Light Pollution and Melatonin Suppression: Implications for Pediatrics Russel J. Reiter University of Texas Health Science Center San Antonio, Texas reiter@uthscsa.edu Evolution has dictated biological rhythmicity and physiology influenced by the light/dark cycle BIOLOGICAL CLOCK The key elements of the circadian system 1
The pineal gland is the source of the circadian blood melatonin rhythm The pineal gland is roughly the size of the tip of your little finger Cerebrum Melanopsin-containing ganglion cell SCN PVN Pineal gland Postganglionic sympathetic neuron Adult melatonin rhythms Eye Retinohypothalamic tract Cerebellum 8 Upper thoracic cord Intermediolateral cell column Pinealocyte Superior cervical ganglion Preganglionic sympathetic neuron Melatonin (pg/ml) 4 2 Norepinephrine Postganglionic sympathetic nerve ending α-1/ β-adrenergic receptor Tryptophan 5-hydroxytryptophan Amino acid camp Serotonin Adenylate AA-NAT cyclase Protein ATP synthesis N-Acetylserotonin HIOMT Melatonin Night 2
Essentially every function in the body exhibits a 24 hour rhythm N-acetyl-5-methoxytrypatmine (melatonin) Plasma Melatonin (pg/ml) Plasma Melatonin (pg/ml) 7 5 4 3 2 1 7 5 4 3 2 1 8 18 8 L:D 16:8 L:D 1:14 1879, a critical year for circadian rhythms The quantity of melatonin produced is proportional to the duration of darkness 3
12 1 8 4 2 pg melatonin / ml serum 12 1 8 4 2 12 1 8 4 2 12 1 25 lux 5 lux 15 lux Light at night suppresses melatonin levels proportional to the brightness 8 4 2 12 2 22 24 1 3 8 1 Time of date (h) The eyes are required for light inhibition of melatonin production and for adjusting circadian rhythms Classic photoreceptors (rods and cones) are not involved in regulation of circadian rhythms 4
Light regulation of circadian rhythms involves a unique set of ganglion cells and melanopsin Blue-green wavelengths (peaking at 48 nanometers) is most inhibitory to the biological clock and melatonin levels Light regulation of the biological clock and pineal melatonin production 5
Epidemiological studies have reported an increased cancer incidence in night shift workers Science News, 26 Light at night may promote all cancer types 6
62% of world population and 99% of US and European populations are exposed nightly to sky brightness greater than baseline levels The World Health Organization has classified light at night as Group 2A carcinogen due to (a) melatonin suppression (b) chronodisruption (c)or both 7
Increasing nighttime light intensity accelerates the growth of rat hepatoma and human MCF-7 xenografts Environmental chamber Rat hepatoma Human MCF-7 tumors Blood levels of melatonin of premenopausal women at day and night and the effects of this blood perfused through rat hepatoma or human breast cancers Cancer Research, 25 Simulated jet lag also eliminates the circadian melatonin rhythm Plasma Melatonin (pg/ml) 7 5 4 3 2 1 18 8 8
Multiple mechanisms of cancer inhibition by melatonin Cell cycle arrest Anti-angiogenesis Increased quinone reductase activity Immunomodulation Inhibition of cellular proliferation MELATONIN Endocrine modulation Apoptosis induction H 3C O NH O CH 3 Interference with ERα Antioxidative actions and free radical scavenging actions Dedifferentiation of cancer cells Actions via nuclear binding sites N H Aromatase inhibition Telomerase inhibition Inhibition of growth factor uptake The wrong message! Think beyond cancer 9
Melatonin use in childhood sleep disorders ADHD and melatonin 19 references ASD and melatonin 35 publications Neurodevelopmental disorders and melatonin 8 publications Melatonin is the most widely recommended treatment for childhood sleep disorders in the United Kingdom Potoki, L Reiter, R.J., Lupski, J.R. Circadian rhythm abnormalities in Smith-Magenis syndrome. J. Med. Genet. 2; 37:428-433 These individuals have an inverted melatonin rhythm Melatonin: Current research Melatonin-antioxidant Melatonin-diabetes Melatonin-obesity 1,321 ref 133 ref 93 ref Melatonin-metab syndrome 7 ref 1
Oxygen and nitrogen-based reactants and their removal by melatonin Diabetes, hyperglycemia and melatonin Safety of Melatonin No LD 5 has been determined Despite its use for three decades, no toxicity has been reported When test in pregnant animals at exceptionally high doses (>2 mg/kg) no fetal or maternal toxicity 11
Light as a drug 1. It synchronizes circadian and circannual rhythms 2. It inhibits melatonin synthesis and changes the phasing of circadian rhythms As a result of these effects it influences metabolism Melatonin is a readily available and is absorbed when administered via any route 12