[en] Obesity is associated with multiple risk factors such as developmental exposure to endocrine disrupting chemicals (EDC). The aim of the current study is to characterize the transgenerational effects of an EDC mixture on programming of hypothalamic circuits controlling energy balance in male rats. Wistar dams (F0) were orally exposed to a mixture of 13 anti-androgenic or estrogenic EDC at environmentally relevant doses starting 2 weeks before mating and until the end of lactation. Body weight in adult males exposed to EDCs was significantly higher than in control males. This higher weight gain at 3 months of age (Mean ± SD: CTRL: 454.7 ± 19.51 g; EDC: 483.6 ± 26.1 g; T-test p = 0.0027) was associated with a significant increase in food intake (Mean ± SD: CTRL: 32.5 ± 1.3 g; EDC: 36.9 ± 1.1 g; Mann-Whitney test p <0.0001). Consistently, the weight of gonadic white adipose tissue (WATg) (Mean ± SD: CTRL: 6.85 ± 1.2 g; EDC: 9.16 ± 2.8 g; T-test p =0.0133) and the average adipocyte size (Mean ± SD:CTRL: 3051 ± 369 µm²; EDC: 4507 ± 341 µm²; T-test p <0.0001) were higher in ancestrally EDC exposed males. From a mechanistic perspective, the study of the hypothalamic melanocortin system controlling energy balance showed that ancestral EDC exposure altered the neuronal network controlling satiety. Density of POMC (α-MSH) neuron axonal fibers was reduced in the paraventricular nucleus of the hypothalamus (PVN) of EDC exposed F3 males (Mean α-MSH fiber density ± SD: CTRL: 0.032 ± 0.002; EDC: 0.028 ± 0.002; T-test = 0.0249). Nonetheless, this alteration was not due to a modification of the postnatal leptin surge (Mean ± SD: CTRL 3.87 ± 1.3ng/ml; EDC: 4.54 ± 1.3ng/ml; Mixed-effect analysis >0.05) which is necessary for the development of the melanocortin system. This phenotype and mechanistic alterations are only present in the F3 generation. F1 males, exposed to the EDC mixture in utero and via lactation, did not show any alteration of body weight (Mean ± SD: CTRL: 467.5 ± 22.73 g; EDC: 470.5 ± 41.3 g; Mixed-effect analysis >0.05), food intake (Mean ± SD: CTRL: 33.4 ± 2.3 g; EDC: 32.95 ± 4.3 g; Mixed-effect analysis >0.05), WATg mass (Mean ± SD: CTRL: 6.95 ± 2.23 g; EDC: 7.69 ± 1.66 g; T-test >0.05), adipocyte size (Mean ± SD: CTRL: 3391 ± 546 µm²; EDC: 3116 ± 709 µm²; T-test >0.05), and of fiber density of POMC neurons in the PVN (Mean α-MSH fiber density ± SD: CTRL: 0.035 ± 0.006; EDC: 0.036 ± 0.008; T-test >0.05).
In conclusion, ancestral exposure to a mixture of EDC leads to an obesogen-like phenotype
exclusively in F3 males, coupled with an alteration of the hypothalamic melanocortin system controlling energy balance.
