Insecticide cytotoxicity and CYP1A1/2 induction in primary human and rat hepatocyte cultures

International audienc

Insecticides cytotoxicity and CYP1A1 induction in primary human and rat hepatocytes cultures

With the increasing demand for insecticide products, the question of their safety has become one of the serious world public health concerns. The capability of compounds belonging to the major insecticide families [such as chlorinated hydrocarbons (DDT), carbamates (carbaryl: CBR), organophosphorus compounds (malathion, tetrachlorvinfos: MAL, TCV), pyrethroids (cypermethrin: CPR) and benzoylurea (diflubenzuron: DFU)] in inducing CYP1 Al in rat and human hepatocyte cultures has been tested. Cells were treated during 3 days with six non-toxic increasing doses of insecticides and CYP1A1 expression was assessed by ethoxyresorufin O-deethylase (EROD) activity and by Northern blots. A strong and dose-dependent induction was observed with TCV and DFU, both in human (approx. five- and sevenfold over control, respectively) and in rat hepatocytes (approx. sevenfold). However, EROD induction and CYP/A1 mRNA levels were correlated for DFU but not for TCV, suggesting different regulation mechanisms for PCYP1A1 gene expression by the two compounds. CBR and CPR exerted less induction in both cell types (approx. 2.5-fold induction compared with approximately 16-fold for 3-methylcholanthrene), whereas DDT and MAL showed no action on human hepatocytes but decreased EROD activity in rat cells. Finally, cytotoxicity studies performed using the MTT and the neutral red tests demonstrated significant differences between insecticides

Comparative study of CYP1A1 induction by 3-methylcholanthrene in various human hepatic and epidermal cell types

International audienc

The middle Pleistocene transition as a generic bifurcation on a slow manifold

The final publication is available at Springer via http://dx.doi.org/10.1007/s00382-015-2501-9The Quaternary period has been characterised by a cyclical series of glaciations, which are attributed to the change in the insolation (incoming solar radiation) from changes in the Earth’s orbit around the Sun. The spectral power in the climate record is very different from that of the orbital forcing: prior to 1000 kyr before present most of the spectral power is in the 41 kyr band while since then the power has been in the 100 kyr band. The change defines the middle Pleistocene transition (MPT). The MPT does not indicate any noticeable difference in the orbital forcing. The climate response to the insolation is thus far from linear, and appears to be structurally different before and after the MPT. This paper presents a low order conceptual model for the oscillatory dynamics of the ice sheets in terms of a relaxation oscillator with multiple levels subject to the Milankovitch forcing. The model exhibits smooth transitions between three different climate states; an interglacial (i), a mild glacial (g) and a deep glacial (G) as proposed by Paillard (Nature 391:378–381, 1998). The model suggests a dynamical explanation in terms of the structure of a slow manifold for the observed allowed and “forbidden” transitions between the three climate states. With the model, the pacing of the climate oscillations by the astronomical forcing is through the mechanism of phase-resetting of relaxation oscillations in which the internal phase of the oscillation is affected by the forcing. In spite of its simplicity as a forced ODE, the model is able to reproduce not only general features but also many of the details of oscillations observed in the climate record. A particular novelty is that it includes a slow drift in the form of the slow manifold that reproduces the observed dynamical change at the MPT. We explain this change in terms of a transcritical bifurcation in the fast dynamics on varying the slow variable; this bifurcation can induce a sudden change in periodicity and amplitude of the cycle and we suggest that this is associated with a branch of “canard oscillations” that appear for a small range of parameters. The model is remarkably robust at simulating the climate record before, during and after the MPT. Even though the conceptual model does not point to specific mechanisms, the physical implication is that the major reorganisation of the climate response to the orbital forcing does not necessarily imply that there was a big change in the environmental conditions