The Complex Interplay between Endocannabinoid System and the Estrogen System in Central Nervous System and Periphery

International Journal of Molecular Sciences - Tập 22 Số 2 - Trang 972
Antonietta Santoro1, Elena Mele2, Marianna Marino1, Andrea Viggiano1, Stefania Lucia Nori3, Rosaria Meccariello2
1Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, Italy
2Department of Movement Sciences and Wellbeing, Parthenope University of Naples, 80133 Naples, Italy
3Department of Pharmacy, University of Salerno, 84084 Fisciano, Italy

Tóm tắt

The endocannabinoid system (ECS) is a lipid cell signaling system involved in the physiology and homeostasis of the brain and peripheral tissues. Synaptic plasticity, neuroendocrine functions, reproduction, and immune response among others all require the activity of functional ECS, with the onset of disease in case of ECS impairment. Estrogens, classically considered as female steroid hormones, regulate growth, differentiation, and many other functions in a broad range of target tissues and both sexes through the activation of nuclear and membrane estrogen receptors (ERs), which leads to genomic and non-genomic cell responses. Since ECS function overlaps or integrates with many other cell signaling systems, this review aims at updating the knowledge about the possible crosstalk between ECS and estrogen system (ES) at both central and peripheral level, with focuses on the central nervous system, reproduction, and cancer.

Từ khóa


Tài liệu tham khảo

McPartland, 2006, Evolutionary origins of the endocannabinoid system, Gene, 370, 64, 10.1016/j.gene.2005.11.004

Fasano, 2009, The endocannabinoid system: An ancient signaling involved in the control of male fertility, Ann. N. Y. Acad. Sci., 1163, 112, 10.1111/j.1749-6632.2009.04437.x

Elphick, 2012, The evolution and comparative neurobiology of endocannabinoid signalling, Philos. Trans. R. Soc. Lond. B Biol. Sci., 367, 3201, 10.1098/rstb.2011.0394

Lu, 2016, An Introduction to the Endogenous Cannabinoid System, Biol. Psychiatr., 79, 516, 10.1016/j.biopsych.2015.07.028

Gaoni, 1964, Isolation, structure and partial synthesis of an active constituent of hashish, J. Am. Chem. Soc., 86, 1646, 10.1021/ja01062a046

Proto, 2012, Interaction of endocannabinoid system and steroid hormones in the control of colon cancer cell growth, J. Cell. Physiol., 227, 250, 10.1002/jcp.22727

Ayakannu, 2013, The Endocannabinoid System and Sex Steroid Hormone-dependent cancers, Int. J. Endocrinol., 2013, 259676, 10.1155/2013/259676

Cacciola, 2013, Estrogens and spermiogenesis: New insights from type 1 cannabinoid receptor knockout mice, Int. J. Endocrinol., 2013, 501350, 10.1155/2013/501350

Hojnik, 2016, Overlapping molecular pathways between cannabinoid receptors type 1 and 2 and estrogens/androgens on the periphery and their involvement in the pathogenesis of common diseases (Review), Int. J. Mol. Med., 38, 1642, 10.3892/ijmm.2016.2779

Lipina, 2017, The endocannabinoid system: ‘NO’ longer anonymous in the control of nitrergic signalling?, J. Mol. Cell Biol., 9, 91, 10.1093/jmcb/mjx008

Chianese, 2018, Impact of dietary fat on brain functions, Curr. Neuropharmacol., 16, 1059, 10.2174/1570159X15666171017102547

Meccariello, R. (2020). Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives. Int. J. Mol. Sci., 21.

Haspula, D., and Clark, M.A. (2020). Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases. Int. J. Mol. Sci., 21.

Bifulco, 2009, Cannabinoid receptor CB1 antagonists state of the art and challenges, Vitam. Horm., 81, 159, 10.1016/S0083-6729(09)81007-8

Devane, 1992, Isolation and structure of a brain constituent that binds to the cannabinoid receptor, Science, 258, 1946, 10.1126/science.1470919

Maccarrone, 2017, Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years, Front. Mol. Neurosci., 10, 166, 10.3389/fnmol.2017.00166

Howlett, 2002, International Union of Pharmacology. XXVII. Classification of cannabinoid receptors, Pharmacol. Rev., 54, 161, 10.1124/pr.54.2.161

Klein, 2003, The cannabinoid system and immune modulation, J. Leukoc. Biol., 74, 486, 10.1189/jlb.0303101

Bialuk, 2011, AM251, cannabinoids receptor ligand, improves recognition memory in rats, Pharmacol. Rep., 63, 670, 10.1016/S1734-1140(11)70578-3

Litvin, 2013, CB1 receptor signaling regulates social anxiety and memory, Genes Brain Behav., 12, 479, 10.1111/gbb.12045

Morena, 2014, The endocannabinoid system: An emotional buffer in the modulation of memory function, Neurobiol. Learn. Mem., 112, 30, 10.1016/j.nlm.2013.12.010

Grimaldi, 2006, Anandamide inhibits adhesion and migration of breast cancer cells, Exp. Cell. Res., 312, 363, 10.1016/j.yexcr.2005.10.024

Cacciola, 2008, Expression of type-1 cannabinoid receptor during rat postnatal testicular development: Possible involvement in adult Leydig cell differentiation, Biol. Reprod., 79, 758, 10.1095/biolreprod.108.070128

Barchi, M., Innocenzi, E., Giannattasio, T., Dolci, S., Rossi, P., and Grimaldi, P. (2019). Cannabinoid Receptors Signaling in the Development, Epigenetics, and Tumours of Male Germ Cells. Int. J. Mol. Sci., 21.

Duncan, 2005, Identification and functional characterization of brainstem cannabinoid CB2 receptors, Science, 310, 329, 10.1126/science.1115740

Benito, 2014, Changes in CB(1) and CB(2) receptors in the post-mortem cerebellum of humans affected by spinocerebellar ataxias, Br. J. Pharmacol., 171, 1472, 10.1111/bph.12283

Lanciego, 2011, Expression of the mRNA coding the cannabinoid receptor 2 in the pallidal complex of Macaca fascicularis, J. Psychopharmacol., 25, 97, 10.1177/0269881110367732

Ramos, 2010, Cannabinoid–Dopamine Interaction in the Pathophysiology and Treatment of CNS Disorders, CNS Neurosci. Ther., 16, 72

Lutz, 2020, Neurobiology of cannabinoid receptor signalling, Dialogues Clin. Neurosci., 22, 207, 10.31887/DCNS.2020.22.3/blutz

Stempel, 2016, Cannabinoid type 2 receptors mediate a cell type-specific plasticity in the hippocampus, Neuron, 90, 795, 10.1016/j.neuron.2016.03.034

Zhang, 2017, Expression of functional cannabinoid CB2 receptor in VTA dopamine neurons in rats, Addict. Biol., 22, 752, 10.1111/adb.12367

Jordan, 2019, Progress in brain cannabinoid CB2 receptor research: From genes to behavior, Neurosci. Biobehav. Rev., 98, 208, 10.1016/j.neubiorev.2018.12.026

Yu, S.J., Reiner, D., Shen, H., Wu, K.J., Liu, Q.R., and Wang, Y. (2015). Time-dependent protection of CB2 receptor agonist in stroke. PLoS ONE, 10.

Morgan, 2009, Functional CB2 type cannabinoid receptors at CNS synapses, Neuropharmacology, 57, 356, 10.1016/j.neuropharm.2009.07.017

Santoro, 2018, Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain, J. Leukoc. Biol., 103, 509, 10.1002/JLB.3MR0118-003R

Carlisle, 2002, Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation, Int. Immunopharm., 2, 69, 10.1016/S1567-5769(01)00147-3

Benito, 2005, A glial endogenous cannabinoid system is upregulated in the brains of macaques with simian immunodeficiency virus-induced encephalitis, J. Neurosci., 25, 2530, 10.1523/JNEUROSCI.3923-04.2005

Maresz, 2005, Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli, J. Neurochem., 2, 437, 10.1111/j.1471-4159.2005.03380.x

Nephi, 2010, Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas, Glia, 58, 1017, 10.1002/glia.20983

Nilsson, 2001, Mechanisms of estrogen action, Physiol. Rev., 81, 1535, 10.1152/physrev.2001.81.4.1535

Frith, 2004, Genomic targets of nuclear estrogen receptors, Mol. Endocrinol., 18, 1859, 10.1210/me.2003-0044

Gottlicher, 1998, Transcriptional cross-talk, the second mode of steroid hormone receptor action, J. Mol. Med., 76, 480, 10.1007/s001090050242

Liu, 2013, Neuroprotective effect of estrogen: Role of nonsynaptic NR2B-containing NMDA receptors, Brain Res. Bull., 93, 27, 10.1016/j.brainresbull.2012.10.004

Meyer, 2009, Non-genomic regulation of vascular cell function and growth by estrogen, Mol. Cell. Endocrinol., 308, 9, 10.1016/j.mce.2009.03.009

Vail, 2019, Membrane-initiated estrogen signaling via Gq-coupled GPCR in the central nervous system, Steroids, 142, 77, 10.1016/j.steroids.2018.01.010

2004, Estrogen and the brain: Beyond ER-α and ER-β, Exp. Gerontol., 39, 1579, 10.1016/j.exger.2004.05.006

Losel, 2003, Nongenomic actions of steroid hormones, Nat. Rev. Mol. Cell. Biol., 4, 46, 10.1038/nrm1009

Mellon, 2002, Neurosteroids: Biochemistry and clinical significance, Trends Endocrinol. Metab., 13, 35, 10.1016/S1043-2760(01)00503-3

Leranth, 2002, Gonadal hormones are responsible for maintaining the integrity of spine synapses in the CA1 hippocampal subfield of female nonhuman primates, J. Comp. Neurol., 447, 34, 10.1002/cne.10230

Hasegawa, 2015, Estradiol rapidly modulates synaptic plasticity of hippocampal neurons: Involvement of kinase networks, Brain. Res., 1621, 147, 10.1016/j.brainres.2014.12.056

Marx, 2006, Neuroactive steroids are altered in schizophrenia and bipolar disorder: Relevance to pathophysiology and therapeutics, Neuropsychopharmacology, 3, 1249, 10.1038/sj.npp.1300952

Maggio, 2015, DHEA and cognitive function in the elderly, J. Steroid Biochem. Mol. Biol., 145, 281, 10.1016/j.jsbmb.2014.03.014

Yilmaz, 2019, Neurosteroids as regulators of neuroinflammation, Front. Neuroendocrinol., 55, 100788, 10.1016/j.yfrne.2019.100788

Hampson, 1990, Estrogen-related variations in human spatial and articulatory-motor skills, Psychoneuroendocrinology, 15, 97, 10.1016/0306-4530(90)90018-5

Kimura, 1992, Sex differences in the brain, Sci. Am., 267, 119, 10.1038/scientificamerican0992-118

Sherwin, 1996, “Add-back” estrogen reverses cognitive deficits induced by a gonadotropin-releasing hormone agonist in women with leiomyomata uteri, J. Clin. Endocrinol. Metab., 81, 2545

Costa, E., and Paul, S.M. (1991). The effects of oestrogen and progesterone on GABA and glutamate responses at extrahypothalamic sites. Neurosteroids and Brain Function, Thieme Medical.

Kimoto, 2001, Neurosteroid synthesis by cytochrome p450-containing systems localized in the rat brain hippocampal neurons: N-methyl-D-aspartate and calcium-dependent synthesis, Endocrinology, 142, 3578, 10.1210/endo.142.8.8327

Kawato, 2002, Histological and metabolism analysis of P450 expression in the brain, Methods Enzymol., 357, 241, 10.1016/S0076-6879(02)57682-5

Kawato, 2003, Brain neurosteroids are 4th generation neuromessengers in the brain: Cell biophysical analysis of steroid signal transduction, Adv. Biophys., 37, 1, 10.1016/S0065-227X(03)80002-3

Hojo, 2004, Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017alpha and P450 aromatase localized in neurons, Proc. Natl. Acad. Sci. USA, 101, 865, 10.1073/pnas.2630225100

Hojo, 2008, Estrogen synthesis in the brain--role in synaptic plasticity and memory, Mol. Cell. Endocrinol., 290, 31, 10.1016/j.mce.2008.04.017

Murakami, 2006, Role of cytochrome p450 in synaptocrinology: Endogenous estrogen synthesis in the brain hippocampus, Drug Metab. Rev., 38, 353, 10.1080/03602530600724068

Kretz, 2004, Hippocampal synapses depend on hippocampal estrogen synthesis, J. Neurosci., 24, 5913, 10.1523/JNEUROSCI.5186-03.2004

Fester, 2006, Proliferation and apoptosis of hippocampal granule cells require local oestrogen synthesis, J. Neurochem., 97, 1136, 10.1111/j.1471-4159.2006.03809.x

Fester, 2006, Inhibition of hippocampal estrogen synthesis causes region-specific downregulation of synaptic protein expression in hippocampal neurons, Hippocampus, 16, 464, 10.1002/hipo.20173

Higo, 2009, Comparison of sex-steroid synthesis between neonatal and adult rat hippocampus, Biochem. Biophys. Res. Commun., 385, 62, 10.1016/j.bbrc.2009.05.005

Ishii, 2007, Local production of sex hormones and their modulation of hippocampal synaptic plasticity, Neuroscientist, 13, 323, 10.1177/10738584070130040601

Hojo, 2009, Comparison between hippocampus-synthesized and circulation-derived sex steroids in the hippocampus, Endocrinology, 150, 5106, 10.1210/en.2009-0305

McEwen, 1999, Estrogen actions in the central nervous system, Endocr. Rev., 20, 279

Cui, 2013, Estrogen synthesis and signaling pathways during aging: From periphery to brain, Trends Mol. Med., 19, 197, 10.1016/j.molmed.2012.12.007

Hewitt, 2018, Estrogen Receptors: New Directions in the New Millennium, Endocr. Rev., 39, 664, 10.1210/er.2018-00087

Blakemore, 2016, Aromatase: Contributions to Physiology and Disease in Women and Men, Physiology (Bethesda), 31, 258

Hess, 2018, Estrogen in the male: A historical perspective, Biol. Reprod., 99, 27, 10.1093/biolre/ioy043

Franks, 2018, Androgen Action in the Ovary, Front. Endocrinol. (Lausanne), 9, 452, 10.3389/fendo.2018.00452

Chianese, 2016, Kisspeptins, estrogens and male fertility, Curr. Med. Chem., 23, 4070, 10.2174/0929867323666160902155434

McCarthy, 2008, Estradiol and the Developing Brain, Physiol. Rev., 88, 91, 10.1152/physrev.00010.2007

Gegenhuber, B., and Tollkuhn, J. (2019). Sex Differences in the Epigenome: A Cause or Consequence of Sexual Differentiation of the Brain?. Genes, 10.

Santoro, 2019, Neuro-toxic and Reproductive Effects of BPA, Curr. Neuropharmacol., 17, 1109, 10.2174/1570159X17666190726112101

Sharpe, 1998, The roles of oestrogen in the male, Trends Endocrinol. Metab., 9, 371, 10.1016/S1043-2760(98)00089-7

Rochira, 2002, Congenital estrogen deficiency in men: A new syndrome with different phenotypes; clinical and therapeutic implications in men, Mol. Cell. Endocrinol., 193, 19, 10.1016/S0303-7207(02)00092-8

Jones, 2006, Of mice and men: The evolving phenotype of aromatase deficiency, Trends Endocrinol. Metab., 17, 55, 10.1016/j.tem.2006.01.004

Roselli, 2009, Brain aromatization: Classic roles and new perspectives, Semin. Reprod. Med., 27, 207, 10.1055/s-0029-1216274

Simpson, 2003, Prepulse inhibition of acoustic startle in aromatase knock-out mice: Effects of age and gender, Genes Brain Behav., 2, 93, 10.1034/j.1601-183X.2003.00014.x

Hill, 2007, Estrogen deficient male mice develop compulsive behavior, Biol. Psychiatry, 61, 359, 10.1016/j.biopsych.2006.01.012

Herbison, 2005, Major sex differences in non-genomic estrogen actions on intracellular signaling in mouse brain in vivo, Neuroscience, 131, 945, 10.1016/j.neuroscience.2004.10.046

Murphy, 1997, Morphological plasticity of dendritic spines in central neurons is mediated by activation of cAMP response element binding protein, Proc. Natl. Acad. Sci. USA, 94, 1482, 10.1073/pnas.94.4.1482

Frankfurt, 1990, Gonadal steroids modify dendritic spine density in ventromedial hypothalamic neurons: A Golgi study in the adult rat, Neuroendocrinology, 51, 530, 10.1159/000125387

Carrer, 1982, Ultrastructural changes in the hypothalamic ventromedial nucleus of ovariectomized rats after estrogen treatment, Brain Res., 240, 221, 10.1016/0006-8993(82)90218-9

Frankfurt, 1991, Estrogen increases axodendritic synapses in the VMN of rats after ovariectomy, NeuroReport, 2, 380, 10.1097/00001756-199107000-00006

Gould, 1990, Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood, J. Neurosci., 10, 1286, 10.1523/JNEUROSCI.10-04-01286.1990

Lewis, 1995, Estrogen-induction of dendritic spines in ventromedial hypothalamus and hippocampus: Effects of neonatal aromatase blockade and adult castration, Dev. Brain Res., 87, 91, 10.1016/0165-3806(95)00052-F

Amantea, 2007, Modulation of the endocannabinoid system by focal brain ischemia in the rat is involved in neuroprotection afforded by 17 beta-estradiol, FEBS J., 274, 4464, 10.1111/j.1742-4658.2007.05975.x

Hill, 2007, Estrogen recruits the endocannabinoid system to modulate emotionality, Psychoneuroendocrinology, 32, 350, 10.1016/j.psyneuen.2007.02.003

Vitiello, 2014, Pregnenolone can protect the brain from cannabis intoxication, Science, 343, 94, 10.1126/science.1243985

Rasmusson, 2017, Neuroactive steroids and PTSD treatment, Neurosci. Lett., 10, 156, 10.1016/j.neulet.2017.01.054

Pierantoni, 2002, Evolutionary aspects of cellular communication in the vertebrate hypothalamo-hypophysio-gonadal axis, Int. Rev. Cytol., 218, 69, 10.1016/S0074-7696(02)18012-0

Pinilla, 2012, Kisspeptins and Reproduction: Physiological Roles and Regulatory Mechanisms, Physiol. Rev., 92, 1235, 10.1152/physrev.00037.2010

Moenter, 2020, Central aspects of systemic oestradiol negative- and positive-feedback on the reproductive neuroendocrine system, Neuroendocrinology, 32, 12724, 10.1111/jne.12724

Hewitt, 2016, What’s new in estrogen receptor action in the female reproductive tract, J. Mol. Endocrinol., 56, 55, 10.1530/JME-15-0254

Meccariello, 2014, Intratesticular signals regulate germ cell progression and production of qualitatively mature spermatozoa in vertebrates, Front. Endocrinol., 5, 69, 10.3389/fendo.2014.00069

Chianese, 2018, Bisphenol A in reproduction: Epigenetic effects, Curr. Med. Chem., 25, 748, 10.2174/0929867324666171009121001

Scafuro, 2019, BPA and nutraceuticals, simultaneous effects on endocrine functions, Endocr. Metab. Immune Disord. Drug Targets, 19, 594, 10.2174/1871530319666190101120119

Meccariello, R., Santoro, A., D’Angelo, S., Morrone, R., Fasano, S., Viggiano, A., and Pierantoni, R. (2020). The epigenetics of the Endocannabinoid system. Int. J. Mol. Sci., 21.

Wang, 2006, Jekyll and Hyde: Two Faces of Cannabinoid Signaling in Male and Female Fertility, Endocr. Rev., 27, 427, 10.1210/er.2006-0006

Bovolin, 2014, Endocannabinoids are involved in male vertebrate reproduction: Regulatory mechanisms at central and gonadal level, Front. Endocrinol., 5, 54, 10.3389/fendo.2014.00054

Schuel, 2002, N-Acylethanolamines in human reproductive fluids, Chem. Phys. Lipids, 121, 211, 10.1016/S0009-3084(02)00158-5

Meccariello, 2014, Updates in reproduction coming from the endocannabinoid system, Int. J. Endocrinol., 2014, 412354, 10.1155/2014/412354

Brents, 2016, Marijuana, the Endocannabinoid System and the Female Reproductive System, Yale J. Biol. Med., 89, 175

Battista, 2012, The role of endocannabinoids in gonadal function and fertility along the evolutionary axis, Mol. Cell. Endocrinol., 355, 1, 10.1016/j.mce.2012.01.014

Cobellis, 2016, Effects of neuroendocrine CB1 activity on adult Leydig cells, Front. Endocrinol., 7, 47, 10.3389/fendo.2016.00047

Agarwal, 2015, Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility, J. Assist. Reprod. Genet., 32, 1575, 10.1007/s10815-015-0553-8

Walker, 2019, The role of the endocannabinoid system in female reproductive tissues, J. Ovarian Res., 12, 3, 10.1186/s13048-018-0478-9

Takeda, 2013, Δ(9)-Tetrahydrocannabinol disrupts estrogen-signaling through up-regulation of estrogen receptor β (ERβ), Chem. Res. Toxicol., 26, 1073, 10.1021/tx4000446

Fiori, 2011, EGF receptor and its ligands via destabilization of estrogen-related receptor α protein, Br. J. Pharmacol., 164, 1026, 10.1111/j.1476-5381.2011.01384.x

Wang, 2006, Fatty acid amide hydrolase deficiency limits early pregnancy events, J. Clin. Investig., 116, 2122, 10.1172/JCI28621

Buckley, 2008, The peripheral cannabinoid receptor knockout mice: An update, Br. J. Pharmacol., 153, 309, 10.1038/sj.bjp.0707527

Sun, 2009, Genetic loss of FAAH compromises male fertility in mice, Biol. Reprod., 80, 235, 10.1095/biolreprod.108.072736

Sun, 2012, Endocannabinoid Signaling in Female Reproduction, ACS Chem. Neurosci., 3, 349, 10.1021/cn300014e

Acone, 2009, Low type I cannabinoid receptor levels characterize placental villous in labouring delivery, Placenta, 30, 203, 10.1016/j.placenta.2008.11.018

Trabucco, 2009, Endocannabinoid System in First Trimester Placenta: Low FAAH and High CB1 Expression Characterize Spontaneous Miscarriage, Placenta, 30, 516, 10.1016/j.placenta.2009.03.015

Li, 2019, Mice Missing Cnr1 and Cnr2 Show Implantation Defects, Endocrinology, 160, 938, 10.1210/en.2019-00024

Cobellis, 2010, A Gradient of 2-Arachidonoylglycerol Regulates Mouse Epididymal Sperm Cell Start-Up, Biol. Reprod., 82, 451, 10.1095/biolreprod.109.079210

Chioccarelli, 2010, Cannabinoid Receptor 1 Influences Chromatin Remodeling in Mouse Spermatids by Affecting Content of Transition Protein 2 mRNA and Histone Displacement, Endocrinology, 151, 5017, 10.1210/en.2010-0133

Chioccarelli, T., Manfrevola, F., Porreca, V., Fasano, S., Altucci, L., Pierantoni, R., and Cobellis, G. (2020). The Cannabinoid Receptor CB1 Stabilizes Sperm Chromatin Condensation Status During Epididymal Transit by Promoting Disulphide Bond Formation. Int. J. Mol. Sci., 21.

Cacciola, 2013, Nuclear size as estrogen-responsive chromatin quality parameter of mouse spermatozoa, Gen. Comp. Endocrinol., 193, 2019, 10.1016/j.ygcen.2013.07.018

Cacciola, 2013, Low 17beta-estradiol levels in CNR1 knock-out mice affect spermatid chromatin remodeling by interfering with chromatin reorganization, Biol. Reprod., 88, 152, 10.1095/biolreprod.112.105726

Maia, 2017, The endocannabinoid system expression in the female reproductive tract is modulated by estrogen, J. Steroid Biochem. Mol. Biol., 74, 40, 10.1016/j.jsbmb.2017.07.023

Ernst, 2016, The endocannabinoid system in the human granulosa cell line KGN, Mol. Cell. Endocrinol., 423, 67, 10.1016/j.mce.2016.01.006

Waleh, 2002, Transcriptional regulation of the mouse fatty acid amide hydrolase gene, Gene, 291, 203, 10.1016/S0378-1119(02)00598-X

Ciaramella, 2016, Anandamide acts via kisspeptin in the regulation of testicular activity of the frog, Pelophylax esculentus, Mol. Cell. Endocrinol., 420, 75, 10.1016/j.mce.2015.11.011

Grimaldi, 2012, The FAAH gene is the first direct target of estrogen in the testis: Role of histone demethylase LSD1, Cell. Mol. Life Sci., 69, 4177, 10.1007/s00018-012-1074-6

Rossi, 2007, Follicle-stimulating hormone activates fatty acid amide hydrolase by protein kinase A and aromatase-dependent pathways in mouse primary Sertoli cells, Endocrinology, 148, 1431, 10.1210/en.2006-0969

Farkas, 2010, Retrograde endocannabinoid signaling reduces GABAergic synaptic transmission to gonadotropin-releasing hormone neurons, Endocrinology, 151, 5818, 10.1210/en.2010-0638

Meccariello, 2008, Interplay between the endocannabinoid system and GnRH-I in the forebrain of the anuran amphibian Rana esculenta, Endocrinology, 149, 2149, 10.1210/en.2007-1357

Liposits, 2016, Estrogen Receptor Beta and 2-arachidonoylglycerol Mediate the Suppressive Effects of Estradiol on Frequency of Postsynaptic Currents in Gonadotropin-Releasing Hormone Neurons of Metestrous Mice: An Acute Slice Electrophysiological Study, Front. Cell. Neurosci., 10, 77

Vazquez, 2019, Novel mechanisms for the metabolic control of puberty: Implications for pubertal alterations in early-onset obesity and malnutrition, J. Endocrinol., 242, 51, 10.1530/JOE-19-0223

D’Angelo, S., Motti, M.L., and Meccariello, R. (2020). ω-3 and ω-6 Polyunsaturated Fatty Acids, Obesity and Cancer. Nutrients, 12.

Forte, N., Fernández-Rilo, A.C., Palomba, L., Di Marzo, V., and Cristino, L. (2020). Obesity Affects the Microbiota-Gut-Brain Axis and the Regulation Thereof by Endocannabinoids and Related Mediators. Int. J. Mol. Sci., 21.

Pucci, M., Zaplatic, E., Micioni Di Bonaventura, M.V., Micioni Di Bonaventura, E., Paolo De Cristofaro, P., Maccarrone, M., Cifani, C., and D’Addario, C. (2021). On the Role of Central Type-1 Cannabinoid Receptor Gene Regulation in Food Intake and Eating Behaviors. Int. J. Mol. Sci., 22.

Washburn, 2013, Receptor subtypes and signal transduction mechanisms contributing to the estrogenic attenuation of cannabinoid-induced changes in energy homeostasis, Neuroendocrinology, 97, 160, 10.1159/000338669

Meccariello, 2020, Kisspeptins, new local modulators of male reproduction: A comparative overview, Gen. Comp. Endocrinol., 299, 113618, 10.1016/j.ygcen.2020.113618

Motti, M.L., and Meccariello, R. (2019). Minireview: The epigenetic modulation of KISS1 in cancer and reproduction. Int. J. Environ. Res. Public Health, 16.

Karamikheirabad, 2013, A role for endocannabinoids in acute stress-induced suppression of the hypothalamic-pituitary-gonadal axis in male rats, Clin. Exp. Reprod. Med., 40, 155, 10.5653/cerm.2013.40.4.155

Cobellis, 2006, Endocannabinoid system in frog and rodent testis: Type-1 cannabinoid receptor and fatty acid amide hydrolase activity in male germ cells, Biol. Reprod., 75, 82, 10.1095/biolreprod.106.051730

Meccariello, 2006, Type-1 cannabinoid receptor expression in the frog, Rana esculenta, tissues: A possible involvement in the regulation of testicular activity, Mol. Reprod. Dev., 73, 551, 10.1002/mrd.20434

Chianese, 2008, Non mammalian vertebrate models and the endocannabinoid system: Relationships with gonadotropin-releasing hormone, Mol. Cell. Endocrinol., 286, 46, 10.1016/j.mce.2008.01.009

Chianese, 2011, Anandamidemodulates the expression of GnRH-II and GnRHRs in frog, Rana esculenta, diencephalon, Gen. Comp. Endocrinol., 173, 389, 10.1016/j.ygcen.2011.07.001

Chianese, 2012, Anandamide regulates the expression of GnRH-I, GnRH-II and GnRHRs in frog testis, Am. J. Physiol. Endrocrinol. Metab., 303, 475, 10.1152/ajpendo.00086.2012

Chianese, 2014, Hypothalamus-pituitary axis: An obligatory target for endocannabinoids to inhibit steroidogenesis in frog testis, Gen. Comp. Endocrinol., 205, 88, 10.1016/j.ygcen.2014.02.010

Chianese, 2013, Endocannabinoids and endovanilloids: A possible balance in the regulation of the testicular GnRH signalling, Int. J. Endocrinol., 2013, 904748, 10.1155/2013/904748

Ciaramella, 2015, Expression analysis of Gnrh1 and Gnrhr1 in spermatogenic cells of rat, Int. J. Endocrinol., 2015, 982726, 10.1155/2015/982726

Chianese, 2013, Kisspeptin Receptor, GPR54, as a Candidate for the Regulation of Testicular Activity in the Frog, Rana esculenta, Biol. Reprod., 88, 73, 10.1095/biolreprod.112.103515

Chianese, 2015, Kisspeptin drives germ cell progression in the anuran amphibian Pelophylax esculentus: A study carried out in ex vivo testes, Gen. Comp. Endocrinol., 211, 81, 10.1016/j.ygcen.2014.11.008

Chianese, 2017, Kisspeptin regulates steroidogenesis and spermiation in the anuran amphibian Pelophylax esculentus testis, Reproduction, 154, 403, 10.1530/REP-17-0030

Kabir, 2015, A review on endocrine disruptors and their possible impacts on human health, Environ. Toxicol. Pharmacol., 40, 241, 10.1016/j.etap.2015.06.009

Kiyama, 2015, Estrogenic endocrine disruptors: Molecular mechanisms of action, Environ. Int., 83, 11, 10.1016/j.envint.2015.05.012

Nowak, 2018, Parabens and their effects on the endocrine system, Mol. Cell. Endocrinol., 474, 238, 10.1016/j.mce.2018.03.014

Grimaldi, 2015, Reporter cell lines for the characterization of the interactions between human nuclear receptors and endocrine disruptors, Front. Endocrinol. (Lausanne), 11, 62

Corrales, 2015, Global Assessment of Bisphenol A in the Environment: Review and Analysis of Its Occurrence and Bioaccumulation, Dose-Response, 13, 1559325815598308, 10.1177/1559325815598308

Wang, Y., Zhu, H., and Kannan, K. (2019). A Review of Biomonitoring of Phthalate Exposures. Toxics, 7.

Li, 2017, Molecular mechanisms of PFOA-induced toxicity in animals and humans: Implications for health risks, Environ. Int., 99, 43, 10.1016/j.envint.2016.11.014

Morck, 2010, Placental transport and in vitroeffects of Bisphenol A, Reprod. Toxicol., 30, 131, 10.1016/j.reprotox.2010.02.007

Corbel, 2014, Bidirectional placental transfer of Bisphenol A and its main metabolite, Bisphenol A Glucuronide, in the isolated perfused human placenta, Reprod. Toxicol., 47, 51, 10.1016/j.reprotox.2014.06.001

Viggiano, 2020, Bisphenol A induces DNA damage in cells exerting immune surveillance functions at peripheral and central level, Chemosphere, 254, 126819, 10.1016/j.chemosphere.2020.126819

Chianese, 2018, Chronic exposure to low dose of bisphenol A impacts on the first round of spermatogenesis via SIRT1 modulation, Sci. Rep., 8, 2961, 10.1038/s41598-018-21076-8

Boberg, 2016, Multiple endocrine disrupting effects in rats perinatally exposed tobutylparaben, Toxicol. Sci., 152, 244, 10.1093/toxsci/kfw079

Smarr, 2017, Urinary concentrations of parabens and other antimicrobial chemicals and their association with couples’ fecundity, Environ. Health Perspect., 125, 730, 10.1289/EHP189

Smith, 2013, Urinary paraben concentrations and ovarian aging among women from a fertility center, Environ. Health Perspect., 121, 1299, 10.1289/ehp.1205350

Ali, 2013, Combined prenatal and postnatal butyl paraben exposureproduces autism-like symptoms in offspring: Comparison with valproic acid autistic model, Pharmacol. Biochem. Behav., 111, 102, 10.1016/j.pbb.2013.08.016

Rocha, 2017, Propylparaben suppresses epileptiform activity in hippocampal CA1 pyramidal cells in vitro, Epilepsy Res., 136, 126, 10.1016/j.eplepsyres.2017.08.006

Kodani, 2016, Parabens inhibit fatty acid amide hydrolase: A potential role in paraben-enhanced 3T3-L1 adipocyte differentiation, Toxicol. Lett., 262, 92, 10.1016/j.toxlet.2016.09.011

Santangeli, 2018, Role of Bisphenol A on the Endocannabinoid System at central and peripheral levels: Effects on adult female zebrafish, Chemosphere, 205, 118, 10.1016/j.chemosphere.2018.04.078

Mylonas, 2018, Endocrine disruptors in the diet of male Sparus aurata: Modulation of the endocannabinoid system at the hepatic and central level by Di-isononyl phthalate and Bisphenol A, Environ. Int., 119, 54, 10.1016/j.envint.2018.06.011

Cocci, 2017, Differential tissue regulation of peroxisome proliferator-activated receptor α (PPARα) and cannabinoid receptor 1 (CB1) gene transcription pathways by diethylene glycol dibenzoate (DEGB): Preliminary observations in a seabream (Sparus aurata) in vivo model, Environ. Toxicol. Pharmacol., 55, 87, 10.1016/j.etap.2017.08.015

Pomatto, 2011, Xenoestrogens elicit a modulation of endocannabinoid system and estrogen receptors in 4NP treated goldfish, Carassius auratus, Gen. Comp. Endocrinol., 174, 30, 10.1016/j.ygcen.2011.08.001

Beato, 2020, Effects of BPA on zebrafish gonads: Focus on the endocannabinoid system, Environ. Pollut., 264, 114710, 10.1016/j.envpol.2020.114710

Forner-Piquer, I., Fakriadis, I., Mylonas, C.C., Piscitelli, F., Di Marzo, V., Maradonna, F., Calduch-Giner, J., Pérez-Sánchez, J., and Carnevali, O. (2019). Effects of Dietary Bisphenol A on the Reproductive Function of Gilthead Sea Bream (Sparus aurata) Testes. Int. J. Mol. Sci., 20.

Mylonas, 2019, Effects of diisononyl phthalate (DiNP) on the endocannabinoid and reproductive systems of male gilthead sea bream (Sparus aurata) during the spawning season, Arch. Toxicol., 93, 727, 10.1007/s00204-018-2378-6

Rossi, G., Dufrusine, B., Lizzi, A.R., Luzi, C., Piccoli, A., Fezza, F., Iorio, R., D’Andrea, G., Dainese, E., and Cecconi, S. (2020). Bisphenol A Deranges the Endocannabinoid System of Primary Sertoli Cells with an Impact on Inhibin B Production. Int. J. Mol. Sci., 21.

Zbucki, 2018, Evaluation of Bisphenol A influence on endocannabinoid system in pregnant women, Chemosphere, 203, 387, 10.1016/j.chemosphere.2018.03.195

Zamkowska, 2018, Environmental exposure to non persistent endocrine disrupting chemicals and semen quality: An overview of the current epidemiological evidence, Int. J. Occup. Med. Environ. Health, 31, 377

Tournaye, 2015, Human exposure to endocrine disrupting chemicals and fertility: A case-control study in male subfertility patients, Environ. Int., 84, 154, 10.1016/j.envint.2015.07.017

Desai, 2015, Epigenomics, gestational programming and risk of metabolic syndrome, Int. J. Obes., 39, 633, 10.1038/ijo.2015.13

Gillette, 2018, Passing experiences on to future generations: Endocrine disruptors and transgenerational inheritance of epimutations in brain and sperm, Epigenetics, 13, 1106, 10.1080/15592294.2018.1543506

Maamar, 2020, Epigenetic transgenerational inheritance of parent-of-origin allelic transmission of outcross pathology and sperm epimutations, Dev. Biol., 458, 106, 10.1016/j.ydbio.2019.10.030

Lee, 2006, Estrogenic effects of marijuana smoke condensate and cannabinoid compounds, Toxicol. Appl. Pharmacol., 214, 270, 10.1016/j.taap.2005.12.019

Zufferey, 2020, Semen endocannabinoids are correlated to sperm quality in a cohort of 200 young Swiss men, Andrology, 8, 1126, 10.1111/andr.12785

Ambrosini, 2006, Oleoylethanolamide protects human sperm cells from oxidation stress: Studies on cases of idiopathic infertility, Biol. Reprod., 74, 659, 10.1095/biolreprod.105.046060

Bar, 2000, Regulation of platelet aggregation and adenosinetriphosphate release in vitro by 17beta-estradiol and medroxyprogesterone acetate in postmenopausal women, Thromb. Haemost., 84, 695, 10.1055/s-0037-1614089

Mendelsohn, 1999, The protective effects of estrogen on the cardiovascular system, N. Engl. J. Med., 340, 1801, 10.1056/NEJM199906103402306

Sachais, 2001, Platelet–endothelial interactions in atherosclerosis, Curr. Atheroscler. Rep., 3, 412, 10.1007/s11883-001-0080-1

Stefano, 2000, Cell-surface estrogen receptors mediate calcium-dependent nitric oxide release in human endothelia, Circulation, 101, 1594, 10.1161/01.CIR.101.13.1594

Maccarrone, 2002, Estrogen stimulates arachidonoylethanolamide release from human endothelial cells and platelet activation, Blood, 100, 4040, 10.1182/blood-2002-05-1444

Kunos, 2000, Endocannabinoids as cardiovascular modulators, Chem. Phys. Lipids, 108, 159, 10.1016/S0009-3084(00)00194-8

Maccarrone, 2002, Endocannabinoids and their actions, Vitam. Horm., 65, 225, 10.1016/S0083-6729(02)65066-6

Maccarrone, 2003, Progesterone activates fatty acid amide hydrolase (FAAH) promoter in human T lymphocytes through the transcription factor Ikaros. Evidence for a synergistic effect of leptin, J. Biol. Chem., 278, 32726, 10.1074/jbc.M302123200

Ramer, 2019, Modulation of the Endocannabinoid System as a Potential Anticancer Strategy, Front. Pharmacol., 10, 430, 10.3389/fphar.2019.00430

Xu, 2006, Overexpression of cannabinoid receptors CB1 and CB2 correlates with improved prognosis of patients with hepatocellular carcinoma, Cancer Genet. Cytogenet., 171, 31, 10.1016/j.cancergencyto.2006.06.014

Melck, 2000, Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation, Endocrinology, 141, 118, 10.1210/endo.141.1.7239

Mimeault, 2003, Antiproliferative and apoptotic effects of anandamide in human prostatic cancer cell lines: Implication of epidermal growth factor receptor downregulation and ceramide production, Prostate, 56, 1, 10.1002/pros.10190

Ligresti, 2013, Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: Pro-apoptotic effects and underlying mechanisms, Br. J. Pharmacol., 168, 79, 10.1111/j.1476-5381.2012.02027.x

Chung, 2009, A high cannabinoid CB 1 receptor immunoreactivity is associated with disease severity and outcome in prostate cancer, Eur. J. Cancer, 45, 174, 10.1016/j.ejca.2008.10.010

Czifra, 2009, Increased expressions of cannabinoid receptor-1 and transient receptor potential vanilloid-1 in human prostate carcinoma, J. Cancer Res. Clin. Oncol., 135, 507, 10.1007/s00432-008-0482-3

Caffarel, 2010, Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition, Mol. Cancer, 9, 196, 10.1186/1476-4598-9-196

Melck, 1998, The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation, Proc. Natl. Acad. Sci. USA, 95, 8375, 10.1073/pnas.95.14.8375

Laezza, 2012, Anandamide inhibits the Wnt/β-catenin signalling pathway in human breast cancer MDA MB 231 cells, Eur. J. Cancer, 48, 3112, 10.1016/j.ejca.2012.02.062

Fonseca, 2018, Cannabinoid-induced cell death in endometrial cancer cells: Involvement of TRPV1 receptors in apoptosis, J. Physiol. Biochem., 74, 261, 10.1007/s13105-018-0611-7

Hasenoehrl, 2018, G protein-coupled receptor GPR55 promotes colorectal cancer and has opposing effects to cannabinoid receptor 1, Int. J. Cancer, 142, 121, 10.1002/ijc.31030

Santoro, 2009, Rimonabant inhibits human colon cancer cell growth and reduces the formation of precancerous lesions in the mouse colon, Int. J. Cancer, 125, 996, 10.1002/ijc.24483

Ligresti, 2003, Possible endocannabinoid control of colorectal cancer growth, Gastroenterology, 125, 677, 10.1016/S0016-5085(03)00881-3

Jacenik, 2019, G protein-coupled estrogen receptor in colon function, immune regulation and carcinogenesis, World J. Gastroenterol., 25, 4092, 10.3748/wjg.v25.i30.4092

Williams, 2016, Estrogen receptor beta as target for colorectal cancer prevention, Cancer Lett., 372, 48, 10.1016/j.canlet.2015.12.009

Pisanti, 2009, Use of cannabinoid receptor agonists in cancer therapy as palliative and curative agents, Best Pract. Res. Clin. Endocrinol. Metab., 23, 117, 10.1016/j.beem.2009.02.001

Ligresti, 2016, From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles through Complex Pharmacology, Physiol. Rev., 96, 1593, 10.1152/physrev.00002.2016

Laezza, C., Pagano, C., Navarra, G., Pastorino, O., Proto, M.C., Fiore, D., Piscopo, C., Gazzerro, P., and Bifulco, M. (2020). The Endocannabinoid System: A Target for Cancer Treatment. Int. J. Mol. Sci., 21.

Sarnataro, 2006, The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits human breast cancer cell proliferation through a lipid raft-mediated mechanism, Mol. Pharmacol., 70, 1298, 10.1124/mol.106.025601

Notarnicola, 2008, Estrogenicinduction of cannabinoid CB1 receptor in human colon cancercell lines, Scand. J. Gastroenterol., 43, 66, 10.1080/00365520701559011

Guida, 2010, The levels of the endocannabinoid receptor CB2 and its ligand 2-arachidonoylglycerol are elevated in endometrial carcinoma, Endocrinology, 151, 921, 10.1210/en.2009-0883

Tavares, 2016, Expression of estrogen and progesterone receptors in astrocytomas: A literature review, Clinics, 71, 481, 10.6061/clinics/2016(08)12

Zhang, 2019, The Increased Expression of Estrogen-Related Receptor α Correlates with Wnt5a and Poor Prognosis in Patients with Glioma, Mol. Cancer Ther., 18, 173, 10.1158/1535-7163.MCT-17-0782

Wu, 2012, Alteration of endocannabinoid system in human gliomas, J. Neurochem., 120, 842, 10.1111/j.1471-4159.2011.07625.x