Puberty is defined as the transition from infancy to reproductive maturity characterized by the acceleration of growth velocity and the development of secondary sexual characteristics and genitals. Normal puberty onset ranges between 8-13 years old for girls, and 9-14 years old for boys. It is clinically defined as the onset of Tanner stage 2 in thelarche for girls (development of breast buds) and by Tanner stage 2 in external genitalia development for boys (increase in testicular volume to >4mL). Age at menarche in girls and age at peak height velocity in both sexes are landmarks which can be used to evaluate pubertal timing.

Endocrine disrupting chemicals (EDCs) have become increasingly prevalent in the past century as manmade products and chemicals have been made essential in our daily lives. There are nearly 85 000 human-made chemicals in the world, and 1000 or more of those could be endocrine disruptors. There are two main types of EDCs: the persistent organic compounds with decade-long half-lives such as dichloro-diphenyl-trichloroethane (DDT) in pesticides and polychlorinated biphenyls (PCBs), and those that have a shorter half-life but can cause long-term health consequences such as phthalates and bisphenol A. EDCs disrupt the body’s delicate endocrine homeostasis by acting as an agonist or antagonist when binding to hormone receptors, thereby causing unwanted effects, such as earlier timing of puberty in girls and boys. The four EDCs of interest in our study are dibutyl phthalate, bisphenol A (BPA), dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyl (PCB).

Phthalates are a large group of omnipresent compounds used as liquid plasticizers. They are found in food packaging, cosmetic products, shampoo, children’s toys and medical device tubing. It was found that first and second-trimester exposure to Bis(2-ethylhexyl) phthalate (DEHP) was associated with increased peripubertal serum estradiol levels, whereas third-trimester exposure was associated to a delay of pubarche onset. BPA is used to make polycarbonate plastic and epoxy resin. It can be found in food packaging, toys, and canned beverages’ linings. At low concentrations, BPA and other phenol compete with endogenous estrogens for binding, whereas at higher concentrations they have anti-androgenic properties.
DDT was used in many organochlorine pesticides and insecticides before being banned in 1972 in multiple countries. In 2006 however, it was reintroduced in some areas by the World Health Organization in order to fight malaria and control other vector-borne diseases. DDT exposure begins prenatally and lasts throughout a lifetime, as it is found in abundance in consumed food products, and is found to have anti-androgenic properties. PCBs were found in lubricants, electrical equipment and plasticizers up until they were banned in 1979. Studies show that childhood exposures of PCBs are associated with earlier pubertal milestones in boys, such as earlier Tanner stages.
Although a large body of evidence from observational studies exists linking EDCs to pubertal timing variations, these associations can be confounded by factors such as low socio-economic status and obesity and cannot establish causality. In the absence of evidence from randomized controlled trials- which would be unethical to employ, the causal link between EDCs and pubertal timing remains undetermined. We have generated preliminary results using two-sample Mendelian randomization for 19 EDCs, most of which do not support a causal association of genetically determined levels of these EDCs with age at menarche in girls or age at voice change or facial hair in boys. Using genetic variants associated with levels of these EDCs, which are not influenced by environmental confounders, we aim to investigate if genetic predisposition to higher levels of these chemicals could affect pubertal timing in ALSPAC children.
In the proposed project, we hypothesize that genetic risk scores (GRS) composed of one to multiple single nucleotide polymorphisms (SNPs) associated with levels of 19 endocrine disrupting chemicals (dibutyl phthalate, BPA, DDT and 16 types of PCBs) in the largest available genome-wide association studies for EDC levels, could be associated to an altered age at menarche in girls or age at peak height velocity in both girls and boys (adjusting for sex) with and without adjusting for BMI SDS at age 8 and socio-economic status.