The case for puberty as the canary in the coal mine Frank M Biro - PowerPoint PPT Presentation

The case for puberty as the canary in the coal mine Frank M Biro On behalf of the BCERC and BCERP CCTST Grand Rounds

A canary in the coal mine… “Early coal mines did not feature ventilation systems, so miners would routinely bring a caged canary into new coal seams. Canaries are especially sensitive to methane and carbon monoxide, which made them ideal for detecting any dangerous gas build-ups. As long as the canary in a coal mine kept singing, the miners knew their air supply was safe.”

The case for puberty as the canary in the coal mine: Basic premises � Age of pubertal onset (in girls) is decreasing � Puberty is a time of biologic change; the timing of puberty may serve as a sensitive indicator of environmental influences (the canary) � Natural selection favors earlier reproductive development

The case for puberty as the canary in the coal mine � Puberty is a time of biologic change; the timing of puberty may serve as sensitive indicator of environmental influences

Contemporary studies of the onset of puberty in girls Authors Year Age B2 Reynolds & Wines 1948 10.8 Marshall & Tanner 1969 11.2 Harlan (NHES) 1980 12.8 Herman-Giddens (PROS) 1997 8.9/10.0 Sun (NHANES III) 2002 9.5/10.4 Biro (NGHS) 2006 9.8/10.4 Aksglaede (Copenhagen) 2009 9.96 (10.88)

Breast development by age Cincinnati BCERC compared to PROS 90 percent with breast devel 80 70 60 BCERC AA 50 PROS AA 40 BCERC Wh 30 PROS Wh 20 10 0 6 7 8 9 10 Age in years

Correlation of age at onset of puberty to age at menarche 1 0.9 0.8 0.7 correlation 0.6 0.5 0.4 0.3 0.2 0.1 0 3 0 7 4 1 8 5 3 4 4 5 6 6 7 9 9 9 9 9 9 9 1 1 1 1 1 1 1 year of birth These data suggest onset of puberty and age of menarche are, increasingly, independent events

Sequence of pubertal events- girls Data from NHLBI Growth & Health Study; Peak height Biro 2006 velocity Height velocity Onset of Completion Menarche puberty of puberty 8 9 10 11 12 13 14 15 16 17 Age in years

FFMI and FMI, by BMI group at age 9, and by age, NGHS girls 20 18 16 FFMI hi BMI component 14 FFMI mid 12 FFMI lo 10 FMI hi 8 FMI mid 6 FMI lo 4 2 0 9 10 11 12 13 14 15 16 17 18 age

Sequence of pubertal events- boys Peak height Sperm in velocity urine Data multiple sources: Biro 1995; Neu 2001; Karpati 2002; Dore 2005 Height Strength velocity spurt Pubic hair Increase in Completion stage 2 testicular vol of pubic hair 5 10 11 12 13 14 15 16 17 18 Age in years

The case for puberty as the canary in the coal mine � Puberty is a time of biologic change; the timing of puberty may serve as sensitive indicator of environmental influences � Bogalusa Heart Study: trends in menarcheal age between 1973 and 1994; menarcheal age decreased 9.5 months among black and 2 months among white girls- same environment, suggesting interaction between genes and environment (Freedman 2002) � Several studies report lead exposure with delay of breast development and menarche (Selevan 2003; Wu 2003)

The case for puberty as the canary in the coal mine � Natural selection favors earlier reproductive development � Probability of mortality greater than zero � Early development increases total reproductive output through shorter generation times

Factors impacting onset of puberty � 4-5 year variability in onset of puberty � Genetic factors account for 30-70% of variability � Twin studies (MZ vs DZ, raised together or apart) � Sisters higher correlation than mother/daughter � Polygenetic factors (similar to height, weight) � Polymorphisms E receptor; CYP17, CYP3, CYP3A4 � Behavioral/ environmental factors � Health, public health issues � Nutrition/ overnutrition � (Lack of) physical activity � Environmental exposures

Factors impacting onset of puberty � Single most important environmental factor is nutritional (up to 25% of variance)~ � Interaction between genetics and environment � Studies have shown an interaction between BMI and race on age of onset of puberty � Gene expression favors conservation of energy; storage of excess energy as fat � Maladaptive in rapidly changing environment that maximizes opportunities for energy intake, minimizes expenditure (genetic homology past 10,000 yrs)

Obesity trends among US adults BRFSS: 1990, 1999, 2009 2009 2 0 0 7

Trends in overweight for girls (BMI > 95%tile), by age and year 18 percentage overweight 16 14 NHANES I 12 NHANES II 10 NHANES III 8 NHANES99 6 NHANES06 4 NHANES08 2 0 6-11 yo girls 12-19 yo girls NHANES I ’71-74; NHANES II ’76-80; NHANES III ’88-94; NHANES ’99-00; NHANES ’03-6; NHANES ’07-08

And don’t forget the boys: the testicular dysgenesis syndrome � Four conditions: hypospadias, cryptorchidism, reduced semen quality, testicular cancer � Similar trends in incidence and prevalence noted in 1990’s with hypothesis of underlying environmental causes; in 2001 Skakkebaek proposed “testicular dysgenesis syndrome” � Testicular dysgenesis syndrome: in utero exposure leading to abnormal Sertoli cell dysfunction and decreased Leydig cell function � More recently, association of prenatal phthalate exposure and reduced anogenital distance

The testicular dysgenesis syndrome � Increased incidence hypospadias (x4 in Netherlands; x2 in US) with increased proportion of severe cases � TDS associated with some cases hypospadias and impaired spermatogenesis � Decline in sperm motility and concentration; incr levels of EDCs with herbicide and pesticide levels � Increased risk cryptorchidism in sons of female gardeners � Increased incidence of testicular cancer; higher levels of organochlorines in mothers of men with testicular cancer

Mean sperm density by year and geographic area 180 160 140 Sperm density 120 Europe 100 North America 80 Other 60 40 20 0 1930 1940 1950 1960 1970 1980 1990 year of sample collection Adapted from Swan, 2000

The canary in the coal mine � The age of breast development is declining � BMI and prevalence of obesity are increasing � Prevalence of components of the testicular dysgenesis syndrome is increasing � Exposure to several potential Endocrine Disrupting Chemicals (EDCs) are ubiquitous � Phthalates are associated with central adiposity, precocious thelarche

Many thanks to our all of our colleagues, advocacy community, families! Drawn by two study participants when in second grade