In Vitro Effect of Octyl – Methoxycinnamate (OMC) on the Release of Gn-RH and Amino Acid Neurotransmitters by Hypothalamus of Adult Rats

Abstract

OMC (octyl-methoxycinnamate), an endocrine disruptor having estrogenic activity, is used in sunscreen creams as UV filter. We studied its “in vitro” effects on the hypothalamic release of Gn-RH as well as on the amino acid neurotransmitter system. OMC significantly decreased Gn-RH release in normal male and female rats as well as in castrated rats with substitutive therapy. No effects were observed in castrated rats without substitutive therapy. In males OMC increases the release of GABA, decreasing the production of glutamate (GLU) while in the female decreases the excitatory amino acid aspartate (ASP) and GLU without modifications in the hypothalamic GABA release. These results suggest that OMC acting as endocrine disruptor could alter the sex hormone-neurotransmitter-Gn-RH axis relationships in adult rats.

Key words

UV filters - hypothalamic Gn-RH - amino acid neurotransmitters - OMC

References

• 1 Arias P, Jarry H, Leonarhdt S. et al . Estradiol Modulates the LH Release Response to N-Methyl-D-Aspartate in adult female rats: Studies on hypothalamic luteinizing hormone-releasing hormone neurotransmitter release.  Neuroendocrinology. 1993;  57 710-715
• 2 Brann DW, Mahesh VB. Excitatory amino acid regulation of gonadotropin secretion modulation by steroid hormones.  J Steroid Biochem Mol Biol. 1992;  41 847-850
• 3 Brann E, Mahesh VD. Excitatory amino-acids neurotransmission. Evidence for a role in neuroendocrine regulation.  Trends Endocrinol Metab. 1992;  3 122-126
• 4 Carbone S, Szwarcfarb B, Losada M. et al . Effect of ovarian hormones on the hypothalamic excitatory amino acids system during sexual maturation in female rats.  Neuroendocrinology. 1995;  61 235-242
• 5 Holbech H, Norum U, Korgsraard B. et al . The chemical UV-filters 3-benzolydene camphor causes an estrogenic effect in an “in vitro” and “in vivo” fish assay.  Pharmacol Toxicol. 2002;  91 204-208
• 6 Hayden CG, Roberts MS, Benson HA. Systematic absorption of sunscreen after topical application.  Lancet. 1997;  350 863-864
• 7 Janjua NR, Kongshoj B, Andesson AM. et al . Sunscreens in human plasma and urine after repeated whole-body topical application.  J Eur Acad Dermatol Venereol. 2008;  22 456-461
• 8 Janjua NR, Mogensen B, Anderson AM. et al . Systemic absorption of the sunscreens benzophenone-3, octyl-methoxycinnamate and 3-(4-methyl-benzylidene) camphor after whole-body topical application and reproductive hormone levels in humans.  J Invest Dermatol. 2004;  123 57-61
• 9 Janjua NR, Kongshoj B, Petersen JH. et al . Sunscreens and thyroid function in humans after short-term whole-body topical application: a single-blinded study.  Br J Dermatol. 2007;  156 1080-1082
• 10 Jarry H, Hirsch B, Leonhardt S. et al . Amino acid neurotransmitter release in the preoptic area of rats during the positive feedback actions of estradiol on LH release.  Neuroendocrinology. 1992;  56 133-140
• 11 Justo S, Rossano G, Szwarcfarb B. et al . Effect of serotoninergic system on FSH secretion in male and female rats. Evidence for stimulatory and inhibitory actions.  Neuroendocrinology. 1989;  50 382-386
• 12 Kanamaru H, Kakecyama M, Seki T. et al . Estrogen potentiated N- methyl D-aspartate receptor subunit R2B mRNA expresion during prepubertal period in female rats.  Neurosci Lett. 2002;  300 9-12
• 13 Karanth S, Yu WH, Mastronardi CM. McCann SM. Inhibition of melatonin-induced ascorbic acid and LHRH release by a nitric oxide synthase and cyclic GMP inhibitor.  Exp Biol Med. 2004;  229 926-934
• 14 Klammer H, Schlecht C, Wuttke W. et al . Multiorganic risk assesment of estrogenic properties of octyl-methoxycinnamate in vivo. A-5 days sub-acute pharmacodynamic study with ovariectomized rats.  Toxicology. 2005;  215 90-96
• 15 Kordon C, Douvra SV, Martinez de la Escalera RI. et al .Role of classic and peptide neuromediators in the neuroendocrine regulation of LH and prolactin.. In:, Knobil E., Neill J, (Eds) The Physiology of reproduction 2nd Edn. Raven Press, New York; 1994: pp1621-1683
• 16 Lariviere K, Samia M, Lister A. et al . Sex steroid regulation of brain glutamic acid decarboxilase (GAD) mRNA is season-dependent and sexually dimorphic in the goldfish Carassius auratus.  Mol Brain Res. 2005;  141 1-9
• 17 Ma R, Couton B, Lichensteiger W. et al . UV filters with antagonism action on androgen receptor in the MDA-kh2 cell transcriptional-activation assay.  Toxicol Sci. 2003;  74 43-50
• 18 Moguilevsky JA, Wuttke W. Changes in the control of Gonadotrophins secretion by neurotransmitters during sexual development in rats.  Exp Clin Endocrinol Diabetes. 2001;  109 189-197
• 19 Moguilevsky JA, Carbone S, Szwarcfarb B. et al . New concepts in the neurotransmitter control of gonadotropin secretion during sexual development. (1995) In “Puberty Basic and Clinic Aspects”. Bergadá C and Moguilevsky JA. Edts.  Frontiers in Endocrinology Serono Symposium Series. 1995;  10 199-213
• 20 Ponzo OJ, Rondina D, Szwarcfarb B. et al . Effect of an aproteic diet on gonadotro release response to Gn-RH and estrogen-progesterone in rats.  Endocrine Res. 1999;  25 251-262
• 21 Schlumpf M, Cotton B, Conscience M. et al . Linchtensteiger W. In vitro and in vivo estrogenicity of UV screens Environ Health Perspect.  2001;  109 239-244
• 22 Schreurs RH, Sonneveld E, Jansen JH. et al . Interaction of polycyclic musks and UV filters with the estrogen receptor, androgen receptor and progesterone receptor and progesterone receptor in reporter gene bioassays.  Toxicol Sci. 2005;  83 264-272
• 23 Seidlová-Wuttke D, Jarry H, Christoffel J. et al . Comparison of effects of estradiol (E2) with those of octylmethoxycinnamate (OMC) and 4-methylbenzylidene camphor (4MBC)-2 filters of UV light - on several uterine, vaginal and bone parameters.  Toxicol Appl Pharmacol. 2006;  210 245-254
• 24 Seidlová-Wuttke D, Christoffel J, Rimoldi G. et al . Comparison of effects of estradiol with those of octylmethoxycinnamate and 4-methylbenzylidene camphor on fat tissue, lipids and pituitary hormones.  Toxicol Appl Pharmacol. 2006;  214 1-7
• 25 Szwarcfarb B, Carbone S, Stein M. et al . Sexual differences in the effect of the GABAergic system on LH secretion and in the hypothalamic ontogenesis of GABA-A receptors in peripubertal rats.  Brain Res. 1991;  646 351-356
• 26 Szwarcfarb B, Carbone S, Reynoso R. et al . Octyl-methoxycinnamate (OMC), an ultraviolet (UV) filter, alters LHRH and amino acid neurotransmitters release from hypothalamus of immature rats.  Exp Clin Endocrinol Diabetes. 2008;  116 94-98
• 27 Touitou E, Godin B. Skin nonpenetrating sunscreens for cosmetic and pharmaceutical formulations.  Clin Dermatol. 2008;  26 375-379
• 28 Tukey JW. Comparing individual means in the analysis of variance.  Biometrics. 1949;  5 99-114
• 29 Weilan NG. Estradiol selectively regulates agonist binding sites on the N-methyl-D-aspartate receptor complex in the CA1 region of hippocampus.  Endocrinology. 1992;  131 662-668

1 This work was supported by Grants from Agencia de Promoción Científica y Técnica BID 1728 PIC 2003 and the University of Buenos Aires.

Correspondence