Early life effects of Bisphenol A on the maturing gut barrier and metabolic programming in the liver and adipose tissue: long term consequences in adulthood – PerinaTox

In the last decade evidences have accumulated that exposure to low doses of endocrine disruptors during the foetal and neonatal periods may favour the emergence of diseases in adulthood. Regarding the striking example of diethylstilbestrol prescribed to pregnant women from the 1940s to the 80s, recent studies have reported adverse effects in adulthood of perinatal exposure to another non-steroidal xenoestrogen, namely bisphenol A (BPA). Consequently, in 2010, risk evaluation agencies such as the FDA and AFSSA reevaluated their positions concerning this compound and emphasized the need for new investigations. BPA is the monomer of polycarbonate and epoxy resins found in a wide array of plastic goods including food/drinks packaging and baby bottles. Its release from plastic goods leads to significant levels of exposure, mainly via oral route, for a large majority of the population of industrial countries, especially babies and infants. Exposure to BPA is considered as a major concern for human health, since recent animal studies demonstrate deleterious effects at environmentally relevant doses in developing organs including the gut, the liver and the white adipose tissue. However, the precise events disrupted by BPA during the foetal and early life remain unknown. Such data are critically needed to identify the molecular targets of low BPA doses, and to understand how disruption in different target organs may promote diseases in adults.
The partners of the PerinaTox project propose to investigate the effects of perinatal exposure to low doses of BPA on the coordinate development of gut, liver and adipose tissue, as well as the resulting impacts in susceptibility to develop inflammatory (Inflammatory Bowel disease and Irritable Bowel Syndrome), neoplastic (colon cancer) or metabolic diseases in adulthood. Recently, we have shown that BPA exposure in adults targets the gut (Braniste et al, PNAS 2010), reducing gut permeability and inflammatory response, but increasing visceral sensitivity, thus evoking the effects of endogenous estrogens. Conversely, perinatal exposure to BPA results in an increased inflammatory response in offspring female rats and reduced expression of estrogen receptor (ER) beta in the gut of males, demonstrating that exposure during this critical window of development is able to disrupt organ physiology for long term. Other groups have also shown that perinatal BPA exposure results in some level of metabolic disruption, especially in adipose tissue and liver, favouring overweight in adult rodents. To unravel the mechanisms underlying this range of effects, and to further characterize the perinatal BPA imprinting, we propose: 1) to investigate the coordinate chronological development/maturation of the gut, liver and adipose tissue during the perinatal period, and to evaluate the effects of BPA on this coordinate maturation process, 2) to assess whether BPA-mediated ERbeta downregulation in males results in increased susceptibility to colorectal cancer, 3) to evaluate the impacts of perinatal BPA exposure on adult liver and adipose tissue functions related to metabolic pathways and chronic low grade inflammation, both being key factors of the metabolic syndrome, 4) to evaluate the effects of BPA in specific human cell models of each organ studied, 5) to systematically evaluate in each model used the exposure levels of tissues and cells to BPA and its main metabolites.
To take up these challenges, we have gathered expertises in toxicology, endocrinology, metabolism, physiology, molecular and cellular biology, biochemistry and analytical chemistry. We expect from the PerinaTox program that it unravels mechanisms that would shed a new light on both the generic and transgenerational effects of perinatal xenoestrogen exposure, and the interplay between targeted organs in the emergence of altered physiology at adulthood. These outputs should contribute to the reevaluation of BPA safety for babies, and young infants.