The Interplay between Environmental Exposures and Obesity

Onset of puberty, obesity, and

endocrine disrupting chemicals

Frank M Biro

March 2, 2015

Acknowledgements:

ES-12770 and ES-019453

(NCI and NIEHS) and my

BCERP colleagues

What is puberty?

• Interrelated changes that incorporate several systems

– Linear growth, change in body composition

– Maturation of adrenal axis, reactivation of the

hypothalamic-pituitary-gonadal axis

– Achievement of ability to reproduce

• Consideration of puberty as a window of susceptibility

Changes associated with puberty

• Adrenarche (activation adrenal cortex for production

of adrenal androgens)

• Pubarche (appearance of pubic hair; PH2)

• Thelarche (appearance of breast tissue; B2)

• Gonadarche (appearance secondary characteristics)

(gonadal production of sex steroids)

• Menarche (age of first menstrual period)

Sequence of pubertal events- girls

8 9 10 11 12 13 14 15 16 17

Onset of

puberty

Completion

of puberty

Peak height

velocity

Menarche

Height

velocity

Age in years Data from NHLBI Growth & Health Study

Onset of puberty and relationship to obesity: girls

• Multiple studies have reported on association of obesity and

earlier breast maturation in girls

– BCERP: BMI accounted for >14% of variance in age of B2

• Frisch 1974 proposed critical weight, subsequently critical

body fat for onset puberty/ menarche

– Matkovic 1997: increased leptin associated with earlier menarche

• 1 ng/mL with one month decrease

• Grumbach 2002: leptin necessary but not sufficient

• Bianco 2012: increased adiposity with earlier activation LHRH

pulse generator

Onset of breast development: Comparison of white participants in PROS and BCERP

Onset of puberty and adiposity: boys

• Relationship less clear-cut in boys

• Increased BMI may be related to earlier onset of puberty until

in obesity range, when there may be a delay in onset of

puberty

Increased obesity/

visceral fat

Inadequate

prenatal

growth

Energy

imbalance Endocrine

disrupting

chemicals

Insulin

resistance/

Elevated insulin

Adrenals: Incr

androgens Liver: Decr

SHBG

Ovaries: Incr

androgens

Adipocytes: Incr

aromatase

Earlier adrenarche

Earlier thelarche

Figure adopted from

Ahmed, Ong, Dunger;

2009

Potential mechanisms mediating BMI

(or body fat) and onset of puberty

Greater

levels of

leptin

Serum hormone concentrations of

estradiol by BMI and onset of puberty

JCEM, 2014

Traditional LOD

RFA: Environmental and Genetic

Determinants of Puberty

“Collect data on markers of breast

development and other physiologic

changes of sexual maturation,

assessment of environmental stressors of

importance to future breast cancer risk,

including lifestyle… nutrition…

anthropometry…exposures”

BCERC/BCERP epidemiology projects

• MSSM – PI: Mary Wolff, PhD; East Harlem;

– Neighborhood health centers; schools

– Girls 6-8 years of age, seen every year

• KPNC – PI: Larry Kushi, ScD; San Francisco Bay Area

– Families enrolled Kaiser Permanente N CA

– Girls 6-8 years of age, seen every year

• Cincinnati – PI: Frank Biro, MD; greater Cincinnati

– Schools, BCRGC; schools, GCRC

– Girls 6-7 years of age, seen every 6 months

• 1239 girls recruited 2004-07

Study Participants at Enrollment

Puberty, obesity, and endocrine disrupting chemicals

Endocrine disrupting chemicals

• Interfere with hormone biosynthesis or metabolism, or act on

hormone receptors; effect may depend on timing and gender

– Soy formula consumption with earlier menarche (Adgent 2012)

– 0.5-0.7 year delay in B2 with isoflavones (Cheng 2010) and flavonols

(Mervish 2013)

• Molecular mechanisms of EDCs

– BPA with increased aromatase activity; phthalates and PFCs with

decreased activity 3b-HSD and 17b-HSD (Hampl 2014)

– BPA stimulated KiSS1 gene transcription, decreased expression of

puberty inhibitors (Mueller 2014)

Phthalates • Urinary metabolites typically measured (helps protect against

contamination from parent compounds); current exposure

• Two general categories – Low molecular weight phthalates (<250 D): fragrance; personal care products

– High molecular weight phthalates (>250 D): soft plastics, sealants, flooring

• Increased BMI and waist circumference (Stahlhut 2007; Hutch 2008; Teitelbaum 2011) [in overweight girls only]

• Increased insulin resistance with DEHP (Trasande 2013)

• Earlier onset of B2 in low MWP in unadjusted analyses, but effect due to increased BMI (Wolff 2014)

• Later onset of PH2 (Frederiksen 2012; Wolff 2014) with high MWP; greater effect among normal weight girls (figure)

Kaplan-Meier curve for age at pubarche

(age of PH2) by DEHP and BMI %tile

Wolff, Human Repro 2014

Phenols

• Ubiquitous compounds used in diverse ways

– Antiseptic (phenol), monomers for polymers/ resins (e.g., BPA), sunscreen

(BP-3), mothballs (2,5 DCP), hand sanitizer (triclosan), phytoestrogens

(polyphenols, e.g. genistein), thermal paper (BPA, BPS)

– BPS had been used as pharmacologic estrogen (replaced by DES)

• Chapel Hill consensus statement on BPA (AJPH 2009)

– “BPA at concentrations found in the human body is associated with

organizational changes in the prostate, breast, testis, mammary glands, body

size, brain structure and chemistry, and behavior of laboratory animals”

Perfluorochemicals

• Polyfluoroalkyl compounds (PFCs) and their derivatives, such as

perfluorooctanoate (PFOA), have wide consumer (water, stain,

grease repellent) and industrial applications (Teflon production)

– Serum samples from NHANES participants indicate that PFC exposure

is widespread in our population

– Several medical issues related to PFOA, including HBP (especially

during pregnancy), hypercholesterolemia, thyroid disease (Nicole 2013),

kidney and liver cancer (Barry 2013)

Future directions

• Examining replacement chemicals

– BPS for BPA; PFUnA for PFOA

• Examining mixture of compounds

– Rarely exposed to one chemical

• Examining the role of obesogens