (PPARs)
EDCs can affect these receptors in several different ways By directly interfering with receptor signaling. By activating other signaling pathways, in particular that of the aryl hydrocarbon receptor (Ah. R). Swedenborg et al(2009). Endocrine disruptive chemicals: Mechanisms of action and involvement in metabolic disorders. Journal of Molecular Endocrinology.
Aryl hydrocarbon receptor The Ah. R is a ligand-activated transcription factor and a key regulator of the cellular response to xenobiotic exposure. It is a basic helix-loop-helix transcription factor. It is strongly activated by organic compounds such as dioxins. Leads to the activation of cytochrome P 450 enzymes needed for their clearance from the body. Swedenborg et al(2009). Endocrine disruptive chemicals: Mechanisms of action and involvement in metabolic disorders. Journal of Molecular Endocrinology>
Interference with the hormone receptors of the nuclear receptor family Annual reviews of Endocrinology
Mechanisms of endocrine disruption Hypothalamic /pituitary/gonad axis Hypothalamic /pituitary/thyroid axis Interference with the estrogen or androgen binding to their receptors Interference with thyroid hormone distribution in the blood Affecting aromatase action Interference with iodine uptake by the thyroid gland. Other nuclear receptors (PPARs) Interference with thyroid receptor activation. Lauretta, R et al, (2019). Endocrine Disrupting Chemicals: Effects on Endocrine Glands. Frontiers in Endocrinology, 10, 178.
Disrupting aromatase action A member of Cytochrome P 450 family. Converts androgens into oestrogens. Present in Endoplasmic reticulum of: Gonads, brain, adipose tissue, placenta and bone. EDCs Could increase or decrease aromatase activity or expression Gore, A. C. , V. A. Chappell, et al. , EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals. Endocr Rev, 2015.
Mechanisms of endocrine disruption Hypothalamic /pituitary/gonad axis Hypothalamic /pituitary/thyroid axis Interference with the estrogen or androgen binding to their receptors Interference with thyroid hormone distribution in the blood Affecting aromatase action Interference with iodine uptake by the thyroid gland. Interference with thyroid receptor activation. Other nuclear receptors(PPARs)
Disrupt hypothalamic /pituitary/thyroid axis
Endocrine disruption and obesity Evidence pointing to the role of the environment in obesity prevalence is increasingly supported by: Epidemiological observations of geographic disparity of obesity Experimental evidence supportive of ubiquitously present environmental EDCs that can promote adipose tissue accumulation. Veiga-Lopez et al, 2018. Obesogenic Endocrine Disrupting Chemicals: Identifying Knowledge Gaps. Trends in Endocrinology & Metabolism.
Adipose tissue as an endocrine organ Coelho, M. et al. (2013) Biochemistry of adipose tissue: an endocrine organ. Arch. Med. Sci. 9, 191– 200
Increase in pre-adipocyte differentiation. Increase in the fate of mesenchymal stem cells (MSCs) to undergo adipogenic differentiation. Increase in adipose tissue mass.
Act as PPARγ ligands. Alter PPARγ expression through Ahr. The Open Rheumatology Journal, 2012
EDCs have been also linked to: Disruption of adipocyte function leading to increased lipid production. Disruption in metabolic hormone profiles. Induction of dyslipidemia. Disruption of thyroid hormone function is another mechanism by which obesogenic chemicals can act, due to the thyroid gland’s important role in normal maintenance of metabolism. Veiga-Lopez et al, 2018. Obesogenic Endocrine Disrupting Chemicals: Identifying Knowledge Gaps. Trends in Endocrinology & Metabolism.
Filled arrows: demonstrated obesogenic effect. Dotted lines : conflicting evidence. Absence of a link : no demonstrated effect.
EDCs and gut microbiota Microbial metabolism of chemicals including EDCs by gut microbiota can be accompanied by microbial dysbiosis. Bisphenol A (BPA) could contribute to the diabetes epidemic because it disturbs lipid metabolism and pancreatic b-cell function. Dietary intake of BPA favored the growth of Proteobacteria and Helicobacteraceae, with a decline in the populations of Firmicutes and Clostridia. These microbiota alterations parallel the microbial structure in diabetes patients. Lai, K. P. et al. (2016) Bisphenol A alters gut microbiome: comparative metagenomics analysis. Environ. Pollut. 218, 923– 930
Rosenfeld, C. S. (2017). Gut Dysbiosis in Animals Due to Environmental Chemical Exposures. Frontiers in Cellular and Infection Microbiology, 7, 396.
EDCs exposure and epigenetics Zeng, Y. , & Chen, T. (2019). DNA Methylation Reprogramming during Mammalian Development. Genes, 10(4), 257.
During foetal development, significant changes in methylation patterns in the germ cells occur, with complex waves of DNA de-methylation and re-methylation occur, modulating gene expression through epigenetic changes Zeng, Y. , & Chen, T. (2019). DNA Methylation Reprogramming during Mammalian Development. Genes, 10(4), 257.
Steroid hormones act as transcription factors that modulate expression of target genes (e. g. DNA methyl transferases) during those critical developmental periods when methylation status is being established. EDCs act on steroid hormone receptors; therefore, developmental exposures to EDCs in parents may alter programming of the genome in subsequent generations. Walker, D. M. , & Gore, A. C. (2011). Transgenerational neuroendocrine disruption of reproduction. Nature Reviews Endocrinology, 7(4), 197– 207.
Endocrine disruption and cancer Female gender related neoplasms including breast, uterine cancers are estrogen dependent malignancies Any EDC exhibiting estrogenic effects may increase the risk of estrogen dependent malignancies. BPA is the most abundant EDC exhibiting estrogenic properties. Rachoń, D. (2015). Endocrine disrupting chemicals (EDCs) and female cancer: Informing the patients. Reviews in Endocrine and Metabolic Disorders, 16(4), 359– 364.
In vivo, early life exposure to BPA rewrites the epigenetic code to alter gene expression in the breast, uterus and prostate. Seachrist, D. D. , Bonk, K. W. , Ho, S. -M. , Prins, G. S. , Soto, A. M. , & Keri, R. A. (2016). A review of the carcinogenic potential of bisphenol A. Reproductive Toxicology, 59, 167– 182.
Legal approaches to manage risks of EDs • In 1998, the EPA announced the Endocrine Disruptor Screening Program by establishment of a framework for screening and testing more than 85, 000 chemicals in commerce. As of 2016, the EPA had estrogen screening results for 1, 800 chemicals. • The EU Parliament demanded a concrete action plan and legislative proposals to remove endocrine disruptors from cosmetics, toys, and food packaging by June 2020.
MANAGING THE RISK INCURRED BY EDs : Endocrine Disruptors: from Scientific Evidence to Human Health Protection, Updated version, May 2019
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EDCs are exogenous in nature and can interfere with any aspect of hormone action. Endocrine disruptors produce complex , non linear dose responses. Endocrine disruptor activity can be exerted on estrogen, androgen, thyroid hormones. Some are known to interact with multiple hormone receptors simultaneously. Sensitivity to endocrine disruption is highest during tissue development. Effects of EDCs may be transmitted trans-generationally through molecular changes to the germ-line. Chronic exposure to EDs may provoke epigenetic and genetic modifications in tissue stem cells that can lead to cancer. EDCs interfere with the endocrine system, including the adipose tissue. They can alter adipo-genesis, circulating lipid profile, and body weight.
References • Rosenfeld, C. S. (2017). Gut Dysbiosis in Animals Due to Environmental Chemical Exposures. Frontiers in Cellular and Infection Microbiology, 7, 396. • Seachrist, D. D. , Bonk, K. W. , Ho, S. -M. , Prins, G. S. , Soto, A. M. , & Keri, R. A. (2016). A review of the carcinogenic potential of bisphenol A. Reproductive Toxicology, 59, 167– 182. • Zeng, Y. , & Chen, T. (2019). DNA Methylation Reprogramming during Mammalian Development. Genes, 10(4), 257. • Coelho, M. et al. (2013) Biochemistry of adipose tissue: an endocrine organ. Arch. Med. Sci. 9, 191– 200. • Rachoń, D. (2015). Endocrine disrupting chemicals (EDCs) and female cancer: Informing the patients. Reviews in Endocrine and Metabolic Disorders, 16(4), 359– 364. • Veiga-Lopez et al, 2018. Obesogenic Endocrine Disrupting Chemicals: Identifying Knowledge Gaps. Trends in Endocrinology & Metabolism. • Walker, D. M. , & Gore, A. C. (2011). Transgenerational neuroendocrine disruption of reproduction. Nature Reviews Endocrinology, 7(4), 197– 207.
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