Grant: Project Grant

Reduced testosterone has been linked to obesity, cardiovascular diseases, erectile dysfunction and infertility. Adrenal dysfunction can lead to changes in blood pressure. Phthalate esters are used as plasticizers to add softness and flexibility to polyvinyl chloride (PVC) plastics, used for a wide variety of products, including personal care products, toys, food wrappings, medical devices, and building and household products. DEHP is the most commonly used phthalate in industry. Because it is not covalently bound to the PVC polymer, it leaches into the environment and comes into contact with humans mainly through dermal exposure, oral ingestion, and inhalation. Active metabolites of DEHP are found in humans of all ages, from fetus to adulthood, and have been shown to decrease fetal testosterone production in animals. In men, there is an inverse correlation between DEHP metabolites and circulating androgen levels. In rats, fetal DEHP exposure results in reduced circulating testosterone and aldosterone levels in the adult offspring, affecting blood pressure and adipose tissue function. Recently, a new plasticizer DINCH has been introduced to replace DEHP in medical devices, toys and food packaging. Based upon preliminary data we hypothesize that in utero exposure to low doses of DEHP as well as DINCH leads to changes in testicular and adrenal function in the adult offspring, and that the altered endocrine physiology results in increased vulnerability to additional exposures to drugs and pollutants. We propose to determine the endocrine and metabolic changes occurring in adult males following in utero exposure to relevant doses of plasticizers, and to identify the mechanisms underlying long-term effects on androgen and adrenal steroids. It is critical to determine whether plasticizer exposure could be a risk factor in the origin of reproductive and metabolic disorders and identify targets for the potential pharmacological reversal of their detrimental effects.