A putative adverse outcome pathway network for disrupted female pubertal onset to improve testing and regulation of endocrine disrupting chemicals

The average age for pubertal onset in girls has declined over recent decades. Epidemiological studies in humans and experimental studies in animals suggest a causal role for Endocrine Disrupting Chemicals (EDCs) that are present in our environment. Of concern, current testing and screening regimens are inadequate in identifying EDCs that may affect pubertal maturation, not least because they do not consider early-life exposure. Also, the causal relationship between EDC exposure and pubertal timing is still a matter of debate. To address this issue, we have used current knowledge to elaborate a network of putative Adverse Outcome Pathways (pAOPs) to identify how chemicals can affect pubertal onset. By using the AOP framework, we highlight current gaps in mechanistic understanding that needs to be addressed and simultaneously point towards events causative of pubertal disturbance that could be exploited for alternative test methods. We propose six pAOPs that could explain the disruption of pubertal timing by interfering with the central hypothalamic trigger of puberty, GnRH neurons, and by so doing highlight specific modes of action that could be targeted for alternative test method development.