Il la%e: c Il la%e: colp olpevole o assolt ole o assolto. o. La - PowerPoint PPT Presentation

Il la%e: c Il la%e: colp olpevole o assolt ole o assolto. o. La v La voce del v ce del veterinario erinario Gianfranco Gabai Dipar-mento di Biomedicina Comparata e Alimentazione Università degli Studi di Padova ACNE Ferrara 2017 14° Meeting di aggiornamento su acne e dermatosi correlate FERRARA, 24-25 novembre 2017

Outline Hormones & ACNE 1 Why measuring hormones in milk Hormones in Milk 2 Hormones & Lacta3on Colostrum vs Milk 3 Hormones in Milk vs. 4 Milk Hormones vs. Hormones in Human Blood Host Intes3ne IGF-1 absorp3on? Pep3de Hormones (IGF-1) Entero-Hepa3c Circula3on & Steroid Hormones (E2 & DHEA) Hormone inac3va3on G.A.L.T. interac3on

Hormo mones & ACNE Oestrogens Androgens Sebo production during ? Progesterone menstrual cycle? Increase TLR2 expression & ? Glucocorticoids enhance immune response in skin? Local HPA axis! IGF-1 Review by: Arora et al., 2011 – Clinical Biochem. 44, 1035-1040

Hormo mones & ACNE Reduction in local Androgen production in ACNE lesions Estrogens Inhibition of chemokines Blocking pro-inflammatory cytokines by resident immune cells Inhibition of MMP-9 Review by: Arora et al., 2011 – Clinical Biochem. 44, 1035-1040

Oestrogens in mi milk pr produc ducts ts Fat E2 E2/serving Product (%) (pg/mL) (ng) Skim milk < 0.05 0.4 ± 0.03 0.1 (237 mL) Milk 1 0.6 ± 0.03 0.1 (237 mL) Milk 2 0.9 ± 0.06 0.2 (237 mL) Whole milk 3.25 1.1 ± 0.05 0.3 (237 mL) Cream 36 6.0 ± 0.29 0.1 (15 mL) BuRer 80 15.8 ± 1.17 0.2 (14 g) Pape-Zambito et al. 2010 – J. Dairy Sci. 93, 2533-2540

Hormo mones & ACNE Androgens ACNE patients Normal Androgen in Blood Higher Androgen in Blood More reactive sebaceous glands Sulfatase 3 β HSD 5 α Reduc 17 β HSD DHEA TST DHT DHEA-S AND PPAR γ Activity DHT Sebaceous Interaction with Glands fibroblasts (growth factors) Review by: Arora et al., 2011 – Clinical Biochem. 44, 1035-1040

Growth F Gr Fact ctor ors & Ker & K eraEno aEnocy cytes es s. corneum Inhibit Growth: s. lucidum 1. TGF β 2. Vitamin D3 s. granulosum 3. INF γ s. spinosum Promote Growth & Migra-on: 1. EGF 2. FGF 3. HGF s. basale 4. IGF 5. GM-CSF

Hormo mones & ACNE IGF-1 Insulin FGF 5HT CRH IL-1 α Nicotin (?) α nAChR IR IGF1R FGFR2 5HTR CRHR IL1R PI3K Akt Fox01 Lipogenesis Cell proliferation Inflammation Androgenesis

Hormo mones & ACNE

Can mi milk contribute to AC ACNE pathogenesis? Neuroendocrine & Gut microbiota Immune systems Hormone Absorption Blood Hormones Endocrine cells

Hormo mones in Milk, Mamma mmary Gl Gland Bi Biol olog ogy & & Newborn Developme ment

Why Measuring Wh Measuring Hormo mones in in Milk? Milk? Milk is a biological matrix alternative to blood Monitoring reproductive activity/fertility E2; P4; (PAG) Monitoring metabolism IGF-1, Insulin, GH Monitoring “stress” & “welfare” HC; DHEA Monitoring immune status HC, Cytokines; TNF α Studying mammary biology PRL; PL; IGF-1; IGF-2

Hormones in Milk Newborn • Development: • Gastrointestinal tract • Immune system • Neuroendocrine system • Metabolic functions Hormones / Growth factors ?

The cow’s reproduc3ve cycle Ø Period of maximum placental oestrogen production Ø Maximum hormone effects on mammogensis Pregnancy Dry Period Parturition Parturition The dairy cow is contemporarily pregnant during most lactation

Pr Proteins eins in in Col Colos ostrum an and Milk Milk *Growth Factors are low in milk Growth Factors Caseins Lactoferrin development colostrum lacta3on involu3on

This sentence is true not only for oestrogens “…, over the past recent years, concern has been raised about the possible adverse effect of milk- borne oestrogens by epidemiologically found correlations, but without scientific evidence for a relationship ”. Malekinejad et al., 2006 – J. Agric. Food Chem, 54, 9785-9791

IGF- F-1 Colostrum Mature milk (day 2) (week 4) Hormone NOT SOLD SOLD IGF-1 Resistant to heat 103 ± 21 4 ± 1 (ng/mL) (pasteurization) & acid Insulin Several studies suggested that 4.6 ± 1.0 0.4 ± 0.0 (ng/mL) growth factors in colostrum (and milk) are important for the TNF-a development of the newborn 5.0 ± 0.6 1.8 ± 0.2 (ng/mL) intes-ne. Ontsouka et al., 2002 – J Dairy Sci, 86:2005-2011

IGF-1 IGF-1 concentration in milk Hormone Research, ≈ 3.0 ng/ml Milsom et al. 2008 Human 69:307-311 2.8 ng/ml Elmlinger et al. 2007 Hormone Research, Human 68:124-131 2.8 ng/ml Cow (ctrl) Prosser et al. 1989 J Dairy Res, 56:17-26 11.2 ng/ml (bST) J Am Diet Ass, 3.1 ng/ml Vicini et al. 2008 Retail cow 108:1198-1203 3.9 ng/ml Cow (ctrl) Dom Anim Endocrinol, Collier et al. 2008 35:16-23 4.3 ng/ml (bST)

IGF- F-1

Milk & IGF- F-1 in Blood Metanalysis by: Harrison et al., 2017, Cancer Causes Control 28, 497-528 7239 papers Several steps of exclusion 172 papers 142 papers 31 papers IGF vs Prostate cancer Milk vs IGF There is moderate evidence that circulating IGF-1 and IGFBP-3 increase with milk (and dairy protein) intake. Standardized effect : 0.1 SD increase in blood IGF-1 per 1 SD increase in Milk intake

In IntesE esEnal Ab al Absorp sorpEon on of of Milk IGF- F-1? “in vivo” experiment in neonatal subjects NEONATES OF FARMED SPECIES Odle et al. 1996 J Anim Sci 74:2509-2522 (Review) Xu & Wang 1996 PIGLETS J Pediatric Gastroenterology and Nutrition 23:430-437 Vacher et al. 1995 CALVES Biology of the Neonate 68:354-367

In IntesE esEnal Ab al Absorp sorpEon on of Milk of Milk IGF- F-1? Kimura et al. 1997 - J Pharmacol Exp Therapeutics 283:611-618 Adult RATS “ ex vivo ” + casein 0.2 g/100 ml • Degradation study • Absorption studies • Oral administration IGF-1 200 µ g/ml • In situ loop method • In situ single pass perfusion • In vito everted sac Alone

DegradaEon of Milk IGF- F-1 Kimura et al. 1997 J Pharmacol Exp Therapeutics 283:611-618 100 100 Stomach Stomach Degrada-on (%) Degrada-on (%) 80 80 Small Int. Small Int. 60 60 40 40 20 20 0 0 0 10 20 30 0 10 20 30 Time (min) Time (min) IGF-1 alone IGF-1 + Casein

In IntesE esEnal Ab al Absorp sorpEon on of Milk of Milk IGF- F-1? Kimura et al. 1997 - J Pharmacol Exp Therapeutics 283:611-618 400 Plasma IGF-1 (ng/ml) 300 IGF-1 200 IGF-1+Casein 100 0 0 3 6 9 12 IGF-1 Time (h) 200 µ g/ml IGF-1 Casein 200 µ g/ml 0.2 g/100 ml

In IntesE esEnal Ab al Absorp sorpEon on of Milk of Milk IGF- F-1? Kimura et al. 1997 - J Pharmacol Exp Therapeutics 283:611-618 200 µ g/ml Keywords : escapes digestion in the • stomach; Absorptive-mediated transcytosis poor absorption • BUT protective effect of • casein local action • Receptor-mediated transcytosis

Intes3nal Absorp3on of Milk IGF-1? Physiological condi3ons Experimental sehng • IGF-1 concentra-on in • IGF-1 concentra-on in cow milk: ≈4 ng/ml saline: 200 µ g/ml • Casein concentra-on in • Casein concentra-on in cow milk: 2.8 g/100 ml saline: 0.2 g/100 ml • Casein does not escape • Casein added intact to stomach diges3on and the small intes3ne does not reach the environment small intes-ne intact Kimura et al. 1997 - J Pharmacol Exp Therapeutics 283:611-618

Indirect efffects of mi milk in sEmu mulaEng endogenous IGF- F-1 release 200 • 8-year-old boys (N=57) P<0.001 175 • Eating their habitual diet 150 IGF-1 (NG/ML) • Problem : most subjects 125 drank milk (<500 ml/day) 100 • Supplemented with milk- 75 based drinks: 50 25 In 540 ml/day 0 Whey (g) 10.5 BASELINE DAY 7 Casein (g) 42.0 Whey Casein Hoppe et al., 2009 – Eur J Clin Nutr 63 , 1076-1083

DHE DHEA Blood DHEA Milk DHEA 1400 1200 DHEA (pg/mL) 1000 800 600 400 200 0 -7 -1 1 2 4 Weeks from Parturi-on

DHE DHEA (andr (androgen pr en prec ecur urso sor) r) DHEA-S in cow’s plasma: Same magnitude of DHEA

DHEA in human blood DHEA (Active) 2- 2- SO 4 SO 4 Reversible ! Sulfotransferase Sulfatase Need Inves3ga3on in rela3on to ACNE DHEA-S (Inactive)

High concentrations Steroid Hormone One CYP Xenobiotic isoform CYP CPY3A Phase I - Activation Many Substrates Reactive intermediate (drugs/hormones) Phase II - Conjugation Conjugate Excretion

Wha What we we ge get in in a a glass glass of of milk ? mi ? 100 mL Hormone Quan3ty Oestradiol 40-110 pg DHEA 80-100 ng IGF-1 400-800 ng Can a glass of milk affect circulating hormone concentrations?

Esiste un «r «rischio ormo monale» » associato al consumo mo di la%e? la%e? L’interazione tra l’alimento e il Letteratura scientifica consumatore dovrebbe (talvolta, pseudoscientifica considerare ogni basata su conoscenze possibile contesto “aneddotiche”) mette in e dubbio l’utilità Mettere in evidenza i dell’assunzione di latte meccanismi di (rischio per la salute umana). interazione tra alimento e organismo. ACNE Ferrara 2017 14° Meeting di aggiornamento su acne e dermatosi correlate FERRARA, 24-25 novembre 2017

Th The e Ne Next Qu QuesEon: (How) Can Disease/Intes3nal Environment Affect Intes3nal Hormone Absorp3on?